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

NCT01940809 | Terminated Phase 1

• 6 other identifiers: NCI-2013-0170313-3049377P30CA006516U01CA062490UM1CA186709
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

BRAF V600E Mutation Present; BRAF V600K Mutation Present; Metastatic Melanoma; 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

Outcome Measures

Primary Outcomes (1)

• Incidence of grade 3 or higher immune-related adverse events (irAEs), graded according to the National Cancer Institute (NCI) CTCAE v4.0

  Presented with 90% confidence intervals calculated using exact binomial methods.

  Up to 3 weeks after end of ipilimumab induction

Secondary Outcomes (3)

• Proportion of patients receiving dabrafenib and trametinib with grade 3 or higher irAEs after disease progression on ipilimumab, according to the NCI CTCAE v4.0

  Up to 4 weeks after completion of study treatment

• Response rate for the total treatment period according to Response Evaluation Criteria in Solid Tumors v1.1

  Up to 4 weeks after completion of study treatment

• Disease-control rate

  Up to 4 weeks after completion of study treatment

Other Outcomes (3)

• Biomarker expression levels

  Baseline

• Fold-changes in biomarkers

  Baseline to 3 weeks after fourth ipilimumab dose

• Change in immune activation, measured by changes in biomarker levels

  Baseline to 3 weeks after fourth ipilimumab dose

Study Arms (8)

Arm A1 (ipilimumab, dabrafenib, trametinib)

EXPERIMENTAL

Patients receive dabrafenib PO BID and 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.

Drug: Dabrafenib; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Drug: Trametinib

Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab)

EXPERIMENTAL

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.

Drug: Dabrafenib; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Drug: Trametinib

Arm B1 (ipilimumab, trametinib)

EXPERIMENTAL

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.

Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Drug: Trametinib

Arm B2 (trametinib, nivolumab, ipilimumab)

EXPERIMENTAL

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.

Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Drug: Trametinib

Arm C1 (ipilimumab, dabrafenib)

EXPERIMENTAL

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.

Drug: Dabrafenib; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis

Arm C2 (dabrafenib, nivolumab, ipilimumab)

EXPERIMENTAL

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.

Drug: Dabrafenib; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Arm D1 (ipilimumab)

EXPERIMENTAL

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

Biological: Ipilimumab; Other: Laboratory Biomarker Analysis

Arm D2 (nivolumab, ipilimumab)

EXPERIMENTAL

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

Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Interventions

Dabrafenib DRUG

Given PO

Also known as: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436

Arm A1 (ipilimumab, dabrafenib, trametinib); Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab); Arm C1 (ipilimumab, dabrafenib); Arm C2 (dabrafenib, nivolumab, ipilimumab)

Ipilimumab BIOLOGICAL

Given IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, Yervoy

Arm A1 (ipilimumab, dabrafenib, trametinib); Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab); Arm B1 (ipilimumab, trametinib); Arm B2 (trametinib, nivolumab, ipilimumab); Arm C1 (ipilimumab, dabrafenib); Arm C2 (dabrafenib, nivolumab, ipilimumab); Arm D1 (ipilimumab); Arm D2 (nivolumab, ipilimumab)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm A1 (ipilimumab, dabrafenib, trametinib); Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab); Arm B1 (ipilimumab, trametinib); Arm B2 (trametinib, nivolumab, ipilimumab); Arm C1 (ipilimumab, dabrafenib); Arm C2 (dabrafenib, nivolumab, ipilimumab); Arm D1 (ipilimumab); Arm D2 (nivolumab, ipilimumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo

Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab); Arm B2 (trametinib, nivolumab, ipilimumab); Arm C2 (dabrafenib, nivolumab, ipilimumab); Arm D2 (nivolumab, ipilimumab)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212

Arm A1 (ipilimumab, dabrafenib, trametinib); Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab); Arm B1 (ipilimumab, trametinib); Arm B2 (trametinib, nivolumab, ipilimumab)

Eligibility Criteria

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

You may qualify if:

• Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma
• Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death \[PD\]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Absolute neutrophil count (ANC) \>= 1.2 x 10\^9/L
• Hemoglobin \>= 9 g/dL
• Platelets \>= 100 x 10\^9/L
• Albumin \>= 2.5 g/dL
• Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x institutional ULN
• Serum creatinine =\< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) \>= 50 mL/min
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =\< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization
• Left ventricular ejection fraction \>= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
• Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided

You may not qualify if:

• Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment
• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study
• Study participants with a history of prior treatment with BRAF or MEK inhibitors
• Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
• Study participants who have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses \< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if \< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
• Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody
• Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
• Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed)
• Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; Ipilimumab; CTLA-4 Antigen; Nivolumab; 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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Study Officials

• Patrick A Ott

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: September 9, 2013
• First Posted: September 12, 2013
• Study Start: August 28, 2013
• Primary Completion: July 17, 2020
• Study Completion: March 4, 2022
• Last Updated: March 10, 2022

Record last verified: 2022-03

Locations

US (2)