A Phase II Study of the Anti-PD-1 Antibody Nivolumab in Combination with Dabrafenib and/or Trametinib in Patients with BRAF or NRAS-mutated Metastatic Melanoma
The goal of this clinical research study is to learn if nivolumab and trametinib (either alone or in combination with dabrafenib) can help to control metastatic melanoma in patients who have a BRAF or NRAS mutation.
Disease Group: Melanoma
Treatment Agent: Dabrafenib,Nivolumab,Trametinib
Treatment Location: Only at MDACC
Primary Objectives To determine the safety, tolerability, and efficacy (objective response rates by RECIST 1.1) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF- mutated or BRAF-wild type metastatic melanoma. Secondary Objectives Safety and tolerability of the doublet (NT) and triplet combinations (NDT) Efficacy of the combinations as measured by the depth and duration of response Pharmacodynamic evaluation of combination on circulating markers (immune monitoring) Pharmacodynamic evaluation of combination on tumor tissues Progression- free survival and overall survival
IRB Review and Approval Date: 12/09/2016
Recruitment Status: Open
Projected Accrual: N/A
1) Histologically confirmed metastatic melanoma (Stage IV) or
unresectable Stage III. Patients with BRAF or BRAF-wild-type are
eligible. Only BRAF V600 mutated melanoma will be eligible for the
triplet arm while BRAF-wild-type or NRAS-mutated melanoma will be
eligible for the doublet arm.
2) Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-, immuno, biological and vaccine-therapy as long as they did not include BRAFi, MEKi. Prior ipilimumab or PD-1 directed therapy will be allowed with a washout period of 4 weeks and if all autoimmune adverse events have resolved to grade 1 (except endocrine abnormalities that require continuous replacement).
3) Evidence of evaluable disease.
4) ECOG Performance Status of 0 or 1.
5) Patients with melanoma brain metastases are 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 of the first dose of nivolumab administration; or (b) if they are untreated but asymptomatic or c) if they are untreated and symptomatic but symptoms are controlled on stable or decreasing doses of steroids for 14 days prior to drug administration. Patients are excluded if they require high doses of systemic corticosteroids (> 8 mg equivalent of dexamethasone) to control CNS symptoms.
6) 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 one week prior to registration a.) WBC >/= 2000/µL b.) Neutrophils >/=1500/µL c.) Platelets >/= 100 x103/µL d.) Hemoglobin > 9.0 g/dL e.) 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 f.) AST/ALT </=3 x ULN g.) Total Bilirubin </=1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
7) Men and women age >/= 18 years
8) Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year.
9) Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of nivolumab.
10) Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception.
11) Ability to understand and the willingness to sign a written informed consent document.
1) Patients that had grade 3/4 immune-related AEs on ipilimumab that
required more than 12 weeks of immune suppression with corticosteroids.
2) History of interstitial lung disease or pneumonitis.
3) History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
4) Active leptomeningeal metastases
5) Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism and/or hypophysitis 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.
6) Require systemic treatment with either corticosteroids (> 8 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease.
7) Known history of a positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
8) 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.
9) 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.
10) 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.
11) Uncontrolled intercurrent illness (requiring IV antibiotic treatment) 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.
12) 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 nivolumab, dabrafenib, and trametinib, breastfeeding should be discontinued if the mother is treated with nivolumab, dabrafenib, and trametinib. These potential risks may also apply to other agents used in this study.
Information and next steps
Melanoma Medical Oncology
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