Patient case: 64-year-old male with melanoma; genetic feature: BRAF (V600E)

Clinical trial: Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib in Patients With BRAF or NRAS-mutated Metastatic Melanoma

Summary: The goal of this clinical research study is to learn if nivolumab and trametinib (with or without dabrafenib) can help to control metastatic melanoma in patients who have a BRAF, NRAS, or BRAF-wild-type mutation.
  The safety of these drug combinations will also be studied.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups based on the type of mutation you have.
  -  If you are in Group A, you will receive nivolumab, dabrafenib, and trametinib (BRAF-mutated patients).
  -  If you are in Group B, you will receive nivolumab and trametinib (BRAF-wild-type or NRAS-mutation patients).
  You and the study staff will know which group you have been assigned.
  Study Drug Administration:
  Each study cycle is 4 weeks.
  All participants will receive nivolumab by vein over about 30 minutes on Days 1 and 15 of each cycle.
  If you are in Group A, you will take dabrafenib capsules 2 times each day and trametinib tablets 1 time every day. Dabrafenib and trametinib should be taken at the same time in the morning, and the second dose of dabrafenib should be taken about 12 hours after the first dose. You should take the dabrafenib and trametinib with a cup of water (about 8 ounces) every time, either 1 hour before or 2 hours after a meal.
  If you are in Group B, you will take trametinib tablets by mouth every day while you are on study. Each dose should be taken 1 time every day in the morning at about the same time with a cup of water (about 8 ounces), either 1 hour before or 2 hours after a meal.
  If you vomit after your dose of study drugs, do not retake the dose. Wait until your next scheduled dose. If you are in Group A and you miss a dose of dabrafenib, you may take the dose as soon as you remember, as long as your next dose is more than 6 hours later. If you miss a dose of trametinib, you may take the dose as soon as you remember as long as the next dose is scheduled for at least 12 hours later.
  Length of Study:
  You may continue taking the study drugs for 3 years You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, if you are unable to follow study directions, or if the study doctor thinks it is in your interest.
  Your participation in this study will be over after about 3 years of follow-up (described below).
  Study Visits:
  During Week 1 of Cycle 1:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 5 teaspoons) will be drawn for routine tests and to check your autoimmune status.
  During Weeks 2 and 4 of Cycles 1-3 and Week 3 of Cycle 3, blood (about 3 teaspoons) will be drawn for routine tests.
  During Week 3 of Cycle 1:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 3 teaspoons) will be drawn for routine, PD, and PBMC testing.
  During Week 1 of Cycle 2:
  -  You will have a physical exam, including a skin exam.
  -  You will have an EKG.
  -  You will have an eye exam.
  -  Blood (about 5 teaspoons) will be drawn for routine tests
  -  If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test.
  During Week 3 of Cycle 2:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 3 teaspoons) will be drawn for routine tests.
  During Week 1 of Cycles 3 and beyond:
  -  You will have a physical exam, including a skin exam.
  -  You will have an EKG.
  -  Blood (about 3 teaspoons) will be drawn for routine tests. During Cycle 3, this blood sample will also be used for PD and PBMC testing.
  -  If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test.
  During Week 3 of Cycle 3 and beyond, blood (about 3 teaspoons) will be drawn for routine tests.
  At Months 3, 6, 12, and if you stop taking the stuy drugs before Month 12, you will have an eye exam. Additional eye exams will be performed if the study doctor thinks it is needed.
  Every 12 weeks:
  -  You will have an MRI and/or CT scan.
  -  You will have an ECHO.
  End-of-Treatment Visit:
  About 30 days after your last dose of study drugs:
  -  You will have a physical exam.
  -  You will have an EKG.
  -  Blood (about 2 teaspoons) will be drawn for routine, PD, and PBMC testing.
  -  You will have an MRI and/or CT scan.
  -  If the study doctor thinks it is needed, you will have an eye exam.
  Long-Term Follow-Up:
  After you stop taking the study drugs, the study doctor or study staff will continue to check on your health every 3 months for up to 3 years. This information may be collected at your routine, standard of care clinic visits; it may be collected from your medical records; or you may be called by the study staff and asked. If you are called, it should take about 10 minutes.
  Your participation will be over after you have completed long-term follow-up.
  This is an investigational study. Nivolumab, trametinib, and dabrafenib are each FDA approved and commercially available for the treatment of melanoma. However, it is considered investigational to use these drugs in combination with each other to treat melanoma. The study doctor can explain how the study drugs are designed to work.
  Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  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.
  Exclusion Criteria:
  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.

Relevance to patient case: possibly relevant