Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib

NCT02357732 | Withdrawn Phase 1 DMC

• 1 other identifier: 14-115
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study evaluates nivolumab in combination drug treatments involving 1) nivolumab and dabrafenib 2) nivolumab and trametinib and 3) nivolumab, dabrafenib and trametinib in patients with BRAF or NRAS-mutated metastatic melanoma.

Conditions

Metastatic Melanoma

Keywords

Metastatic Melanoma

Outcome Measures

Primary Outcomes (1)

• To determine the Maximally Tolerated Dose and/or Recommended Phase II Dose (RP2D) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF- or NRAS-mutated metastatic melanoma

  It is planned to determine the maximum tolerable dose with a modified version of the standard "up and down" (3+3) dose-finding method using cohorts of 3 patients. At the start of the trial, three patients will be placed on dose level 1. The decision rules based on the observed dose limiting toxicities (DLTs) in this and subsequent cohorts are given. Only DLTs observed in a patient during the first cycle (28 days) will be used for the dose escalation decisions. Patients will be considered evaluable for toxicity if they receive 1 complete cycle of therapy, or if they experience DLT; in-evaluable patients will be replaced.

  The first four weeks of dosing

Secondary Outcomes (1)

• Antitumor Effects and Immune Related Response

  Every twelve weeks for three years while on study drug

Study Arms (3)

Nivolumab and Dabrafenib Combination (doublets)

EXPERIMENTAL

Level -1, Nivolumab 1mg/kg IV every 2 weeks (q2 weeks); Dabrafenib 100mg by mouth (PO) twice a day(BID) every day (QD); Level 1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Dabrafenib 150mg PO BID QD;

Drug: Nivolumab; Drug: Dabrafenib

Nivolumab and Trametinib Combination (doublets)

EXPERIMENTAL

Level -1, Nivolumab 1mg/kg IV q2 weeks; Trametinib 1mg PO QD; Level 1, Nivolumab 1mg/kg IV q2 weeks; Trametinib 2mg PO QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Trametinib 2mg PO QD;

Drug: Nivolumab; Drug: Trametinib

Nivolumab, Dabrafenib and Trametinib Combination (triplet)

EXPERIMENTAL

Level -1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 1mg PO QD; Level 1, Nivolumab 1mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 2mg PO QD; Level 2, Nivolumab 3mg/kg IV q2 weeks; Dabrafenib 150mg PO BID; Trametinib 2mg PO QD;

Drug: Nivolumab; Drug: Trametinib; Drug: Dabrafenib

Interventions

Nivolumab DRUG

Nivolumab and Dabrafenib Combination (doublets); Nivolumab and Trametinib Combination (doublets); Nivolumab, Dabrafenib and Trametinib Combination (triplet)

Trametinib DRUG

Nivolumab and Trametinib Combination (doublets); Nivolumab, Dabrafenib and Trametinib Combination (triplet)

Dabrafenib DRUG

Nivolumab and Dabrafenib Combination (doublets); Nivolumab, Dabrafenib and Trametinib Combination (triplet)

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations.
• Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-, immuno-, biological- and vaccine-therapy as long as they did not include BRAFi, MEKi, or nivolumab. Prior ipilimumab therapy will be allowed with a washout period of 8 weeks and if all autoimmune adverse events have resolved to grade 1.
• Evidence of evaluable disease.
• ECOG Performance Status of 0 or 1.
• Stable CNS disease is allowed. Subjects with brain metastases are eligible if (a) metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; or (b) if they are untreated but asymptomatic and do not require steroid therapy. Patients are excluded if they require high doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration, as this could result in immunosuppression.
• Patients must have normal organ and marrow function as defined by the normal laboratory ranges. Screening laboratory values must meet the following criteria and should be obtained within 28 days prior to registration:
• WBC ≥ 2000/μL
• Neutrophils ≥ 1500/μL
• Platelets ≥ 100 x103/μL
• Hemoglobin \> 9.0 g/dL
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
• Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
• AST/ALT ≤ 3 x ULN
• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
• Men and women age≥18 years.

You may not qualify if:

• Histologically confirmed metastatic melanoma (Stage IV) with NRAS and BRAF-wild type.
• Grade 3/4 immune-related AEs on ipilimumab and required more than 12 weeks of immune suppression with corticosteroids.
• History of interstitial lung disease or pneumonitis.
• History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Active leptomeningeal metastases or untreated symptomatic brain metastases.
• Active, known or suspected autoimmune disease. Subjects 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.
• Require 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.
• Known history of a positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib and trametinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• History of allergy or adverse drug reaction to the study drug components (nivolumab, dabrafenib, or trametinib) or drugs of similar chemical or biologic composition. Patients with a history of severe hypersensitivity reaction to any monoclonal antibody should also be excluded.
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and/or breastfeeding women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib and trametinib, breastfeeding should be discontinued if the mother is treated with dabrafenib and trametinib. These potential risks may also apply to other agents used in this study.

Sponsors & Collaborators

• University of Pittsburgh: lead
• Bristol-Myers Squibb: collaborator

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; trametinib; dabrafenib

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

Study Officials

• Hussein Tawbi, MD

  University of Pittsburgh Medical Center / Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: January 27, 2015
• First Posted: February 6, 2015
• Study Start: August 1, 2015
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: December 11, 2015

Record last verified: 2015-12