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Joshua F. Zeidner - One of the best experts on this subject based on the ideXlab platform.
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phase i study of Alvocidib followed by 7 3 cytarabine daunorubicin in newly diagnosed acute myeloid leukemia
Clinical Cancer Research, 2021Co-Authors: Joshua F. Zeidner, David J. Bearss, Stephen P. Anthony, Daniel J. Lee, Mark G. Frattini, Judy Costas, Kathryn Kolibaba, Gil Fine, Douglas B SmithAbstract:Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy. Patients and Methods: A multiinstitutional phase I dose-escalation study of Alvocidib on days 1–3 followed by 7+3 (cytarabine 100 mg/m2/day i.v. infusion days 5–12 and daunorubicin 60 mg/m2 i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. Results: There was no MTD on this study; the recommended phase II dose of Alvocidib was 30 mg/m2 i.v. over 30 minutes followed by 60 mg/m2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Conclusions: Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of Alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
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Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm
Blood, 2020Co-Authors: Joshua F. Zeidner, Stephen P. Anthony, Daniel J. Lee, Gil D Fine, Andrew Dalovisio, Eunice S. Wang, Pau Montesinos, Vijaya Raj Bhatt, Kathryn S. Kolibaba, David J. BearssAbstract:Background: Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM. Methods: Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of Alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety. Results: Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received Alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%). Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT. Conclusion: ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from Alvocidib-containing induction regimens. Disclosures Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020Co-Authors: Joshua F. Zeidner, David J. Bearss, Stephen P. Anthony, Daniel J. Lee, Mark G. Frattini, Gil D Fine, Judy Costas, Kathryn Kolibaba, B. Douglas SmithAbstract:Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy. Patients and Methods: A multiinstitutional phase I dose-escalation study of Alvocidib on days 1–3 followed by 7+3 (cytarabine 100 mg/m2/day i.v. infusion days 5–12 and daunorubicin 60 mg/m2 i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. Results: There was no MTD on this study; the recommended phase II dose of Alvocidib was 30 mg/m2 i.v. over 30 minutes followed by 60 mg/m2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Conclusions: Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of Alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
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Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Relapsed/Refractory Acute Myeloid Leukemia (AML)
Blood, 2018Co-Authors: Joshua F. Zeidner, Daniel J. Lee, Mark G. Frattini, Tara L. Lin, Carlos E. Vigil, Andrew Dalovisio, Eunice S. Wang, Moshe Yair Levy, Pau Montesinos, Juan Miguel Bergua BurguesAbstract:Background Multiple studies have shown the clinical activity of Alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib9s anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to Alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that Alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported. Aims To evaluate the efficacy and safety of Alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients. Methods The key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of Alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results. Results A total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR 1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1). Conclusion Our findings indicate that Alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to Alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of Alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. Disclosures Zeidner:Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.
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zella 201 a biomarker guided phase ii study of Alvocidib followed by cytarabine and mitoxantrone in mcl 1 dependent relapsed refractory acute myeloid leukemia aml
Blood, 2018Co-Authors: Joshua F. Zeidner, Daniel J. Lee, Mark G. Frattini, Tara L. Lin, Carlos E. Vigil, Andrew Dalovisio, Eunice S. Wang, Moshe Yair Levy, Pau Montesinos, Juan Miguel Bergua BurguesAbstract:Background Multiple studies have shown the clinical activity of Alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib9s anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to Alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that Alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported. Aims To evaluate the efficacy and safety of Alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients. Methods The key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of Alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results. Results A total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR 1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1). Conclusion Our findings indicate that Alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to Alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of Alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. Disclosures Zeidner:Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.
David J. Bearss - One of the best experts on this subject based on the ideXlab platform.
