Ipilimumab With or Without Dabrafenib, Trametinib, and/or Nivolumab in Treating Patients With Melanoma That Is Metastatic or Cannot Be Removed by Surgery

Metastatic Melanoma Clinical Trial

Official title: A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

Status Terminated

Clinical Trial Summary

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma.

SECONDARY OBJECTIVES:

I. To determine the response rate to ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) after BRAF and MEK inhibitors, either alone or in combination, compared to no prior kinase inhibitor treatment.

II. To determine the safety and tolerability of dabrafenib and trametinib combination in the setting of prior ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 1).

III. To determine the safety and tolerability of dabrafenib and trametinib combination in the setting of prior ipilimumab plus nivolumab without prior BRAF/MEK inhibition or ipilimumab plus nivolumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 2).

IV. To determine the response rate to dabrafenib and trametinib in the setting of prior ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 1).

V. To determine the response rate to dabrafenib and trametinib in the setting of prior ipilimumab plus nivolumab without prior MEK/BRAF inhibition or prior ipilimumab plus nivolumab preceded by BRAF/MEK inhibitors (part 2).

VI. To obtain peripheral blood and tumor tissue for biomarker analysis. VII. To describe the immune impact of kinase inhibitor therapy on the immune response associated with ipilimumab treatment (part 1) or ipilimumab plus nivolumab treatment (part 2).

VIII. To observe and record anti-tumor activity.

OUTLINE: Patients are randomized to 1 of 4 treatment arms for Part 2 (Part 1 closed to accrual 8/25/2015).

PART 1: (Closed to accrual as of 8/25/2015) ARM A1: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) for 25 days. Patients then receive ipilimumab intravenously (IV) over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM B1: Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM C1: Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM D1: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

PART 2:

ARM A2: Patients receive dabrafenib PO BID and trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM B2: Patients receive trametinib PO QD for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM C2: Patients receive dabrafenib PO BID for 25 days followed by nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

ARM D2: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.

After 12 weeks of treatment with ipilimumab, or ipilimumab and nivolumab followed by nivolumab monotherapy, all patients may continue to receive dabrafenib PO BID and trametinib PO QD in the absence of disease progression.

After completion of study treatment, patients are followed up for 14 weeks. ;

Related Conditions & MeSH terms

• BRAF V600E Mutation Present
• BRAF V600K Mutation Present
• Melanoma
• Metastatic Melanoma
• Skin Neoplasms
• Stage III Cutaneous Melanoma AJCC v7
• Stage IIIA Cutaneous Melanoma AJCC v7
• Stage IIIB Cutaneous Melanoma AJCC v7
• Stage IIIC Cutaneous Melanoma AJCC v7
• Stage IV Cutaneous Melanoma AJCC v6 and v7

• NCT number: NCT01940809
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Terminated
• Phase: Phase 1
• Start date: August 28, 2013
• Completion date: March 4, 2022