Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone

MedImmune

Status and phase: Completed; Phase 1

Conditions: Melanoma

Treatments: Biological: Durvalumab; Drug: Trametinib; Drug: Dabrafenib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02027961

CD-ON-MEDI4736-1161

Details and patient eligibility

About

The purpose of this study is to determine the maximum tolerated dose and characterize the safety profile of durvalumab (MEDI4736) in combination with dabrafenib and trametinib or with trametinib alone in participants with metastatic or unresectable melanoma with BRAF-mutation positive or wild-type (WT) BRAF, respectively.

Full description

This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively.

Enrollment: 68 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adults >= 18 years old
• Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease by radiographic or physical examination
• Adequate organ and marrow function
• Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function

Exclusion criteria

• Prior treatment with a BRAF inhibitor or MEK inhibitor
• Any prior Grade >= 3 immune-related adverse event while receiving immunotherapy
• Active or prior documented autoimmune disease within the past 2 years
• History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR)
• History of or current cardiovascular risk including myocardial infarction, >= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension
• Active, untreated central nervous system (CNS) metastases
• Women who are pregnant or lactating

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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68 participants in 4 patient groups

Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib

Experimental group

Description:

Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.

Treatment:

Drug: Dabrafenib

Drug: Trametinib

Biological: Durvalumab

Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib

Experimental group

Description:

Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.

Treatment:

Drug: Dabrafenib

Drug: Trametinib

Biological: Durvalumab

Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)

Experimental group

Description:

Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.

Treatment:

Drug: Trametinib

Biological: Durvalumab

Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)

Experimental group

Description:

Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.

Treatment:

Drug: Trametinib

Biological: Durvalumab