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phase i study of Alvocidib followed by 7 3 cytarabine daunorubicin in newly diagnosed acute myeloid leukemia
Clinical Cancer Research, 2021Co-Authors: Joshua F. Zeidner, David J. Bearss, Stephen P. Anthony, Daniel J. Lee, Mark G. Frattini, Judy Costas, Kathryn Kolibaba, Gil Fine, Douglas B SmithAbstract:Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy. Patients and Methods: A multiinstitutional phase I dose-escalation study of Alvocidib on days 1–3 followed by 7+3 (cytarabine 100 mg/m2/day i.v. infusion days 5–12 and daunorubicin 60 mg/m2 i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. Results: There was no MTD on this study; the recommended phase II dose of Alvocidib was 30 mg/m2 i.v. over 30 minutes followed by 60 mg/m2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Conclusions: Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of Alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
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Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm
Blood, 2020Co-Authors: Joshua F. Zeidner, Stephen P. Anthony, Daniel J. Lee, Gil D Fine, Andrew Dalovisio, Eunice S. Wang, Pau Montesinos, Vijaya Raj Bhatt, Kathryn S. Kolibaba, David J. BearssAbstract:Background: Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM. Methods: Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of Alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety. Results: Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received Alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%). Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT. Conclusion: ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from Alvocidib-containing induction regimens. Disclosures Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020Co-Authors: Joshua F. Zeidner, David J. Bearss, Stephen P. Anthony, Daniel J. Lee, Mark G. Frattini, Gil D Fine, Judy Costas, Kathryn Kolibaba, B. Douglas SmithAbstract:Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy. Patients and Methods: A multiinstitutional phase I dose-escalation study of Alvocidib on days 1–3 followed by 7+3 (cytarabine 100 mg/m2/day i.v. infusion days 5–12 and daunorubicin 60 mg/m2 i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. Results: There was no MTD on this study; the recommended phase II dose of Alvocidib was 30 mg/m2 i.v. over 30 minutes followed by 60 mg/m2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Conclusions: Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of Alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
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Abstract C081: Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models
Therapeutic Agents: Small Molecule Kinase Inhibitors, 2019Co-Authors: Tetyana V Forostyan, Clifford J. Whatcott, Adam Siddiqui-jain, David J. Bearss, Ethika Tyagi, Jason M. Foulks, Evita Weagel, Yuta Matsumura, Steven L. WarnerAbstract:Prostate cancer is the most prevalent cancer in men, comprising 20% of all new cancer cases in United States, as per the Cancer Statistics, 2019. Many therapies for prostate cancer function by lowering androgen levels and include androgen deprivation therapy alone or in combination with surgical or chemical castration. Hormone therapy has been a mainstay treatment for prostate cancer, ultimately leading to progression free disease in over 80% of patients over short time periods. Unfortunately, these effects are not durable, and the majority of patients experience progressive disease. Ultimately, the disease progresses and becomes invasive and lethal in the form of castration-resistant prostate cancer (CRPC). Understanding the mechanism by which prostate cancer cells lose their inherent dependence on the canonical androgen signaling pathway for survival has been critical in developing new therapeutic options for patients with CRPC. CDK9 may constitute one such mechanism. CDK9 phosphorylates RNA polymerase II (RNA Pol II), resulting in gene transcription of anti-apoptotic proteins such as MCL1, that can influence prostate cancer cell survival. Additionally, CDK9 is known to phosphorylate the androgen receptor (AR) and both AR and RNA Pol II cooperate for transcription of key prostate cancer genes, including PSA. Therefore, inhibition of CDK9 has great potential to halt constitutive activity of both AR and the RNA Pol II -driven transcriptional program that drives CRPC. Here, we describe tumor growth inhibition in CRPC models using the CDK9 inhibitor TP-1287, an oral Alvocidib prodrug, alone and in combination with docetaxel or venetoclax, a BCL-2 inhibitor that is currently being evaluated in a Phase II clinical trial for metastatic CRPC. The CDK9 inhibitor Alvocidib demonstrates low nanomolar IC50 values in CRPC cell lines PC3, 22Rv1 and castration dependent PCa cell lines VCAP and LnCAP ranging from 25-175 nM. Alvocidib treatment inhibits RNA Pol II in 22Rv1 cells (~50%) at 80 and 160 nM, 3 and 24 hrs post treatment and regulates MCL-1 protein expression in PC3 cells (300 nM, 24 hrs). Alvocidib treatment also inhibited AR phosphorylation at Ser 81, reducing PSA gene expression (~50%) and inducing caspase activation in 22Rv1 cells (80-160 nM for 24 hrs). We explored the tumor growth inhibition of TP-1287, in several PCa xenograft models namely PC3, 22Rv1, LnCAP and C4-2 models. In androgen sensitive models, 1.25 mpk BID TP-1287 combined well with 10 mpk docetaxel, demonstrating 90% and 81% TGI in C4-2 and LnCAP models respectively. TP-1287 treatment (1.25 mpk BID) in combination with 100 mpk venetoclax demonstrated 64% tumor growth inhibition in the 22Rv1 CRPC model that was resistant to docetaxel, enzalutamide and venetoclax alone. These data support the potential of TP-1287 to be used in combination with currently available or novel therapies to achieve better efficacy for androgen sensitive and CRPC patients. Citation Format: Tetyana V Forostyan, Evita Weagel, Yuta Matsumura, Ethika Tyagi, Jason M Foulks, Clifford J Whatcott, Adam Siddiqui-Jain, David J Bearss, Steven L Warner. Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C081. doi:10.1158/1535-7163.TARG-19-C081
