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Jeffrey R Infante - One of the best experts on this subject based on the ideXlab platform.

  • avelumab anti pd l1 as first line switch maintenance or second line therapy in patients with advanced gastric or gastroesophageal junction cancer phase 1b results from the javelin solid tumor trial
    Journal for ImmunoTherapy of Cancer, 2019
    Co-Authors: Hyun Cheol Chung, Keun Wook Lee, Jeffrey R Infante, Lucjan Wyrwicz, Hendrik Tobias Arkenau, Jeeyun Lee, Sun Young Rha, Yoon Koo Kang, Sung Sook Lee, Margaret M Kemeny
    Abstract:

    We evaluated the antitumor activity and safety of avelumab, a human anti–PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5–13.9% and 1.8–16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0–not estimable) and 3.5 months (95% CI, 2.8–8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3–4.1) and 1.4 months (95% CI, 1.3–1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7–32.4%) and 7.9% (95% CI, 2.6–17.2%), and median OS was 11.1 months (95% CI, 8.9–13.7) and 6.6 months (95% CI, 5.4–9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4–20.6). Across both subgroups, 20.7% had an Infusion-Related Reaction of any grade. Other common treatment-Related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-Related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-Related death. Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.

  • Avelumab (anti–PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial
    BMC, 2019
    Co-Authors: Hyun Cheol Chung, Keun Wook Lee, Jeffrey R Infante, Lucjan Wyrwicz, Hendrik Tobias Arkenau, Jeeyun Lee, Sun Young Rha, Yoon Koo Kang, Sung Sook Lee
    Abstract:

    Abstract Background We evaluated the antitumor activity and safety of avelumab, a human anti–PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. Methods In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. Results Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5–13.9% and 1.8–16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0–not estimable) and 3.5 months (95% CI, 2.8–8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3–4.1) and 1.4 months (95% CI, 1.3–1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7–32.4%) and 7.9% (95% CI, 2.6–17.2%), and median OS was 11.1 months (95% CI, 8.9–13.7) and 6.6 months (95% CI, 5.4–9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4–20.6). Across both subgroups, 20.7% had an Infusion-Related Reaction of any grade. Other common treatment-Related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-Related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-Related death. Conclusion Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. Trial registration ClinicalTrials.gov NCT01772004; registered 21 January 2013

  • Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial
    The Lancet Oncology, 2018
    Co-Authors: Manish R. Patel, Raid Aljumaily, Keun Wook Lee, Carolyn D Britten, Luc Dirix, John Ellerton, Manish Agrawal, Jeffrey R Infante, Michael Gordon, Mathew Taylor
    Abstract:

    Background The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. Methods In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous Infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Findings Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-Related adverse events (any grade in ≥10% patients) were Infusion-Related Reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-Related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event Related to treatment with avelumab, and one treatment-Related death occurred (pneumonitis). Interpretation Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Funding Merck KGaA, and Pfizer Inc.

  • avelumab an anti programmed death ligand 1 antibody in patients with refractory metastatic urothelial carcinoma results from a multicenter phase ib study
    Journal of Clinical Oncology, 2017
    Co-Authors: Andrea B Apolo, Manish R. Patel, Carolyn D Britten, Jeffrey R Infante, Ani Balmanoukian, Ding Wang, Karen Kelly, Anthony Mega, Alain Ravaud, Alain C Mita
    Abstract:

    Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-Related adverse events of any grade were fatigue/asthenia (31.8%), Infusion-Related Reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-Related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

  • abstract ct233 a first in human phase i study of the safety and pharmacokinetic pk activity of dedn6526a an anti endothelin b receptor etbr antibody drug conjugate adc in patients with metastatic or unresectable melanoma
    Cancer Research, 2014
    Co-Authors: Jeffrey R Infante, Jyoti Asundi, Shahneen Sandhu, Catriona M. Mcneil, Omar Kabbarah, Wei Zhong, Katie Wood, Yuwaye Chu, Omid Hamid
    Abstract:

