A Parallel Arm, Biomarker Driven, Phase II Trial to Determine the Role of Circulating Tumour DNA in Guiding a Switch Between Targeted Therapy and Immune Therapy in Patients With Advanced Cutaneous Melanoma
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Melanoma
- Sponsor
- The Christie NHS Foundation Trust
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory
- Status
- Active, Not Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.
Detailed Description
The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors but not resistant have been shown to have increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with decreased response to immune therapy reduces, which may improve efficacy of immunotherapy. A precise definition of response is required in order to decide upon a switch to immune therapy. A radiological definition of response is currently the standard assessment. However a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response dynamics or allow decision making on an individual patient basis. The investigators have developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which are able to accurately monitor tumour burden over time. The aim of this pilot study is to provide a signal as to whether: 1. In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib. 2. Changes in ctDNA levels can be used to accurately inform when to switch from targeted to immune therapy. Data from this study will provide the basis for follow on studies with sufficient power to assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can improve efficacy of immune therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient capable of giving written informed consent
- •Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
- •Histological confirmation of cutaneous melanoma
- •Stage III un-resectable/ IV disease
- •BRAF p.V600E/K/R mutation confirmed (exact point mutation must be provided to the investigators)
- •At least one target lesion measurable by CT or MRI as per RECIST 1.1
- •Baseline ctDNA (as defined by the mutant BRAF VAF in plasma) ≥1.5%
- •Adequate organ function
- •ECOG performance status 0/1
- •Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drug
Exclusion Criteria
- •Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for unresectable Stage III or Stage IV melanoma.
- •Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1 inhibitor is allowed so long as relapse occurred \> 6 months from discontinuation of treatment and treatment not stopped due to grade 3 or 4 toxicity.
- •Current use of a prohibited medication
- •History of another malignancy. Exception: patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago) or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study.
- •Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patients safety, obtaining informed consent, or compliance with study procedures.
- •Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not active) HBV and HCV infection will be permitted).
- •A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- •Patients with active, known or suspected autoimmune disease. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to enrol.
- •Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
- •Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
Outcomes
Primary Outcomes
CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory
Time Frame: 12 months from last patient starting trial treatment
Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions
Decrease in ctDNA level of mutant BRAF≥80%
Time Frame: Through study completion, an average of 1 year
To assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% on targeted therapy is an appropriate cut off for switching to immune therapy
Secondary Outcomes
- Second progression free survival(When all patients finished follow up, 4 years after last patient starting treatment)
- Screen failure due to ctDNA levels of mutant BRAF VAF <1.5% Efficacy(Through study completion, an average of 1 year)
- First progression free survival(When all patients finished follow up, 4 years after last patient starting treatment)
- Overall survival(When all patients finished follow up, 4 years after last patient starting treatment)
- First progression free survival (PFS) at 12 months(Through study completion, an average of 1 year)