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The CDK9 Inhibitor, Alvocidib, Potentiates the Non-Clinical Activity of Azacytidine or Decitabine in an MCL-1-Dependent Fashion, Supporting Clinical Exploration of a Decitabine and Alvocidib Combination
Blood, 2018Co-Authors: Wontak Kim, Clifford J. Whatcott, Adam Siddiqui-jain, David J. Bearss, Stephen P. Anthony, Steven L. WarnerAbstract:The hypomethylating agents (HMAs) azacytidine and decitabine exert biological activity via two distinct mechanisms, namely, DNA damage and inhibition of DNA methyltransferases. Azacytidine and decitabine are indicated in the treatment of patients with myelodysplastic syndromes (MDS). As a result of DNA methyltransferase inhibition, it is hypothesized that HMAs may function by inducing re-expression of key pro-apoptotic proteins such as NOXA, which sequesters the anti-apoptotic protein MCL-1, preventing its association with the mitochondrial pore-forming proteins BAX/BAK. Activity of the potent CDK9 inhibitor, Alvocidib, is largely driven by targeting of CDK9-dependent MCL-1 expression. Alvocidib is under active clinical investigation, but has also has demonstrated high complete response rates in newly diagnosed AML patients, particularly when administered as part of a cytarabine and mitoxantrone containing regimen (ACM regimen). Given the dual NOXA/MCL-1-targeting ability of combining Alvocidib and azacytidine or decitabine, the combination may synergize therapeutically in the treatment of non-clinical models of AML or MDS by means of transcriptional induction of NOXA and repression of MCL-1 expression. Cell viability and induction of apoptosis was assessed following treatment with Alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of Alvocidib administration with HMAs, were performed. Treatment of AML cell lines with Alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with Alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The Alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with Alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating Alvocidib activity compared to azacytidine. These non-clinical data suggest that an Alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of Alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single Alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of Alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency. Disclosures Kim:Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.
Raoul Tibes - One of the best experts on this subject based on the ideXlab platform.
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Alvocidib Potentiates the Activity of Azacytidine in an MCL-1-Dependent Fashion
Blood, 2015Co-Authors: Wontak Kim, James M Bogenberger, Clifford J. Whatcott, Katherine K. Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-jain, Steven D. Weitman, Jeremiah J. Bearss, Raoul TibesAbstract:Despite significant efforts, the clinical mechanism of action of hypomethylating agents such as 5-azacytidine (5-aza) is still poorly understood. 5-aza is currently indicated for the treatment of patients with myelodysplastic syndrome (MDS). While 5-aza has achieved good single-agent activity in acute myeloid leukemia (AML), complete response rates remain low when used as a single agent. In a recent report aimed at identifying rational therapeutic combinations with 5-aza, Bogenberger and colleagues identified multiple BCL-2 family member/BH3-containing therapeutic targets, which synergize with 5-aza when inhibited genetically or pharmacologically. The CDK9 inhibitor, Alvocidib, has achieved significant improvement in complete response rates of newly diagnosed AML patients when administered before cytarabine and mitoxantrone (FLAM regimen) in a randomized multi-center Phase 2 trial when compared to 7+3 standard of care treatment. Recent reports suggest that the transcriptional repression of key anti-apoptotic proteins (eg., MCL-1) mediated by Alvocidib9s CDK9 inhibition, drive the pro-apoptotic activity of Alvocidib in the FLAM regimen. We, therefore, hypothesized that Alvocidib and 5-aza would synergize therapeutically in the treatment of AML by means of transcriptional repression of MCL-1 and sensitization to 5-aza. In this report, we demonstrate that treatment of AML cell lines with Alvocidib inhibits both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with Alvocidib, to repress MCL-1 expression prior to 5-aza treatment, reduced the 5-aza cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The Alvocidib/5-aza combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. Therefore, following reports suggesting inhibition of BCL-2 family members including MCL-1, sensitizes cells to 5-aza, our data suggest that the Alvocidib/5-aza combination may constitute a viable therapeutic regimen. We also conclude that a CDK9 inhibitor/5-aza combination may be an effective clinical approach for the treatment of AML. Disclosures Kim:Tolero Pharmaceuticals: Employment. Soh:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment. Lee:Tolero Pharmaceuticals: Employment. Peterson:Tolero Pharmaceuticals: Employment. Whatcott:Tolero Pharmaceuticals: Employment. Siddiqui-Jain:Tolero Pharmaceuticals: Employment. Weitman:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment. Warner:Tolero Pharmaceuticals: Employment.