    Background: ETBR, a G-protein coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma compared with normal skin. DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin (MMAE) linked to the humanized IgG1 anti-ETBR monoclonal antibody and represents a novel targeted treatment against melanoma. In preclinical models, DEDN6526A shows dose-dependent anti-tumor activity in ETBR-expressing tumor xenografts. Methods: DEDN6526A (0.3-2.8 mg/kg) was given intravenously every 3 weeks (q3w) to pts with metastatic or unresectable cutaneous, mucosal, or ocular (uveal) melanoma in a 3+3 design to determine the maximum-tolerated dose, followed by cohort expansion at the recommended phase II dose (RP2D). PK samples were collected, and archival tumor tissue was assessed for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. Results: As of 25 November 2013, 28 pts with median age 65 (range 24-82), ECOG PS 0-1, and median 2.5 prior therapies (range 0-5) enrolled in dose escalation and received median 6 doses of DEDN6526A (range 1-28). Based on cumulative safety data, the RP2D of DEDN6526A is 2.4 mg/kg q3w. Three DLTs occurred: G3 Infusion-Related Reaction (IRR) (1.8 mg/kg), G3 transaminitis (2.4 mg/kg), and G3 elevated ALT and AST and transient G2 elevated bilirubin meeting criteria for drug induced liver injury (2.8 mg/kg). The most common treatment-emergent adverse events (AEs) of any grade (G) in ≥ 20% of pts were fatigue (57%), chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), IRRs (25%), asthenia (21%), peripheral sensory neuropathy (21%), and vomiting (21%). The protocol was amended to allow steroid pre-medications prior to DEDN6526A administration, which mitigated the IRRs. Treatment-Related G≥3 AEs in ≥ 5% of pts, assessed by investigators, were anemia (11%), neutropenia (11%), leukopenia (7%), and white blood count decreased (7%). Exposures of the conjugate (antibody-conjugated MMAE), total antibody, and unconjugated MMAE increased with dose. Among 19 pts treated at doses ≥ 1.8 mg/kg, there were four confirmed partial responses (21%); 6 pts (32%) had stable disease ≥ 6 months. Clinical benefit in pts did not seem to be associated with melanoma origin (cutaneous/mucosal vs. ocular), tumor BRAF mutation status, and/or progression on prior immune therapies. Correlation of ETBR expression with clinical activity will be presented. Conclusions: DEDN6526A administered at the RP2D of 2.4 mg/kg q3w is safe and tolerable. There is early evidence of anti-tumor activity in melanoma pts. Enrollment in the expansion cohort is ongoing. Citation Format: Jeffrey R. Infante, Shahneen K. Sandhu, Catriona M. McNeil, Omar Kabbarah, Chunze Li, Wei Zhong, Jyoti Asundi, Katie Wood, Yu-Waye Chu, Omid Hamid. A first-in-human phase I study of the safety and pharmacokinetic (PK) activity of DEDN6526A, an anti-endothelin B receptor (ETBR) antibody-drug conjugate (ADC), in patients with metastatic or unresectable melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT233. doi:10.1158/1538-7445.AM2014-CT233

Manish R. Patel - One of the best experts on this subject based on the ideXlab platform.

  • Phase I study of the anti-endothelin B receptor antibody-drug conjugate DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma
    Investigational New Drugs, 2019
    Co-Authors: Shahneen Sandhu, Manish R. Patel, Catriona M. Mcneil, Patricia Lorusso, Omar Kabbarah, Chunze Li, Sandra Sanabria, W. Michael Flanagan, Ru-fang Yeh, Flavia Brunstein
    Abstract:

    Background Endothelin B receptor (ET_BR) is involved in melanoma pathogenesis and is overexpressed in metastatic melanoma. The antibody-drug conjugate DEDN6526A targets ET_BR and is comprised of the humanized anti-ET_BR monoclonal antibody conjugated to the anti-mitotic agent monomethyl auristatin E (MMAE). Methods This Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DEDN6526A (0.3–2.8 mg/kg) given every 3 weeks (q3w) in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma. Results Fifty-three patients received a median of 6 doses of DEDN6526A (range 1–49). The most common drug-Related adverse events (>25% across dose levels) were fatigue, peripheral neuropathy, nausea, diarrhea, alopecia, and chills. Three patients in dose-escalation experienced a dose-limiting toxicity (Infusion-Related Reaction, increased ALT/AST, and drug-induced liver injury). Based on cumulative safety data across all dose levels, the recommended Phase II dose (RP2D) for DEDN6526A was 2.4 mg/kg intravenous (IV) q3w. The pharmacokinetics of antibody-conjugated MMAE and total antibody were dose-proportional at doses ranging from 1.8–2.8 mg/kg. A trend toward faster clearance was observed at doses of 0.3–1.2 mg/kg. There were 6 partial responses (11%) in patients with metastatic cutaneous or mucosal melanoma, and 17 patients (32%) had prolonged stable disease ≥6 months. Responses were independent of BRAF mutation status but did correlate with ET_BR expression. Conclusion DEDN6526A administered at the RP2D of 2.4 mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. ClinicalTrials.gov identifier: NCT01522664.

  • Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial
    BMC, 2019
    Co-Authors: Ulrich Keilholz, Manish R. Patel, Janice M. Mehnert, Sebastian Bauer, Hugues Bourgeois, Donald Gravenor, John J. Nemunaitis, Matthew H. Taylor, Lucjan Wyrwicz, Keun Wook Lee
    Abstract:

    Abstract Background We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. Patients and methods Patients received avelumab (10 mg/kg)—a human anti–PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1–31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0–4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3–35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4–6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9–49.3]), PD-L1–positive tumors (42.1% [20.3–66.5]), or prior ipilimumab therapy (30.8% [14.3–51.8]). Thirty-nine patients (76.5%) had a treatment-Related adverse event (TRAE), most commonly Infusion-Related Reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-Related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-Related deaths were reported. Conclusion Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. Trial registration ClinicalTrials.gov identifier: NCT01772004

  • Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial
    The Lancet Oncology, 2018
    Co-Authors: Manish R. Patel, Raid Aljumaily, Keun Wook Lee, Carolyn D Britten, Luc Dirix, John Ellerton, Manish Agrawal, Jeffrey R Infante, Michael Gordon, Mathew Taylor
    Abstract:

    Background The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. Methods In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous Infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Findings Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-Related adverse events (any grade in ≥10% patients) were Infusion-Related Reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-Related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event Related to treatment with avelumab, and one treatment-Related death occurred (pneumonitis). Interpretation Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Funding Merck KGaA, and Pfizer Inc.

  • avelumab an anti programmed death ligand 1 antibody in patients with refractory metastatic urothelial carcinoma results from a multicenter phase ib study
    Journal of Clinical Oncology, 2017
    Co-Authors: Andrea B Apolo, Manish R. Patel, Carolyn D Britten, Jeffrey R Infante, Ani Balmanoukian, Ding Wang, Karen Kelly, Anthony Mega, Alain Ravaud, Alain C Mita
    Abstract:

    Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-Related adverse events of any grade were fatigue/asthenia (31.8%), Infusion-Related Reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-Related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

Loretta J Nastoupil - One of the best experts on this subject based on the ideXlab platform.

  • managing cytokine release syndrome crs and neurotoxicity with step fractionated dosing of mosunetuzumab in relapsed refractory r r b cell non hodgkin lymphoma nhl
    Journal of Clinical Oncology, 2019
    Co-Authors: Nancy L Bartlett, Laurie H Sehn, Sarit Assouline, Francesc Bosch, Catherine Diefenbach, Ian W Flinn, Jungyong Hong, W S Kim, Matthew J Matasar, Loretta J Nastoupil
    Abstract:

    7518Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/Infusion-Related Reaction (IRR). Mosunetuzumab is a...

  • Managing cytokine release syndrome (CRS) and neurotoxicity with step-fractionated dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).
    Journal of Clinical Oncology, 2019
    Co-Authors: Nancy L Bartlett, Laurie H Sehn, Sarit Assouline, Francesc Bosch, Catherine Diefenbach, Ian W Flinn, Jungyong Hong, W S Kim, Matthew J Matasar, Loretta J Nastoupil
    Abstract:

    7518Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/Infusion-Related Reaction (IRR). Mosunetuzumab is a...

  • systematic literature review of the clinical efficacy and safety of treatments in the relapsed refractory setting for patients with follicular lymphoma or marginal zone lymphoma
    Blood, 2017
    Co-Authors: Neerav Monga, Jamie Garside, Peter Odonovan, Joan Quigley, Amie Padhiar, Lori Parisi, Christoph Tapprich, Loretta J Nastoupil
    Abstract:

