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

NCT02027961 | Completed Phase 1 FDA Drug

• 1 other identifier: CD-ON-MEDI4736-1161
• Study Type: interventional
• Target: 68
• Locations: 4 countries
• Sites: 11

Brief Summary

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.

Conditions

Melanoma

Keywords

Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.

  From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

  From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

• Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs

  Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported.

  From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

  Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.

  From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

• Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs

  Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.

  From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Secondary Outcomes (9)

• Percentage of Participants With Objective Response (OR)

  From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

• Duration of Response (DOR)

  From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

• Progression-free Survival (PFS)

  From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

• Overall Survival

  From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

• Percentage of Participants With Disease Control

  From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

Study Arms (4)

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

EXPERIMENTAL

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.

Biological: Durvalumab; Drug: Dabrafenib; Drug: Trametinib

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

EXPERIMENTAL

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.

Biological: Durvalumab; Drug: Dabrafenib; Drug: Trametinib

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

EXPERIMENTAL

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.

Biological: Durvalumab; Drug: Trametinib

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

EXPERIMENTAL

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.

Biological: Durvalumab; Drug: Trametinib

Interventions

Durvalumab BIOLOGICAL

Intravenous dose of 3 or 10 mg/kg durvalumab.

Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib; Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib; Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent); Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)

Dabrafenib DRUG

Oral dose of 150 mg dabrafenib capsule.

Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib; Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib

Trametinib DRUG

Oral dose of 2 mg trametinib tablet.

Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib; Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib; Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent); Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• MedImmune LLC: lead

Study Sites (11)

Research Site

Scottsdale, Arizona, 85258, United States

Location

Research Site

Los Angeles, California, 90095, United States

Location

Research Site

San Francisco, California, 94115, United States

Location

Research Site

Miami Beach, Florida, 33140, United States

Location

Research Site

Chicago, Illinois, 60611, United States

Location

Research Site

Boston, Massachusetts, 02114, United States

Location

Research Site

St Louis, Missouri, 63110, United States

Location

Research Site

Toronto, Ontario, M5G 2M9, Canada

Location

Research Site

Montreal, Quebec, H3A 1A1, Canada

Location

Research Site

Villejuif, 94805, France

Location

Research Site

Napoli, 80131, Italy

Location

Related Publications (3)

• Gordon MS, Lutzky J, Lawrence D, Butler M, Ascierto PA, Hug B, et al. Phase 1 study evaluating safety and tolerability of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with unresectable or metastatic melanoma. Ann Oncol 2014; 25(suppl_4): iv374-iv393 (abstract 8004).

  BACKGROUND

• Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W, et al. Phase 1 study combining anti-PD-L1 (MEDI4736) and BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol 2015; 33 (15_suppl): (abstract 3003).

  RESULT

• Ribas A, Algazi A, Ascierto PA, Butler MO, Chandra S, Gordon M, Hernandez-Aya L, Lawrence D, Lutzky J, Miller WH Jr, Campbell KM, Delafont B, Marshall S, Mueller N, Robert C. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nat Commun. 2020 Dec 7;11(1):6262. doi: 10.1038/s41467-020-19810-w.

  PMID: 33288749 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

durvalumab; dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• MedImmune LLC

  MedImmune LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2013
• First Posted: January 6, 2014
• Study Start: December 20, 2013
• Primary Completion: April 24, 2018
• Study Completion: April 24, 2018
• Last Updated: May 17, 2019

Record last verified: 2019-05

Locations

IT (1); FR (1); US (7); CA (2)