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randomized multicenter phase ii study of flavopiridol Alvocidib cytarabine and mitoxantrone flam versus cytarabine daunorubicin 7 3 in newly diagnosed acute myeloid leukemia
Haematologica, 2015Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, Yair M Levy, Raoul TibesAbstract:Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (Alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
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Randomized multicenter phase II study of flavopiridol (Alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.
Haematologica, 2015Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, M. Yair Levy, Raoul TibesAbstract:Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (Alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
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Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (Alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML).
Journal of Clinical Oncology, 2014Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, M. Yair Levy, Raoul TibesAbstract:7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (667 mg/m2/days 6-8) and mitoxantrone (40 mg/m2 day 9) yields complete remission (CR) rates of nearly 70% in pts with newly diagnosed, poor-risk AML. This trial compares “FLAM” with 7+3 in newly diagnosed AML pts. Methods: Between May 2011-July 2013, 165 (FLAM, n=109; 7+3, n=56) newly diagnosed AML pts (18-70 years) with non-favorable cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day, daunorubicin 90 mg/m2) across 10 institutions. Randomization was stratified by age, secondary AML and leukocyte count. Pts with residual leukemia on day 14 received 5+2 on the 7+3 arm, whereas pts treated with FLAM were not retreated on day 14. The primary endpoint was to compare CR rates between 1 cycle of FLAM and 1 cycle of 7+3. Secondary endpoints were safety, CR rates after 1 cycle of FLAM vs 7+3 ...
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randomized multicenter phase ii trial of timed sequential therapy with flavopiridol Alvocidib cytarabine and mitoxantrone flam versus 7 3 for adults with newly diagnosed acute myeloid leukemia aml
Journal of Clinical Oncology, 2014Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, Yair M Levy, Raoul TibesAbstract:7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (6...
Steven L. Warner - One of the best experts on this subject based on the ideXlab platform.
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A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.
Journal of Clinical Oncology, 2020Co-Authors: Ben George, Steven L. Warner, Donald A. Richards, William Jeffery Edenfield, Lars Mouritsen, Reyna Bishop, Stephen Patrick Anthony, David Bearss, Nicholas J. Vogelzang, Clifford WhatcottAbstract:3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of Alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .
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Abstract C081: Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models
Therapeutic Agents: Small Molecule Kinase Inhibitors, 2019Co-Authors: Tetyana V Forostyan, Clifford J. Whatcott, Adam Siddiqui-jain, David J. Bearss, Ethika Tyagi, Jason M. Foulks, Evita Weagel, Yuta Matsumura, Steven L. WarnerAbstract:Prostate cancer is the most prevalent cancer in men, comprising 20% of all new cancer cases in United States, as per the Cancer Statistics, 2019. Many therapies for prostate cancer function by lowering androgen levels and include androgen deprivation therapy alone or in combination with surgical or chemical castration. Hormone therapy has been a mainstay treatment for prostate cancer, ultimately leading to progression free disease in over 80% of patients over short time periods. Unfortunately, these effects are not durable, and the majority of patients experience progressive disease. Ultimately, the disease progresses and becomes invasive and lethal in the form of castration-resistant prostate cancer (CRPC). Understanding the mechanism by which prostate cancer cells lose their inherent dependence on the canonical androgen signaling pathway for survival has been critical in developing new therapeutic options for patients with CRPC. CDK9 may constitute one such mechanism. CDK9 phosphorylates RNA polymerase II (RNA Pol II), resulting in gene transcription of anti-apoptotic proteins such as MCL1, that can influence prostate cancer cell survival. Additionally, CDK9 is known to phosphorylate the androgen receptor (AR) and both AR and RNA Pol II cooperate for transcription of key prostate cancer genes, including PSA. Therefore, inhibition of CDK9 has great potential to halt constitutive activity of both AR and the RNA Pol II -driven transcriptional program that drives CRPC. Here, we describe tumor growth inhibition in CRPC models using the CDK9 inhibitor TP-1287, an oral Alvocidib prodrug, alone and in combination with docetaxel or venetoclax, a BCL-2 inhibitor that is currently being evaluated in a Phase II clinical trial for metastatic CRPC. The CDK9 inhibitor Alvocidib demonstrates low nanomolar IC50 values in CRPC cell lines PC3, 22Rv1 and castration dependent PCa cell lines VCAP and LnCAP ranging from 25-175 nM. Alvocidib treatment inhibits RNA Pol II in 22Rv1 cells (~50%) at 80 and 160 nM, 3 and 24 hrs post treatment and regulates MCL-1 protein expression in PC3 cells (300 nM, 24 hrs). Alvocidib treatment also inhibited AR phosphorylation at Ser 81, reducing PSA gene expression (~50%) and inducing caspase activation in 22Rv1 cells (80-160 nM for 24 hrs). We explored the tumor growth inhibition of TP-1287, in several PCa xenograft models namely PC3, 22Rv1, LnCAP and C4-2 models. In androgen sensitive models, 1.25 mpk BID TP-1287 combined well with 10 mpk docetaxel, demonstrating 90% and 81% TGI in C4-2 and LnCAP models respectively. TP-1287 treatment (1.25 mpk BID) in combination with 100 mpk venetoclax demonstrated 64% tumor growth inhibition in the 22Rv1 CRPC model that was resistant to docetaxel, enzalutamide and venetoclax alone. These data support the potential of TP-1287 to be used in combination with currently available or novel therapies to achieve better efficacy for androgen sensitive and CRPC patients. Citation Format: Tetyana V Forostyan, Evita Weagel, Yuta Matsumura, Ethika Tyagi, Jason M Foulks, Clifford J Whatcott, Adam Siddiqui-Jain, David J Bearss, Steven L Warner. Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C081. doi:10.1158/1535-7163.TARG-19-C081
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The CDK9 Inhibitor, Alvocidib, Potentiates the Non-Clinical Activity of Azacytidine or Decitabine in an MCL-1-Dependent Fashion, Supporting Clinical Exploration of a Decitabine and Alvocidib Combination
Blood, 2018Co-Authors: Wontak Kim, Clifford J. Whatcott, Adam Siddiqui-jain, David J. Bearss, Stephen P. Anthony, Steven L. WarnerAbstract:The hypomethylating agents (HMAs) azacytidine and decitabine exert biological activity via two distinct mechanisms, namely, DNA damage and inhibition of DNA methyltransferases. Azacytidine and decitabine are indicated in the treatment of patients with myelodysplastic syndromes (MDS). As a result of DNA methyltransferase inhibition, it is hypothesized that HMAs may function by inducing re-expression of key pro-apoptotic proteins such as NOXA, which sequesters the anti-apoptotic protein MCL-1, preventing its association with the mitochondrial pore-forming proteins BAX/BAK. Activity of the potent CDK9 inhibitor, Alvocidib, is largely driven by targeting of CDK9-dependent MCL-1 expression. Alvocidib is under active clinical investigation, but has also has demonstrated high complete response rates in newly diagnosed AML patients, particularly when administered as part of a cytarabine and mitoxantrone containing regimen (ACM regimen). Given the dual NOXA/MCL-1-targeting ability of combining Alvocidib and azacytidine or decitabine, the combination may synergize therapeutically in the treatment of non-clinical models of AML or MDS by means of transcriptional induction of NOXA and repression of MCL-1 expression. Cell viability and induction of apoptosis was assessed following treatment with Alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of Alvocidib administration with HMAs, were performed. Treatment of AML cell lines with Alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with Alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The Alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with Alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating Alvocidib activity compared to azacytidine. These non-clinical data suggest that an Alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of Alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single Alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of Alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency. Disclosures Kim:Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.