    Introduction The objective of this study was to assess the efficacy and safety of current and emerging treatments in patients with follicular lymphoma (FL) or marginal zone lymphoma (MZL) who experienced relapse or refractory disease after ≥ 1 treatment. Methods We performed a systematic literature review to identify all publicly available randomized controlled trials (RCTs) and nonrandomized (NR) prospective interventional studies in the relapsed/refractory (R/R) setting for FL or MZL patients in EMBASE®, MEDLINE®, and the Cochrane Central Register of Controlled Clinical Trials on March 3, 2017. Additionally, four conference proceedings from 2015 and 2016 (the American Society of Hematology, European Hematology Association, European Society for Medical Oncology, and American Society of Clinical Oncology) were searched to present an up-to-date overview. For safety outcomes we extracted grade 3/4 adverse events (AE). Relevant interventions included rituximab (R), idelalisib, lenalidomide (LEN) ± R, ofatumumab (OFA), obinutuzumab (O), bortezomib (V) ± R, bendamustine (B) ± R, VBR, ibrutinib (IBRU) ± chemoimmunotherapy, brentuximab vedotin, fludarabine (F) + R, O ± B, CHOP ± R, and autologous stem cell transplantation (ASCT). Other interventions which were searched for but not identified are seen in Table 1. Results We screened 3255 abstracts and 126 full papers. Ten RCTs and 23 NR prospective interventional studies were selected for inclusion. In total, 29 studies reported results on chemo-based interventions (nine RCTs and 20 NR prospective interventional studies), and limited ASCT data were reported (one RCT and 3 NR prospective interventional studies). The majority of included studies reported largely FL populations with only two studies being conducted specifically in MZL. There was a considerable amount of heterogeneity across the included studies; factors contributing to this included study design, stage of disease, refractory versus relapsed population, and the median number of prior treatments. In the majority of studies patients had stage III/IV disease. Several studies reported the median number of prior treatments with large variation among the ranges presented. Population age varied, with the median age ranging from 46 to 68.5 years. The most common intervention received was R, either as monotherapy or in combination with chemotherapy. The highest objective response rate was reported for FL/MZL patients treated with B (100%) while the lowest was reported for FL/MZL patients treated with OFA (10%). Median PFS for included studies is summarized in Table 1. Four RCTs provided significant PFS hazard ratios (HRs). Two ASCT studies reported median PFS ranging from 2.4 years (ASCT + interferon [INF]) to 83 months (ASCT + R + INF). In total, 12 studies presented duration of response (DOR) data with one study resulting in a significant DOR HR. Overall survival (OS) data were poorly reported, with only eight studies reporting any OS data. In three of eight studies that intended to report OS, median OS had not been reached. Safety and health-Related quality of life (HRQoL) data were not consistently reported in the included studies. The most commonly reported grade 3/4 AE was neutropenia (12 studies) with an incidence ranging from 1.4% (R) to 54.7% (R-CHOP). Fatigue was also reported in nine studies with an incidence ranging from 1% (V + R) to 13% (LEN + R). Other AEs reported were anemia, diarrhea, infection, Infusion-Related Reaction, nausea, pneumonia, sepsis, thrombocytopenia, and vomiting. Only one study presented HRQoL data (EORTC QLQ-C30). Conclusion This literature review provides a robust overview of response and PFS for treatments of R/R FL/MZL; however, heterogeneity in study design and patient population, as well as a general lack of reporting of OS data, make it challenging to identify an optimal treatment regimen in this setting. HRQoL data were not commonly reported despite the important role patient QoL plays in treatment selection. Additional randomized clinical trials, a more consistent approach to the reporting of clinical end points, and continued monitoring of OS data in this population may address some of these data gaps and unmet needs for patients with R/R FL/MZL. Disclosures Monga: Janssen: Other: Janssen employee. Garside: Janssen Pharmaceutica NV: Other: employee of Janssen Pharmaceutica NV. Parisi: Janssen: Other: Janssen employee. Tapprich: Janssen: Other: Janssen employee. Nastoupil: Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Gilead: Honoraria.

  • ibrutinib plus rituximab in treatment naive patients with follicular lymphoma results from a multicenter phase 2 study
    Blood, 2015
    Co-Authors: Nathan Fowler, Ian W Flinn, Loretta J Nastoupil, Mark Knapp, Robert Chen, Ranjana H Advani, Sumeet Bhatia, Peter Martin, Raul Mena, Samuel Suzuki
    Abstract:

