A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma

Roche

Status and phase: Completed; Phase 1

Conditions: Malignant Melanoma

Treatments: Drug: Cobimetinib; Drug: vemurafenib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01271803

NO25395

Details and patient eligibility

About

This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.

Enrollment: 131 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])

• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

• Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1

• Participants must

  1. be previously untreated for locally advanced/unresectable or metastatic melanoma or
  2. previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or
  3. progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or expanded access programs (EAP) immediately prior to enrollment in this study or
  4. progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.

• Life expectancy >/=12 weeks

Exclusion criteria

• History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
• Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
• Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
• Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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131 participants in 12 patient groups

DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

Cobimetinib Monotherapy (100 mg or 60 mg)

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: Cobimetinib

CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib

CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

Experimental group

Description:

Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Treatment:

Drug: vemurafenib

Drug: Cobimetinib