Rilotumumab

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Kelly S. Oliner - One of the best experts on this subject based on the ideXlab platform.

  • Rilotumumab Exposure-Response Relationship in Patients With Advanced or Metastatic Gastric Cancer
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Sameer Doshi, Per Olsson Gisleskog, Yilong Zhang, Min Zhu, Kelly S. Oliner, Elwyn Loh, Juan Jose Perez Ruixo
    Abstract:

    Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase 2 study, trends toward improved survival were observed with Rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response (tumor growth [TG] and overall survival [OS]) relationship for Rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase 2 study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, Rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, non-parametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between Rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to Rilotumumab than MET-negative patients. Simulations predicted a median (95% CI) HR of 0.38 (0.18, 0.60) in MET-positive patients treated with 15 mg/kg Rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase 3 testing of Rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

  • Exploratory RAS analysis of the phase Ib/II 20060447 trial of Rilotumumab (R) or ganitumab (G) plus panitumumab (pmab) versus pmab alone in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
    Journal of Clinical Oncology, 2015
    Co-Authors: Cathy Eng, Kelly S. Oliner, Irina Davidenko, Niall C. Tebbutt, Eric Van Cutsem, E. Nowara, Anna Swieboda-sadlej, Edith P. Mitchell, Oliver E. Lee, Marco Schupp
    Abstract:

    694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evalua...

  • exploratory ras analysis of the phase ib ii 20060447 trial of Rilotumumab r or ganitumab g plus panitumumab pmab versus pmab alone in patients pts with previously treated metastatic colorectal cancer mcrc
    Journal of Clinical Oncology, 2015
    Co-Authors: Cathy Eng, Kelly S. Oliner, Irina Davidenko, Niall C. Tebbutt, Eric Van Cutsem, E. Nowara, Edith P. Mitchell, Oliver E. Lee, Anna Swiebodasadlej, Marco Schupp
    Abstract:

    694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evalua...

  • Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression
    British journal of cancer, 2015
    Co-Authors: Min Zhu, Sameer Doshi, Kelly S. Oliner, Elwyn Loh, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Rui Tang, Sarita Dubey, Yilong Zhang
    Abstract:

    Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression

  • 221pevaluation of met staining in gastric gastroesophageal junction g gej tumor samples as a biomarker for Rilotumumab r benefit
    Annals of Oncology, 2014
    Co-Authors: M.d. Hale, Kelly S. Oliner, Elwyn Loh, Rui Tang, J.g. Vallone, I. Klement, S. Webster, Lisa Chen, Scott D. Patterson
    Abstract:

    ABSTRACT Aim: R is an investigational, fully human monoclonal antibody against hepatocyte growth factor, the only known ligand for the MET proto-oncogene. In a phase 2 study in G/GEJ cancer, trends towards improved overall survival (OS) and progression-free survival (PFS) were seen with R + epirubicin, cisplatin, and capecitabine (ECX) vs placebo + ECX, with benefit due to the MET-positive patients (pts). We describe a methodology to select a cutoff for defining MET positivity. Methods: Eligible pts had unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ECOG performance status ≤ 1, and no prior systemic therapy for this disease. Pts were randomized 1:1:1 to R 15 mg/kg, R 7.5 mg/kg, or placebo IV day 1 Q3W plus ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively). Formalin-fixed paraffin-embedded archival tumor tissues were stained with the Dako MET IHC pharmDx™ kit, which uses the MET4 antibody. Membrane, cytoplasmic, and total (cytoplasmic and membrane) tumor cell staining were evaluated separately. Percent staining at different intensities (0, 1 + , 2 + , 3+) and combinations of intensities were scored directly, whereas overall percent positive, H-score, and predominant staining intensity were derived scores. OS and PFS for subgroups defined by potential cutoff values (5–95%) at 5% increments were analyzed by Cox proportional hazards regression, Kaplan-Meier, and the log rank test, yielding hazard ratios (HRs), median OS and PFS, and p values. Results: 121 pts were randomized; 91 had tumor samples evaluable for MET IHC. Pts whose tumors showed ≥ 25% membranous staining were classified as MET-positive. A strong treatment benefit (R vs placebo) was seen in MET-positive pts (n = 58; OS: HR = 0.46, 95% CI, 0.24–0.87; PFS: HR = 0.46, 95% CI, 0.25–0.85); median OS: 10.6 vs 5.7 mo; median PFS: 6.8 vs 4.4 mo. No benefit or detriment was seen with R in MET-negative pts (n = 33; OS: HR = 1.23; 95% CI, 0.56–2.70; PFS: HR = 1.00; 95% CI, 0.46–2.16). Cutoff values 25–50% showed a similar benefit of R in MET-positive pts. Conclusions: The subgroup defined by a cutoff of 25% MET-positive membranous staining using the Dako MET IHC pharmDx™ kit showed benefit from R + ECX; no negative impact of R was seen in MET-negative pts. This cutoff is being used to select pts in an ongoing phase 3 study of R + ECX in MET-positive G/GEJ cancer (NCT01697072). Disclosure: M.D. Hale, K.S. Oliner, R. Tang, L. Chen, E. Loh and S.D. Patterson have declared:is an employee of and owns stock in Amgen Inc.; S. Webster: Scott Webster is an employee of Dako North America, an Agilent Technologies Company. All other authors have declared no conflicts of interest.

