Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts

Yung Jue Bang, Wu Chou Su, Martin Schuler, Do Hyun Nam, Wan Teck Lim, Todd M. Bauer, Analia Azaro, Ronnie Tung Ping Poon, David Hong, Chia Chi Lin, Mikhail Akimov, Samson Ghebremariam, Sylvia Zhao, Monica Giovannini, Brigette Ma

Research output: Contribution to journalArticle

Abstract

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

Original languageEnglish
Pages (from-to)536-547
Number of pages12
JournalCancer Science
Volume111
Issue number2
DOIs
StatePublished - 1 Feb 2020

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Capsules
Gene Dosage
Tablets
Neoplasms
Safety
Maximum Tolerated Dose
Stomach Neoplasms
Hepatocellular Carcinoma
Colorectal Neoplasms
Animal Models
Adenosine Triphosphate
Immunohistochemistry
Phosphorylation
Biopsy
Mutation
Incidence

Keywords

  • MET amplification
  • MET dysregulation
  • capmatinib
  • phase 1
  • solid tumors

Cite this

Bang, Yung Jue ; Su, Wu Chou ; Schuler, Martin ; Nam, Do Hyun ; Lim, Wan Teck ; Bauer, Todd M. ; Azaro, Analia ; Poon, Ronnie Tung Ping ; Hong, David ; Lin, Chia Chi ; Akimov, Mikhail ; Ghebremariam, Samson ; Zhao, Sylvia ; Giovannini, Monica ; Ma, Brigette. / Phase 1 study of capmatinib in MET-positive solid tumor patients : Dose escalation and expansion of selected cohorts. In: Cancer Science. 2020 ; Vol. 111, No. 2. pp. 536-547.
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Bang, YJ, Su, WC, Schuler, M, Nam, DH, Lim, WT, Bauer, TM, Azaro, A, Poon, RTP, Hong, D, Lin, CC, Akimov, M, Ghebremariam, S, Zhao, S, Giovannini, M & Ma, B 2020, 'Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts', Cancer Science, vol. 111, no. 2, pp. 536-547. https://doi.org/10.1111/cas.14254

Phase 1 study of capmatinib in MET-positive solid tumor patients : Dose escalation and expansion of selected cohorts. / Bang, Yung Jue; Su, Wu Chou; Schuler, Martin; Nam, Do Hyun; Lim, Wan Teck; Bauer, Todd M.; Azaro, Analia; Poon, Ronnie Tung Ping; Hong, David; Lin, Chia Chi; Akimov, Mikhail; Ghebremariam, Samson; Zhao, Sylvia; Giovannini, Monica; Ma, Brigette.

In: Cancer Science, Vol. 111, No. 2, 01.02.2020, p. 536-547.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 1 study of capmatinib in MET-positive solid tumor patients

T2 - Dose escalation and expansion of selected cohorts

AU - Bang, Yung Jue

AU - Su, Wu Chou

AU - Schuler, Martin

AU - Nam, Do Hyun

AU - Lim, Wan Teck

AU - Bauer, Todd M.

AU - Azaro, Analia

AU - Poon, Ronnie Tung Ping

AU - Hong, David

AU - Lin, Chia Chi

AU - Akimov, Mikhail

AU - Ghebremariam, Samson

AU - Zhao, Sylvia

AU - Giovannini, Monica

AU - Ma, Brigette

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

AB - Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).

KW - MET amplification

KW - MET dysregulation

KW - capmatinib

KW - phase 1

KW - solid tumors

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