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The Oral CDK9 Inhibitor, TP-1287, Is Active in Non-Clinical Models of Multiple Myeloma
Blood, 2018Co-Authors: Ethika Tyagi, Clifford J. Whatcott, Adam Siddiqui-jain, David J. Bearss, Jason M. Foulks, Steven L. WarnerAbstract:Background With 31,000 new cases expected in 2018 (US), and a 50% five-year overall survival rate, there is yet a significant unmet need in the treatment of patients with multiple myeloma (MM). The proteasomal inhibitor bortezomib is approved for the treatment of patients with multiple myeloma. Bortezomib inhibits the degradation of many proteins, including the pro-apoptotic protein NOXA. However, low basal levels of NOXA and/or high levels of the anti-apoptotic protein MCL-1 have been implicated in bortezomib resistance and negative patient outcomes. NOXA functions to sequester MCL-1 and prevent its interaction with the apoptosis inducing proteins, BAK or BAX. The BCL-2 inhibitor, venetoclax, has also been investigated in clinical trials for the treatment of multiple myeloma. Increased MCL-1 expression has been shown to be key in the resistance to venetoclax. Considering the central role of MCL-1 to survival and treatment efficacy in myeloma, we investigated the ability of an MCL-1-lowering agent, namely the CDK9 inhibitor, TP-1287, to suppress tumor growth in non-clinical models of multiple myeloma. TP-1287 is an oral form of the CDK9 inhibitor, Alvocidib, and suppresses MCL-1 expression via CDK9-mediated regulation of RNA polymerase II. Alvocidib is currently under clinical investigation in patients with acute myeloid leukemia (AML), in both the frontline and relapse/refractory settings. Hypothesis We hypothesized that TP-1287 would suppress tumor growth in models of multiple myeloma and would be active in combinations with bortezomib or venetoclax. Methods Celltiter-Glo and Caspase-Glo assays were used to evaluate the in vitro anti-tumor activity of TP-1287, bortezomib, and venetoclax. We utilized real time PCR to measure gene expression changes in treated cells. We also measured protein expression changes following treatment, using standard gel electrophoresis and immunoblotting technique. In order to assess the anti-tumor activity of these compounds in vivo, we initiated xenograft studies in the RPMI-8226 model for multiple myeloma. Results In cell viability assays, we observed IC50s ranging from 0.1 nM to over 1000 nM with Alvocidib or venetoclax treatment. The addition of up to 100 nM venetoclax resulted in a 2.8-fold reduction in the IC50 of Alvocidib in the cultured OPM-2 cell line. Venetoclax activity was potentiated with the addition of Alvocidib, resulting in a more than 500-fold decrease in IC50 in the relatively venetoclax-resistant OPM-2 cells. The cleaved form of TP-1287, or Alvocidib, was able to reduce MCL-1 protein and mRNA expression in several multiple myeloma cell lines, in a time-dependent fashion. In the RPMI-8226 xenograft model for multiple myeloma, TP-1287 treatment frequency and dose level were explored, with administration of doses up to 15 mg/kg. As a single agent, TP-1287 achieved tumor growth inhibition (%TGI) of 56.0, 76.6, and 93.9% at doses of 2.5, 7.5, and 15 mg/kg, respectively. Additional studies are currently underway to investigate the efficacy of Alvocidib and venetoclax in the context of bortezomib resistance where low NOXA may contribute to enhanced cell survival via MCL-1. Conclusions Taken together, our data suggest that the combination of Alvocidib with venetoclax may constitute a novel therapeutic regimen in the treatment of MM. Further, it suggests that CDK9-mediated targeting of MCL-1 may offer a route to addressing intrinsic resistance in multiple myeloma patients. Disclosures Tyagi:Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Foulks:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.