Min Zhu - One of the best experts on this subject based on the ideXlab platform.

  • Assessment of pharmacokinetic interaction between Rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer.
    British journal of clinical pharmacology, 2016
    Co-Authors: Yilong Zhang, Sameer Doshi, Min Zhu, Mita Kuchimanchi, Tien Hoang, Sreeneeranj Kasichayanula
    Abstract:

    Aims Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET-positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)-based drug–drug interaction (DDI) between Rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X). Methods This was a Phase 3 double-blind, placebo-controlled study, in which Rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg−1, 50 mg m−2, and 60 mg m−2 Q3W, respectively, while capecitabine was given orally at 625 mg m−2 twice daily. Rilotumumab PK samples were taken at pre-dose and at the end-of-infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non-compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed Rilotumumab serum concentrations with model-predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies. Results The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of Rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co-administration of Rilotumumab. The observed Rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, indicating Rilotumumab exposure was not affected by co-administration of ECX. Conclusions The results suggest lack of PK-based DDI between Rilotumumab and ECX.

  • Pharmacokinetics and pharmacodynamics of Rilotumumab: a decade of experience in preclinical and clinical cancer research
    British journal of clinical pharmacology, 2015
    Co-Authors: Yilong Zhang, Sameer Doshi, Min Zhu
    Abstract:

    Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, Rilotumumab has been extensively tested in preclinical studies and in clinical studies in a variety of cancer types. In this review, we examine the pharmacokinetic and pharmacodynamic data that have been collected in the Rilotumumab programme to date, and discuss retrospectively how the knowledge acquired in this programme can be applied to a number of key issues in oncology drug development, including: (i) using preclinical data to inform first-in-human study design; (ii) the role of biomarkers in the identification of a target patient population; (iii) the potential for drug interactions between therapeutic proteins and other anticancer agents; and (iv) pharmacokinetic and pharmacodynamic considerations in phase 3 study design.

  • Rilotumumab Exposure-Response Relationship in Patients With Advanced or Metastatic Gastric Cancer
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Sameer Doshi, Per Olsson Gisleskog, Yilong Zhang, Min Zhu, Kelly S. Oliner, Elwyn Loh, Juan Jose Perez Ruixo
    Abstract:

    Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase 2 study, trends toward improved survival were observed with Rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response (tumor growth [TG] and overall survival [OS]) relationship for Rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase 2 study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, Rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, non-parametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between Rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to Rilotumumab than MET-negative patients. Simulations predicted a median (95% CI) HR of 0.38 (0.18, 0.60) in MET-positive patients treated with 15 mg/kg Rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase 3 testing of Rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

  • Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression
    British journal of cancer, 2015
    Co-Authors: Min Zhu, Sameer Doshi, Kelly S. Oliner, Elwyn Loh, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Rui Tang, Sarita Dubey, Yilong Zhang
    Abstract:

    Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression

  • Pharmacokinetics (PK) and exposure-response (ER) of Rilotumumab (Rmab) in patients (pts) with small-cell lung cancer (SCLC).
    Journal of Clinical Oncology, 2014
    Co-Authors: Yilong Zhang, Elwyn Loh, Rui Tang, Sarita Dubey, Jenny Zheng, Min Zhu
    Abstract:

    7593 Background: Rmab is a fully human monoclonal antibody against hepatocyte growth factor that was evaluated as a first-line treatment for extensive-stage SCLC in a phase 1b/2 trial (J Thorac Oncol. 2013;8(S2):O21.05). That trial did not show meaningful improvements in progression-free survival (PFS) or overall survival (OS). We characterized Rmab PK in pts with SCLC and performed an ER analysis that related PK to tumor size (TS), PFS, and OS. Methods: Rmab population PK (PPK) and ER were assessed in 132 pts with SCLC who were randomized 1:1 to receive either Rmab (15 mg/kg) or placebo, with etoposide plus carboplatin/cisplatin every 3 weeks (Q3W). A PPK model was developed using data from phase 1 and earlier phase 2 studies. TS vs time was characterized using a tumor dynamic model, and time to tumor growth (TTG) and TS ratios (the ratios of TS at 6, 9, or 12 weeks to TS at baseline) were derived from this model. The relationships between PFS/OS and baseline pt characteristics, exposure metrics, and tum...

Elwyn Loh - One of the best experts on this subject based on the ideXlab platform.

  • Rilotumumab Exposure-Response Relationship in Patients With Advanced or Metastatic Gastric Cancer
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Sameer Doshi, Per Olsson Gisleskog, Yilong Zhang, Min Zhu, Kelly S. Oliner, Elwyn Loh, Juan Jose Perez Ruixo
    Abstract:

    Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase 2 study, trends toward improved survival were observed with Rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response (tumor growth [TG] and overall survival [OS]) relationship for Rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase 2 study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, Rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, non-parametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between Rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to Rilotumumab than MET-negative patients. Simulations predicted a median (95% CI) HR of 0.38 (0.18, 0.60) in MET-positive patients treated with 15 mg/kg Rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase 3 testing of Rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

  • Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression
    British journal of cancer, 2015
    Co-Authors: Min Zhu, Sameer Doshi, Kelly S. Oliner, Elwyn Loh, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Rui Tang, Sarita Dubey, Yilong Zhang
    Abstract:

    Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression

  • 221pevaluation of met staining in gastric gastroesophageal junction g gej tumor samples as a biomarker for Rilotumumab r benefit
    Annals of Oncology, 2014
    Co-Authors: M.d. Hale, Kelly S. Oliner, Elwyn Loh, Rui Tang, J.g. Vallone, I. Klement, S. Webster, Lisa Chen, Scott D. Patterson
    Abstract:

    ABSTRACT Aim: R is an investigational, fully human monoclonal antibody against hepatocyte growth factor, the only known ligand for the MET proto-oncogene. In a phase 2 study in G/GEJ cancer, trends towards improved overall survival (OS) and progression-free survival (PFS) were seen with R + epirubicin, cisplatin, and capecitabine (ECX) vs placebo + ECX, with benefit due to the MET-positive patients (pts). We describe a methodology to select a cutoff for defining MET positivity. Methods: Eligible pts had unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ECOG performance status ≤ 1, and no prior systemic therapy for this disease. Pts were randomized 1:1:1 to R 15 mg/kg, R 7.5 mg/kg, or placebo IV day 1 Q3W plus ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively). Formalin-fixed paraffin-embedded archival tumor tissues were stained with the Dako MET IHC pharmDx™ kit, which uses the MET4 antibody. Membrane, cytoplasmic, and total (cytoplasmic and membrane) tumor cell staining were evaluated separately. Percent staining at different intensities (0, 1 + , 2 + , 3+) and combinations of intensities were scored directly, whereas overall percent positive, H-score, and predominant staining intensity were derived scores. OS and PFS for subgroups defined by potential cutoff values (5–95%) at 5% increments were analyzed by Cox proportional hazards regression, Kaplan-Meier, and the log rank test, yielding hazard ratios (HRs), median OS and PFS, and p values. Results: 121 pts were randomized; 91 had tumor samples evaluable for MET IHC. Pts whose tumors showed ≥ 25% membranous staining were classified as MET-positive. A strong treatment benefit (R vs placebo) was seen in MET-positive pts (n = 58; OS: HR = 0.46, 95% CI, 0.24–0.87; PFS: HR = 0.46, 95% CI, 0.25–0.85); median OS: 10.6 vs 5.7 mo; median PFS: 6.8 vs 4.4 mo. No benefit or detriment was seen with R in MET-negative pts (n = 33; OS: HR = 1.23; 95% CI, 0.56–2.70; PFS: HR = 1.00; 95% CI, 0.46–2.16). Cutoff values 25–50% showed a similar benefit of R in MET-positive pts. Conclusions: The subgroup defined by a cutoff of 25% MET-positive membranous staining using the Dako MET IHC pharmDx™ kit showed benefit from R + ECX; no negative impact of R was seen in MET-negative pts. This cutoff is being used to select pts in an ongoing phase 3 study of R + ECX in MET-positive G/GEJ cancer (NCT01697072). Disclosure: M.D. Hale, K.S. Oliner, R. Tang, L. Chen, E. Loh and S.D. Patterson have declared:is an employee of and owns stock in Amgen Inc.; S. Webster: Scott Webster is an employee of Dako North America, an Agilent Technologies Company. All other authors have declared no conflicts of interest.

  • Pharmacokinetics (PK) and exposure-response (ER) of Rilotumumab (Rmab) in patients (pts) with small-cell lung cancer (SCLC).
    Journal of Clinical Oncology, 2014
    Co-Authors: Yilong Zhang, Elwyn Loh, Rui Tang, Sarita Dubey, Jenny Zheng, Min Zhu
    Abstract:

    7593 Background: Rmab is a fully human monoclonal antibody against hepatocyte growth factor that was evaluated as a first-line treatment for extensive-stage SCLC in a phase 1b/2 trial (J Thorac Oncol. 2013;8(S2):O21.05). That trial did not show meaningful improvements in progression-free survival (PFS) or overall survival (OS). We characterized Rmab PK in pts with SCLC and performed an ER analysis that related PK to tumor size (TS), PFS, and OS. Methods: Rmab population PK (PPK) and ER were assessed in 132 pts with SCLC who were randomized 1:1 to receive either Rmab (15 mg/kg) or placebo, with etoposide plus carboplatin/cisplatin every 3 weeks (Q3W). A PPK model was developed using data from phase 1 and earlier phase 2 studies. TS vs time was characterized using a tumor dynamic model, and time to tumor growth (TTG) and TS ratios (the ratios of TS at 6, 9, or 12 weeks to TS at baseline) were derived from this model. The relationships between PFS/OS and baseline pt characteristics, exposure metrics, and tum...

  • Safety, tolerability, and pharmacokinetics (PK) of Rilotumumab (R) combined with cisplatin (C) and capecitabine (X) in Japanese patients (pts) with MET-positive metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
    Journal of Clinical Oncology, 2014
    Co-Authors: Toshihiko Doi, Elwyn Loh, Kensei Yamaguchi, Yoshito Komatsu, Kei Muro, Tomohiro Nishina, Takako Eguchi Nakajima, Rui Tang, Richard Lizambri, Yilong Zhang
    Abstract:

    4051 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the MET receptor ligand. This study assessed the safety, PK, and tumor response of R + CX in Japanese pts with MET-positive G/GEJ cancer. Methods: An initial cohort evaluating dose-limiting toxicities (DLTs) is described; an expansion cohort has fully enrolled and will be reported. Eligible pts were Japanese, age ≥20 years, ECOG ≤1, and had pathologically confirmed MET-positive unresectable, locally advanced/metastatic G/GEJ adenocarcinoma. In each 21-day cycle, pts received R 15 mg/kg IV (day 1), C 80 mg/m2 IV (day 1; up to 6 cycles), and X 1000 mg/m2 BID orally (days 1−14). Endpoints included DLTs, adverse events (AEs), PK of R and CX, and objective response. Results: The initial cohort enrolled 6 pts; there was 1 DLT (grade 3 decreased appetite). All pts had treatment-emergent AEs (TEAEs). TEAEs occurring in >3 pts were decreased appetite (n=5), nausea (n=5), fatigue (n=4), and palmar-plantar erythrod...

Yilong Zhang - One of the best experts on this subject based on the ideXlab platform.

  • A Phase 1/1b tolerability study of Rilotumumab alone or in combination with cisplatin and capecitabine in Japanese patients with gastric cancer
    Japanese journal of clinical oncology, 2017
    Co-Authors: Toshihiko Doi, Yilong Zhang, Kensei Yamaguchi, Yoshito Komatsu, Kei Muro, Tomohiro Nishina, Takako Eguchi Nakajima, Rui Tang, Hui Yang, A. Scott Jung
    Abstract:

    Objective To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor Rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2). Methods Adult patients received 10 or 20 mg/kg intravenous (IV) Rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV Rilotumumab every 3 weeks plus 80 mg/m2 cisplatin on Day 1 and 1000 mg/m2 capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2). Results Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade ≥3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received Rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months. Conclusions In combination with CX, Rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including Rilotumumab), further development of Rilotumumab in this setting is not being pursued. ClinicalTrials.gov Identifier: NCT01791374.

  • Assessment of pharmacokinetic interaction between Rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer.
    British journal of clinical pharmacology, 2016
    Co-Authors: Yilong Zhang, Sameer Doshi, Min Zhu, Mita Kuchimanchi, Tien Hoang, Sreeneeranj Kasichayanula
    Abstract:

    Aims Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET-positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)-based drug–drug interaction (DDI) between Rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X). Methods This was a Phase 3 double-blind, placebo-controlled study, in which Rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg−1, 50 mg m−2, and 60 mg m−2 Q3W, respectively, while capecitabine was given orally at 625 mg m−2 twice daily. Rilotumumab PK samples were taken at pre-dose and at the end-of-infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non-compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed Rilotumumab serum concentrations with model-predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies. Results The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of Rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co-administration of Rilotumumab. The observed Rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, indicating Rilotumumab exposure was not affected by co-administration of ECX. Conclusions The results suggest lack of PK-based DDI between Rilotumumab and ECX.

  • Pharmacokinetics and pharmacodynamics of Rilotumumab: a decade of experience in preclinical and clinical cancer research
    British journal of clinical pharmacology, 2015
    Co-Authors: Yilong Zhang, Sameer Doshi, Min Zhu
    Abstract:

    Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, Rilotumumab has been extensively tested in preclinical studies and in clinical studies in a variety of cancer types. In this review, we examine the pharmacokinetic and pharmacodynamic data that have been collected in the Rilotumumab programme to date, and discuss retrospectively how the knowledge acquired in this programme can be applied to a number of key issues in oncology drug development, including: (i) using preclinical data to inform first-in-human study design; (ii) the role of biomarkers in the identification of a target patient population; (iii) the potential for drug interactions between therapeutic proteins and other anticancer agents; and (iv) pharmacokinetic and pharmacodynamic considerations in phase 3 study design.