    Background : Follicular lymphoma (FL) is the most common subtype of indolent NHL. Current chemoimmunotherapeutic regimens used for FL are not curative. Rituximab, as a single-agent and in combination with chemotherapy, is a commonly used approach for frontline therapy of FL. Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton's tyrosine kinase, has shown activity in a phase 1, first-in-human, dose-escalation trial in patients with relapsed/refractory FL, with an overall response rate (ORR) of 38% (6/16) including 3 complete responses [CRs]) (Advani, JCO 2013). In a multicenter, open-label phase 2 trial (PCYC-1125-CA), we evaluated the efficacy and safety of ibrutinib in combination with rituximab in treatment-naive patients with FL. Methods : Patients with treatment-naive, histologically confirmed FL (Grade 1, 2 and 3a, stage II-IV disease) received oral ibrutinib 560 mg once daily until progressive disease (PD) or unacceptable toxicity, combined with rituximab 375 mg/m2 IV once weekly for 4 doses for the first 4 weeks of the study. The primary endpoint was ORR (2007 IWG criteria) as assessed by investigators. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Among 60 treated patients in study Arm 1, the median age was 58 years (range, 32-84), with 30% of patients aged ≥65 years, and 98% of patients with an Eastern Cooperative Oncology Group performance status of 0-1. At baseline, 80% of patients had Stage III/IV disease, and 10% of patients had grade 3a FL. The mean duration of treatment on ibrutinib was 9.2 months. At a median follow-up of 10.2 months (range, 1.2-16.2), the investigator-assessed ORR was 82% (95% CI: 70.1-89.4), with a CR rate of 27% and PR rate of 55% in all treated patients (Figure). The median time to best response was 2.7 months (range, 1.1-8.3). Median PFS, OS, and DOR are not reached as a result of a small number of PD (n=5) and death (n=1) events. Any-grade adverse events (AEs; ≥20%) included fatigue (63%), diarrhea (50%), nausea (42%), constipation (28%), headache (27%), maculopapular rash (27%), myalgia (23%), vomiting (23%), cough (22%), Infusion-Related Reaction (22%), and dry eye (20%). Grade ≥3 AEs occurred in 43% of patients, and those occurring in >1 patient included fatigue and maculopapular rash (5% each), and neutropenia and hypertension (3% each). There was 1 death several months after study discontinuation due to Hodgkin's lymphoma. Serious AEs (SAEs) occurred in 13% of patients (12% grade 3 or 4). Any-grade bleeding was reported in 22% of patients, with only 1 grade 2 bleeding event (petechiae); all other events were grade 1. Atrial fibrillation ≥grade 3 occurred in 1 patient. Secondary malignancies were reported in 4 patients: Hodgkin's lymphoma (n=1; grade 3 and 5); fallopian tube cancer (n=1; grade 3); melanocytic nevus (n=1; grade 1); and basal cell carcinoma (n=1; grade 2). Overall, 28% of patients discontinued ibrutinib in the trial (AEs: 12%; PD: 8%; patient decision: 5%; and investigator decision: 3%). At the time of analysis, 72% of patients continued treatment. Overall, the study treatment was well tolerated. Conclusions: In treatment-naive patients with FL, ibrutinib combined with 4 cycles of rituximab demonstrates robust clinical activity with a high overall response rate. The combination is well tolerated; AEs were primarily grade 1-2 and as expected based on experience with single-agent ibrutinib and previously tested ibrutinib combinations. ![Figure 1.][1] Figure 1. Best Overall Response Rates in All Treated Patients (N=60) and Maximum Percentage Improvement from Baseline SPD (N=60) Disclosures Off Label Use: Ibrutinib for follicular lymphoma. Nastoupil: AbbVie: Research Funding; TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Knapp: Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Flinn: Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Chen: Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy. Bhatia: CHOP LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Martin: Genentech, Inc.: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES, Speakers Bureau; Janssen: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Gilead: Consultancy. Suzuki: Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Beaupre: Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Neuenburg: Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. [1]: pending:yes

Keun Wook Lee - One of the best experts on this subject based on the ideXlab platform.