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Abstract B178: Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9
Therapeutic Agents: Small-Molecule Kinase Inhibitors, 2018Co-Authors: Hillary Haws, Wontak Kim, Adam Siddiqui-jain, David J. Bearss, Steven L. Warner, Clifford J. WhatcottAbstract:Of the more than 240,000 estimated new cases of breast cancer in 2016 (US), triple-negative breast cancer (TNBC) was expected to comprise roughly 12%. So named because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, TNBCs pose a unique therapeutic challenge, with only chemotherapeutic options currently available. New therapeutic options are desperately needed for patients with TNBC. Recent reports have identified a cellular addiction of TNBCs to PIM1, suggesting that the addiction is mediated by PIM regulation of Myc and BH3 proteins MCL-1 or BCL-2. The PIM family of serine/threonine kinases are highly conserved and the link between PIM and Myc function has been well studied. The second-generation PIM inhibitor, TP-3654, has been shown to suppress Myc expression in vitro. Additionally, CDK9 inhibitors are also known to suppress Myc expression. CDK9 inhibition mediates specific reductions in transcription of short-lived mRNAs such as Myc and MCL-1. The CDK9/cyclin T complex is a critical component of the P-TEFb complex, promoting productive RNA elongation through phosphorylation of serine 2 of the heptapeptide repeats of the C-terminal domain of RNA Polymerase II (RNAPII-CTD). We are developing a potent CDK9 inhibitor, Alvocidib, and an oral prodrug form of Alvocidib named TP-1287, and are investigating the potential clinical utility of CDK9 inhibition in acute myeloid leukemia (AML). We hypothesized that PIM and CDK9 inhibition would be an active combination in models of TNBC due to the added effect of targeting Myc through two independent mechanisms. In the TNBC cell line, MDA-MB-231, TP-3654 reduced relative Myc protein expression by 74%, while Alvocidib reduced expression by 71%. The combination of TP-3654 and Alvocidib reduced detectable expression 100%, as measured by standard immunoblotting, at concentrations of 100 nM with a 3-hour treatment. To test this hypothesis in vivo, TP-3654 and TP-1287 were tested in the MDA-MB-231 xenograft. Single-agent TP-3654 (150 mg/kg) reduced tumor growth (%TGI) 40.7%, while TP-1287 (3.75 mg/kg) reduced tumor growth 11.6%. The combined-treatment regimen reduced tumor growth by 58.3% at day 18 of treatment. These results support a rationale for further clinical investigation of PIM and CDK9 inhibitors for the suppression of Myc in patients with TNBC. Citation Format: Hillary Haws, Wontak Kim, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner, Clifford J. Whatcott. Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B178.
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A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.
American journal of hematology, 2018Co-Authors: Mark R. Litzow, Judith E. Karp, Xin V. Wang, Martin Carroll, Rhett P. Ketterling, Yanming Zhang, Scott H. Kaufmann, Hillard M. Lazarus, Selina M. Luger, Elisabeth PaiettaAbstract:To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; Alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.
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randomized multicenter phase ii study of flavopiridol Alvocidib cytarabine and mitoxantrone flam versus cytarabine daunorubicin 7 3 in newly diagnosed acute myeloid leukemia
Haematologica, 2015Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, Yair M Levy, Raoul TibesAbstract:Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (Alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
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Randomized multicenter phase II study of flavopiridol (Alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.
Haematologica, 2015Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, M. Yair Levy, Raoul TibesAbstract:Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (Alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
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Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (Alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML).
Journal of Clinical Oncology, 2014Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, M. Yair Levy, Raoul TibesAbstract:7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (667 mg/m2/days 6-8) and mitoxantrone (40 mg/m2 day 9) yields complete remission (CR) rates of nearly 70% in pts with newly diagnosed, poor-risk AML. This trial compares “FLAM” with 7+3 in newly diagnosed AML pts. Methods: Between May 2011-July 2013, 165 (FLAM, n=109; 7+3, n=56) newly diagnosed AML pts (18-70 years) with non-favorable cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day, daunorubicin 90 mg/m2) across 10 institutions. Randomization was stratified by age, secondary AML and leukocyte count. Pts with residual leukemia on day 14 received 5+2 on the 7+3 arm, whereas pts treated with FLAM were not retreated on day 14. The primary endpoint was to compare CR rates between 1 cycle of FLAM and 1 cycle of 7+3. Secondary endpoints were safety, CR rates after 1 cycle of FLAM vs 7+3 ...
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randomized multicenter phase ii trial of timed sequential therapy with flavopiridol Alvocidib cytarabine and mitoxantrone flam versus 7 3 for adults with newly diagnosed acute myeloid leukemia aml
Journal of Clinical Oncology, 2014Co-Authors: Joshua F. Zeidner, Prithviraj Bose, Mark R. Litzow, Matthew C. Foster, Amanda L. Blackford, Lawrence E. Morris, Stephen A. Strickland, Jeffrey E. Lancet, Yair M Levy, Raoul TibesAbstract:7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (6...