  • Rilotumumab Exposure-Response Relationship in Patients With Advanced or Metastatic Gastric Cancer
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Sameer Doshi, Per Olsson Gisleskog, Yilong Zhang, Min Zhu, Kelly S. Oliner, Elwyn Loh, Juan Jose Perez Ruixo
    Abstract:

    Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase 2 study, trends toward improved survival were observed with Rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response (tumor growth [TG] and overall survival [OS]) relationship for Rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase 2 study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, Rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, non-parametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between Rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to Rilotumumab than MET-negative patients. Simulations predicted a median (95% CI) HR of 0.38 (0.18, 0.60) in MET-positive patients treated with 15 mg/kg Rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase 3 testing of Rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

  • Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression
    British journal of cancer, 2015
    Co-Authors: Min Zhu, Sameer Doshi, Kelly S. Oliner, Elwyn Loh, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Rui Tang, Sarita Dubey, Yilong Zhang
    Abstract:

    Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression

Rui Tang - One of the best experts on this subject based on the ideXlab platform.

  • A Phase 1/1b tolerability study of Rilotumumab alone or in combination with cisplatin and capecitabine in Japanese patients with gastric cancer
    Japanese journal of clinical oncology, 2017
    Co-Authors: Toshihiko Doi, Yilong Zhang, Kensei Yamaguchi, Yoshito Komatsu, Kei Muro, Tomohiro Nishina, Takako Eguchi Nakajima, Rui Tang, Hui Yang, A. Scott Jung
    Abstract:

    Objective To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor Rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2). Methods Adult patients received 10 or 20 mg/kg intravenous (IV) Rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV Rilotumumab every 3 weeks plus 80 mg/m2 cisplatin on Day 1 and 1000 mg/m2 capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2). Results Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade ≥3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received Rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months. Conclusions In combination with CX, Rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including Rilotumumab), further development of Rilotumumab in this setting is not being pursued. ClinicalTrials.gov Identifier: NCT01791374.

  • Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression
    British journal of cancer, 2015
    Co-Authors: Min Zhu, Sameer Doshi, Kelly S. Oliner, Elwyn Loh, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Rui Tang, Sarita Dubey, Yilong Zhang
    Abstract:

    Exposure-response analysis of Rilotumumab in gastric cancer: the role of tumour MET expression

  • 221pevaluation of met staining in gastric gastroesophageal junction g gej tumor samples as a biomarker for Rilotumumab r benefit
    Annals of Oncology, 2014
    Co-Authors: M.d. Hale, Kelly S. Oliner, Elwyn Loh, Rui Tang, J.g. Vallone, I. Klement, S. Webster, Lisa Chen, Scott D. Patterson
    Abstract:

    ABSTRACT Aim: R is an investigational, fully human monoclonal antibody against hepatocyte growth factor, the only known ligand for the MET proto-oncogene. In a phase 2 study in G/GEJ cancer, trends towards improved overall survival (OS) and progression-free survival (PFS) were seen with R + epirubicin, cisplatin, and capecitabine (ECX) vs placebo + ECX, with benefit due to the MET-positive patients (pts). We describe a methodology to select a cutoff for defining MET positivity. Methods: Eligible pts had unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ECOG performance status ≤ 1, and no prior systemic therapy for this disease. Pts were randomized 1:1:1 to R 15 mg/kg, R 7.5 mg/kg, or placebo IV day 1 Q3W plus ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively). Formalin-fixed paraffin-embedded archival tumor tissues were stained with the Dako MET IHC pharmDx™ kit, which uses the MET4 antibody. Membrane, cytoplasmic, and total (cytoplasmic and membrane) tumor cell staining were evaluated separately. Percent staining at different intensities (0, 1 + , 2 + , 3+) and combinations of intensities were scored directly, whereas overall percent positive, H-score, and predominant staining intensity were derived scores. OS and PFS for subgroups defined by potential cutoff values (5–95%) at 5% increments were analyzed by Cox proportional hazards regression, Kaplan-Meier, and the log rank test, yielding hazard ratios (HRs), median OS and PFS, and p values. Results: 121 pts were randomized; 91 had tumor samples evaluable for MET IHC. Pts whose tumors showed ≥ 25% membranous staining were classified as MET-positive. A strong treatment benefit (R vs placebo) was seen in MET-positive pts (n = 58; OS: HR = 0.46, 95% CI, 0.24–0.87; PFS: HR = 0.46, 95% CI, 0.25–0.85); median OS: 10.6 vs 5.7 mo; median PFS: 6.8 vs 4.4 mo. No benefit or detriment was seen with R in MET-negative pts (n = 33; OS: HR = 1.23; 95% CI, 0.56–2.70; PFS: HR = 1.00; 95% CI, 0.46–2.16). Cutoff values 25–50% showed a similar benefit of R in MET-positive pts. Conclusions: The subgroup defined by a cutoff of 25% MET-positive membranous staining using the Dako MET IHC pharmDx™ kit showed benefit from R + ECX; no negative impact of R was seen in MET-negative pts. This cutoff is being used to select pts in an ongoing phase 3 study of R + ECX in MET-positive G/GEJ cancer (NCT01697072). Disclosure: M.D. Hale, K.S. Oliner, R. Tang, L. Chen, E. Loh and S.D. Patterson have declared:is an employee of and owns stock in Amgen Inc.; S. Webster: Scott Webster is an employee of Dako North America, an Agilent Technologies Company. All other authors have declared no conflicts of interest.

