An Open-label, Single-arm, Phase I/II, Multicentre Study to Evaluate the Safety and Efficacy of the Combination of Dabrafenib, Trametinib and Palliative Radiotherapy in Patients with Unresectable (stage IIIc) and Metastatic (stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma
Overview
- Phase
- Phase 1
- Intervention
- Palliative radiotherapy
- Conditions
- Metastatic Melanoma
- Sponsor
- Melanoma and Skin Cancer Trials Limited
- Enrollment
- 10
- Locations
- 3
- Primary Endpoint
- Toxicity profile for patients receiving dabrafenib and trametinib in combination with RT, by measuring adverse events and radiotherapy associated toxicities.
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this study is to investigate the side effects and safety, and effectiveness of combining dabrafenib and trametinib with radiotherapy.
Previous and ongoing clinical trials have demonstrated the effectiveness and safety of combining both dabrafenib and trametinib compared with dabrafenib alone. This has led to the approval for the use of both drugs in combination in people with metastatic melanoma with the BRAF mutation. Melanoma that has spread to other parts of the body may also benefit from radiotherapy to help reduce symptoms from melanoma. Previous studies have shown that melanoma may be sensitive to radiotherapy and that it can help to improve quality of life.
The intention of the CombiRT study is to establish if dabrafenib, trametinib and radiotherapy combined is a safe and effective treatment for metastatic melanoma.
Investigators
Eligibility Criteria
Inclusion Criteria
- •≥18 years of age.
- •Signed written informed consent.
- •Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive as determined by a BRAF mutation assay.
- •Note: For Stage IIIC disease, the decision that the disease is unresectable should be formally endorsed by the melanoma multidisciplinary tumour board of the local institution.
- •Have received dabrafenib and trametinib for 2 weeks or more prior to enrolment in the study (i.e. first fraction of palliative RT), and is still continuing with dabrafenib and trametinib.
- •Symptomatic or bulky (greater than 2 cm in diameter) soft tissue, nodal or bony metastases requiring palliative RT.
- •Have measurable disease according to RECIST 1.1 criteria. Note: patients with bony metastases that are not measurable by RECIST 1.1 criteria are allowed in this study.
- •All anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1 in protocol) must be less than or equal to (≤) Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03; NCI, 2009) at the time of study enrolment.
- •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.
- •Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrolment and agree to use effective contraception, from 14 days prior to enrolment throughout the treatment period, and for 4 months after the last dose of study treatment.
Exclusion Criteria
- •Treatment with Ipilimumab or any other anti-CTLA-4 monoclonal antibody therapy within the past 4 weeks.
- •Treatment with anti-PD-1 or anti-PD-L1 monoclonal antibody therapy within the past 4 weeks.
- •Known ocular or primary mucosal melanoma.
- •Four (4) or more lesions requiring palliative RT at the time of study enrolment.
- •Symptomatic brain metastases or those treated \< 3 months previously.
- •Clear evidence of systemic disease progression on dabrafenib and trametinib.
- •Systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within the last 4 weeks. Prior interferon treatment in the adjuvant setting is allowed.
- •Note: Tamoxifen and aromatase inhibitors are allowed in the adjuvant setting of breast cancer.
- •Current use of a prohibited medication (list of prohibited medications in protocol).
- •History of malignancy other than disease under study within 3 years of study enrolment with exceptions below, or any malignancy with confirmed activating RAS mutation.
Arms & Interventions
Radiotherapy
Palliative radiotherapy in combination with dabrafenib and trametinib Eligible subjects are patients who have been on dabrafenib and trametinib for more than 2 weeks, as the current standard management for advanced stage melanoma. Palliative RT will be delivered to symptomatic or bulky (\>2cm) soft tissue, nodal or bony metastases concurrently with dabrafenib and trametinib. Up to 3 areas of disease can be irradiated at the same time. Following RT, dabrafenib and trametinib alone will be continued until disease progression according to RECIST 1.1 criteria.
Intervention: Palliative radiotherapy
Radiotherapy
Palliative radiotherapy in combination with dabrafenib and trametinib Eligible subjects are patients who have been on dabrafenib and trametinib for more than 2 weeks, as the current standard management for advanced stage melanoma. Palliative RT will be delivered to symptomatic or bulky (\>2cm) soft tissue, nodal or bony metastases concurrently with dabrafenib and trametinib. Up to 3 areas of disease can be irradiated at the same time. Following RT, dabrafenib and trametinib alone will be continued until disease progression according to RECIST 1.1 criteria.
Intervention: Dabrafenib and trametinib (combination)
Outcomes
Primary Outcomes
Toxicity profile for patients receiving dabrafenib and trametinib in combination with RT, by measuring adverse events and radiotherapy associated toxicities.
Time Frame: 0-12 months
Secondary Outcomes
- Overall disease response by measuring progression free survival and overall survival.(0-12 months)
- Local treatment response in the irradiated index lesion(s).(0-12 months)
- Patients' pain using a visual analog scale (questionnaire)(0-12 months)
- Time to local progression in the irradiated index lesion(s).(0-12 months)