  • avelumab anti pd l1 as first line switch maintenance or second line therapy in patients with advanced gastric or gastroesophageal junction cancer phase 1b results from the javelin solid tumor trial
    Journal for ImmunoTherapy of Cancer, 2019
    Co-Authors: Hyun Cheol Chung, Keun Wook Lee, Jeffrey R Infante, Lucjan Wyrwicz, Hendrik Tobias Arkenau, Jeeyun Lee, Sun Young Rha, Yoon Koo Kang, Sung Sook Lee, Margaret M Kemeny
    Abstract:

    We evaluated the antitumor activity and safety of avelumab, a human anti–PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5–13.9% and 1.8–16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0–not estimable) and 3.5 months (95% CI, 2.8–8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3–4.1) and 1.4 months (95% CI, 1.3–1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7–32.4%) and 7.9% (95% CI, 2.6–17.2%), and median OS was 11.1 months (95% CI, 8.9–13.7) and 6.6 months (95% CI, 5.4–9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4–20.6). Across both subgroups, 20.7% had an Infusion-Related Reaction of any grade. Other common treatment-Related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-Related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-Related death. Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.

  • Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial
    BMC, 2019
    Co-Authors: Ulrich Keilholz, Manish R. Patel, Janice M. Mehnert, Sebastian Bauer, Hugues Bourgeois, Donald Gravenor, John J. Nemunaitis, Matthew H. Taylor, Lucjan Wyrwicz, Keun Wook Lee
    Abstract:

    Abstract Background We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. Patients and methods Patients received avelumab (10 mg/kg)—a human anti–PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1–31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0–4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3–35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4–6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9–49.3]), PD-L1–positive tumors (42.1% [20.3–66.5]), or prior ipilimumab therapy (30.8% [14.3–51.8]). Thirty-nine patients (76.5%) had a treatment-Related adverse event (TRAE), most commonly Infusion-Related Reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-Related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-Related deaths were reported. Conclusion Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. Trial registration ClinicalTrials.gov identifier: NCT01772004

  • Avelumab (anti–PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial
    BMC, 2019
    Co-Authors: Hyun Cheol Chung, Keun Wook Lee, Jeffrey R Infante, Lucjan Wyrwicz, Hendrik Tobias Arkenau, Jeeyun Lee, Sun Young Rha, Yoon Koo Kang, Sung Sook Lee
    Abstract:

    Abstract Background We evaluated the antitumor activity and safety of avelumab, a human anti–PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. Methods In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. Results Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5–13.9% and 1.8–16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0–not estimable) and 3.5 months (95% CI, 2.8–8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3–4.1) and 1.4 months (95% CI, 1.3–1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7–32.4%) and 7.9% (95% CI, 2.6–17.2%), and median OS was 11.1 months (95% CI, 8.9–13.7) and 6.6 months (95% CI, 5.4–9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4–20.6). Across both subgroups, 20.7% had an Infusion-Related Reaction of any grade. Other common treatment-Related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-Related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-Related death. Conclusion Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. Trial registration ClinicalTrials.gov NCT01772004; registered 21 January 2013

  • Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial
    The Lancet Oncology, 2018
    Co-Authors: Manish R. Patel, Raid Aljumaily, Keun Wook Lee, Carolyn D Britten, Luc Dirix, John Ellerton, Manish Agrawal, Jeffrey R Infante, Michael Gordon, Mathew Taylor
    Abstract:

    Background The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. Methods In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous Infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Findings Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-Related adverse events (any grade in ≥10% patients) were Infusion-Related Reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-Related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event Related to treatment with avelumab, and one treatment-Related death occurred (pneumonitis). Interpretation Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Funding Merck KGaA, and Pfizer Inc.

Ahmed Sawas - One of the best experts on this subject based on the ideXlab platform.

  • mogamulizumab versus investigator s choice of chemotherapy regimen in relapsed refractory adult t cell leukemia lymphoma
    Haematologica, 2019
    Co-Authors: Adrienne A Phillips, Paul Fields, Juan Carlos Ramos, Brady E. Beltran, Farooq Wandroo, Juliana Pereira, Tatyana Feldman, Graham P. Taylor, Olivier Hermine, Ahmed Sawas
    Abstract:

    Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator’s choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-Related adverse (grade ≥3) events with mogamulizumab were Infusion-Related Reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator’s choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.

  • Mogamulizumab versus investigator’s choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma
    Haematologica, 2018
    Co-Authors: Adrienne A Phillips, Paul Fields, Juan Carlos Ramos, Brady E. Beltran, Farooq Wandroo, Juliana Pereira, Tatyana Feldman, Graham P. Taylor, Olivier Hermine, Ahmed Sawas
    Abstract:

    Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator’s choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-Related adverse (grade ≥3) events with mogamulizumab were Infusion-Related Reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator’s choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.

