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Protocol No. EA6134

Principal Investigator Albertini, Mark

Phase III

Age Group Adult

Scope National

Sponsor Type National

Title A Randomized Phase III trial of Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib at Progression in Patients With Advanced BRAFV600 Mutant Melanoma

Objective The purpose of this research study is to compare the good and bad effects of the sequence of immunotherapy followed by BRAF inhibitor therapy if and when the disease becomes resistant, to the sequence of BRAF inhibitor therapy followed by immunotherapy if and when the disease becomes resistant.

Treatment The BRAF inhibitor component will include the combination of two drugs dabrafenib and trametinib that each have been approved by the FDA for the treatment of this patient population and have also been approved for use in combination due to superior effects relative to the single agent treatments. In addition, the study will involve the addition of the FDA approved agent nivolumab to the standard FDA approved ipilimumab immunotherapy in the hopes that it might further improve the good effects of the immunotherapy component of the treatment sequence. The combination of ipilimumab and nivolumab has been shown in recent studies to produce superior antitumor effects but also more side effects than ipilimumab alone. This combination has yet to receive FDA approval and is therefore still considered to be experimental.

Description This research study has two treatment regimens, with a potential to crossover from one to the other. Arm A will receive the study drugs ipilimumab and nivolumab first, and at time of disease progression will crossover to Arm C to receive the study drugs dabrafenib and trametinib. Arm B will receive the study drugs dabrafenib and trametinib first, and at time of disease progression will crossover to Arm D to receive the study drugs ipilimumab and nivolumab. Ipilimumab and Nivolumab are given intravenously. Dabrafenib and Trametinib are taken by mouth. If you are eligible for the study, a computer will assign you by chance to beginning therapy on one of the two treatment arms (A or B) in the research study. This is called randomization. This is done by chance because no one knows if one study arm is better or worse than the other. The ipilimumab/nivolumab combination will be given for a maximum of two years.

Key Eligibility
  • Age ≥ 18 years
  • Patients must have unresectable stage III or stage IV disease
  • Patients must have measurable disease
  • Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive
  • Patients must have BRAFV600 mutation
  • Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease
  • Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting ≥ 4 weeks prior to entering the study and recovered from adverse events due to those agents
  • Patients are ineligible if they have any currently active CNS metastases. Patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery (SRS)) that have been stable on head MRI or contrast CT scan for at least 4 weeks following treatment and within 4 weeks prior to randomization could be eligible
  • Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast
  • Patients must not have any serious or unstable pre-existing medical conditions
  • Individuals who are known to be HIV infected, active Hepatitis B Virus, or Hepatitis C are excluded
  • Patients must not have history of retinal vein occlusion
  • Patients must not have evidence of interstitial lung disease or pneumonitis
  • Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib

Applicable Disease Sites Melanoma/Skin cancer

Therapies Involved Immunotherapy; Other

Drugs Involved BMS-936558 (Nivolumab); Mekinist (Trametinib); Nivolumab; Opdivo (Nivolumab); Tafinlor (dabrafenib); Trametinib; Yervoy (ipilimumab); dabrafenib; ipilimumab

Status Open

Participating Institutions Aspirus UW Cancer Center (formerly Riverview Hospital); Johnson Creek, UW Cancer Center; UW Hospital and Clinics; UWCCC 1 South Park