An Explorative Phase II Study of Anti-PD-1 (Pembrolizumab) Therapy in Metastatic Melanoma (ADAPTeM)
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Advanced Melanoma
- Sponsor
- Royal Marsden NHS Foundation Trust
- Primary Endpoint
- The percentage of patients that undergo serial core biopsies of metastatic lesions during treatment with Pembrolizumab
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
Abbreviated Title: An explorative Phase II study of Anti-PD-1 (Pembrolizumab) in patients with advanced melanoma (ADAPTeM)
Trial Phase: Phase II
Clinical Indication: Stage III unresectable/stage IV metastatic melanoma
Trial Type: Exploratory Phase II trial
Route of administration: Intravenous Pembrolizumab, 200mg, 3weekly
Trial Blinding: Unblinded; open label Phase II study
Treatment Groups: All participants treated with Pembrolizumab, 200mg iv, 3weekly
Number of trial subjects: 40
Estimated duration of trial: 24 months
Duration of Participation: 24 months
Detailed Description
This is a single arm, single agent, open label, exploratory translational research study in patients with unresectable stage III or stage IV melanoma being treated with Pembrolizumab. Suitable patients will undergo serial surgical core biopsies (nonradiological) of subcutaneous or lymph node metastases (as judged by an Oncological Surgical Consultant). As a primary endpoint, the investigators will assess the safety and feasibility of undergoing these biopsies within the patient cohort. A total of forty patients will be recruited over a period of two years. Patients who have provided consent and satisfied the eligibility criteria will undergo baseline CT scanning and peripheral blood sampling. At baseline, biopsies of suitable metastatic lesions will be undertaken and samples sent for histopathological assessment and analysis of molecular and immune parameters. Participants will be treated with Pembrolizumab, 200mg, intravenously, every 3 weeks. At 6 weeks following commencement of Pembrolizumab therapy, a further biopsy or excision of metastatic disease will be performed, unless considered no longer possible on the basis of a near or complete response to treatment. Blood sampling will be performed prior to each cycle and repeat CT scanning will occur every 9 weeks. Response evaluations will be performed according to RECIST 1.1 criteria. Pembrolizumab will be continued as long as study participants are deriving benefit and further biopsies of progressing lesions will be performed where possible. The investigators aim to evaluate the safety and feasibility of obtaining serial tumour biopsies or excisions of metastatic disease during treatment with Pembrolizumab with exploration of the i) mechanistic activity of Pembrolizumab, ii) identification of intratumoural and peripheral factors limiting response, iii) identification of candidate predictive biomarker panels based on (i) and (ii) and iii) use of circulating free DNA (cfDNA) as a surrogate marker of response and guide to duration of therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed metastatic melanoma (cutaneous or mucosal)
- •Male or female, 18 years or older
- •Presence of subcutaneous or lymph nodes metastases amenable to surgical core biopsy (as judged by an Oncological Surgical Consultant)
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumours (RECIST) 1.
- •Have provided tissue from an archival tissue sample or newly obtained core biopsy of a tumour lesion.
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •Any number of previous lines of treatment for metastatic melanoma including treatment naïve patients.
- •Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Female subjects of childbearing potential should 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 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
- •Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Exclusion Criteria
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., Grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Note: Subjects with Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Has a known additional malignancy that is progressing or requires active treatment.
- •Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Arms & Interventions
Pembrolizumab arm
All participants treated with Pembrolizumab, 200mg iv, 3weekly
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
The percentage of patients that undergo serial core biopsies of metastatic lesions during treatment with Pembrolizumab
Time Frame: At study progression (average of 9 months) or 24 months after last patient enrolled
The primary endpoint of the study is to assess the feasibility of obtaining sequential tumour biopsies will be achieved when sequential biopsies (at baseline, week 6 and at disease progression), have successfully been carried out in a minimum of 75% of patients (i.e. 29 out of 40).The percentage of patients with complete tumour response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) will be tabulated. Associated 95% CI will be provided for response rates. The duration of objective response (for patients with CR and PR) will be defined as the time from initial CR or PR to the time of disease progression or death (whichever occurs first). For patients who do not die or experience PD, duration of objective response will be censored on the day of the last tumour assessment.
Secondary Outcomes
- The complication rate associated with undergoing serial core biopsies(At study progression (average of 9 months) or 24 months after last patient enrolled)
- Objective response rate(At study progression (average of 9 months) or 24 months after last patient enrolled)
- Progression free survival(At study progression (average of 9 months) or 24 months after last patient enrolled)
- Overall survival(At study progression (average of 9 months) or 24 months after last patient enrolled)