  • Pharmacokinetics (PK) and exposure-response (ER) of Rilotumumab (Rmab) in patients (pts) with small-cell lung cancer (SCLC).
    Journal of Clinical Oncology, 2014
    Co-Authors: Yilong Zhang, Elwyn Loh, Rui Tang, Sarita Dubey, Jenny Zheng, Min Zhu
    Abstract:

    7593 Background: Rmab is a fully human monoclonal antibody against hepatocyte growth factor that was evaluated as a first-line treatment for extensive-stage SCLC in a phase 1b/2 trial (J Thorac Oncol. 2013;8(S2):O21.05). That trial did not show meaningful improvements in progression-free survival (PFS) or overall survival (OS). We characterized Rmab PK in pts with SCLC and performed an ER analysis that related PK to tumor size (TS), PFS, and OS. Methods: Rmab population PK (PPK) and ER were assessed in 132 pts with SCLC who were randomized 1:1 to receive either Rmab (15 mg/kg) or placebo, with etoposide plus carboplatin/cisplatin every 3 weeks (Q3W). A PPK model was developed using data from phase 1 and earlier phase 2 studies. TS vs time was characterized using a tumor dynamic model, and time to tumor growth (TTG) and TS ratios (the ratios of TS at 6, 9, or 12 weeks to TS at baseline) were derived from this model. The relationships between PFS/OS and baseline pt characteristics, exposure metrics, and tum...

  • Safety, tolerability, and pharmacokinetics (PK) of Rilotumumab (R) combined with cisplatin (C) and capecitabine (X) in Japanese patients (pts) with MET-positive metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
    Journal of Clinical Oncology, 2014
    Co-Authors: Toshihiko Doi, Elwyn Loh, Kensei Yamaguchi, Yoshito Komatsu, Kei Muro, Tomohiro Nishina, Takako Eguchi Nakajima, Rui Tang, Richard Lizambri, Yilong Zhang
    Abstract:

    4051 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the MET receptor ligand. This study assessed the safety, PK, and tumor response of R + CX in Japanese pts with MET-positive G/GEJ cancer. Methods: An initial cohort evaluating dose-limiting toxicities (DLTs) is described; an expansion cohort has fully enrolled and will be reported. Eligible pts were Japanese, age ≥20 years, ECOG ≤1, and had pathologically confirmed MET-positive unresectable, locally advanced/metastatic G/GEJ adenocarcinoma. In each 21-day cycle, pts received R 15 mg/kg IV (day 1), C 80 mg/m2 IV (day 1; up to 6 cycles), and X 1000 mg/m2 BID orally (days 1−14). Endpoints included DLTs, adverse events (AEs), PK of R and CX, and objective response. Results: The initial cohort enrolled 6 pts; there was 1 DLT (grade 3 decreased appetite). All pts had treatment-emergent AEs (TEAEs). TEAEs occurring in >3 pts were decreased appetite (n=5), nausea (n=5), fatigue (n=4), and palmar-plantar erythrod...

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