  • clinical and biological evaluation of the novel cd30 cd16a tetravalent bispecific antibody afm13 in relapsed or refractory cd30 positive lymphoma with cutaneous presentation a biomarker phase ib iia study nct03192202
    Blood, 2018
    Co-Authors: Ahmed Sawas, Hager Elgedawe, George Vlad, Mikel Lipschitz, Peihsuan Chen, Scott J Rodig, Jennifer K Lue, Changchun Deng, Jennifer E Amengual
    Abstract:

    Introduction: Natural Killer cells (NK cells) play an important role in tumor immune-surveillance. NK-mediated cell killing can occur through distinct mechanisms: (1) by activating the receptor NKG2D and natural cytotoxicity receptors (NCR), and (2) through the potent activating receptor CD16 (FcγRIII) which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). Therapeutic strategies to harness the ability of NK cells to induce an ADCC response are emerging. AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NK cells. This study evaluates the ability of AFM13 to engage innate immunity through specific activation and recruitment of NK cells to tumors expressing CD30 and the impact of these effects on clinical outcome. In addition, it examines the immunologic changes in the tumor and peripheral blood as a function of the dose and method of administration of AFM13 over time. Methods: Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 3 treatment cohorts: (1) 1.5 mg/kg IV weekly, (2) 7 mg/kg IV weekly and (3) 7 mg/kg continuous intravenous Infusion (CIVI) over 5 days weekly. Each cohort consisted of 3 patients. Subjects received 8 weeks of therapy each cycle. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and peripheral blood flowcytometry. A second cycle was administered if there was no progression of disease. Subjects underwent mandatory tumor biopsies and peripheral blood immunologic studies during the first cycle of therapy as follows: pretreatment, day 5 post first dose, week 4 and week 8 of therapy. An optional biopsy was also collected at end of study. Tumor biopsies were analyzed and evaluated by a pathologist and IHC image analyzer to characterize immune cell subpopulations. Peripheral blood samples were analyzed by flowcytometry. Results: Nine subjects were accrued. Their age ranged from 37-79 years, 3 of 9 where white and 6 of 9 were men. The median number of prior therapies was 4 (1-11), 2 patients had progressed on Brentuximab vedotin, and 5 patients received total skin electron beam radiotherapy. The disease etiologies were as follows: 4 patients with transformed mycosis fungoides, 2 patients with systemic anaplastic large cell lymphoma-ALK negative, 2 patients with non- transformed mycosis fungoides and 1 patient with cutaneous anaplastic large cell lymphoma. Among the 8 subjects who were evaluable for response 4 of 8 (50%) achieved an objective response rate (ORR). In cohort 1 we observed 1 complete response (CR), 1 partial response (PR) and 1 stable disease (SD). In cohort 2, we observed 3 SD. In cohort 3, we observed 2 PRs and one subject awaiting disease assessment. Infusion Related Reaction (IRR) were observed in 4 of 9 subjects and managed conservatively. Cellulitis was noted in 3 subjects of which 2 developed bacteremia requiring intravenous antibiotics, and was not considered Related to AFM13 treatment. There were no other treatment-emergent adverse events. In the peripheral blood, we observed a decrease in circulating NK cells during therapy (Weeks 1- 8) with post therapy recovery (by week 11) by following cells that were CD56+ CD3- , CD56+ CD16+ and NKp46+ by Flow Cytometry. We observed an increase over time in the expression of the activation marker CD69 on NK cells from responders compared to non-responders. Similarly, tumor biopsies in responders showed increased infiltration of CD56+ NK cells as opposed to non-responders. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) shows a decrease in responders vs. non-responders. Conclusions: AFM13 demonstrated a high ORR of 50 % among a population of heavily pretreated patients with a CD30 positive lymphoproliferative T-cell malignancy. AFM 13 exhibited activity post Brentuximab vedotin failure. In addition, biological changes in NK cells may predict response. This data are the first to demonstrate the therapeutic advantages of this bispecific, and the first to correlate changes in NK cells as a function of dose and schedule. AFM13 is able to engage the innate immune system through a specific activation and recruitment of circulating NK cells to tumors expressing CD30. This immunological tumor response may correlate with clinical response. We have begun to expand the patient cohorts, and pursue additional comprehensive correlative studies in this population. Disclosures Rodig:KITE: Research Funding; Bristol Myers Squibb: Research Funding; Affimed: Research Funding; Merck: Research Funding. O9Connor:Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Celgene: Research Funding.