A Phase I Trial of Combined PD-1 Inhibition (Pembrolizumab) and CCR5 Inhibition (Maraviroc) for the Treatment of Refractory Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- University Hospital Heidelberg
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Feasibility Rate of a Combined Therapy
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a monocentric, single arm, prospective, open-label trial of a combination treatment consisting of pembrolizumab and maraviroc in previously treated subjects who have refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Detailed Description
Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22). Treatment with pembrolizumab / maraviroc combination will continue until progressive disease (PD), unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, administrative reasons requiring cessation of treatment, or completion of treatment per protocol. Subjects with a treatment response or stable disease after completion of the first treatment phase of eight cycles (core treatment period) will be offered, at the discretion of the investigator, participation in a maintenance phase consisting of up to 24 additional treatment cycles of pembrolizumab monotherapy (total treatment duration up to 24 months). Subjects who discontinue for reasons other than PD will have post-treatment follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed for overall survival (OS) until death, withdrawal of consent, loss to follow-up, or the end of the study. After the end of treatment, each subject will be followed for 30 days for AE monitoring. Serious adverse events (SAEs) and AEs of special interest (AESIs) will be collected for 90 days after the end of treatment or for 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.
Investigators
Dirk Jäger
Prof. Dr.
University Hospital Heidelberg
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed metastatic colorectal cancer. Microsatellite stability (MSS) is confirmed by PCR or immunohistochemistry.
- •Patient failed standard therapy or is intolerable towards standard therapy which must include a fluoropyrimidine, oxaliplatin, irinotecan, an antiangiogenic monoclonal antibody (e.g. bevacizumab, aflibercept, ramucirumab), an EGFR inhibitor in case of RAS/BRAF wildtype tumors and optional regorafenib or TAS 102
- •Measurable disease as per RECIST 1.1
- •Metastatic lesion accessible for repetitive biopsies and patient willing to provide tissue from newly obtained biopsies. Patients without accessible lesions might be enrolled after discussion with the principle investigator.
- •ECOG performance status 0 or 1
- •Adequate hematological, hepatic and renal function parameters:
- •Leucocytes\> 3.000/μl
- •Hemoglobin \>9 g/dl
- •Thrombocytes \> 100.000/μl
- •Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or GFR ≥60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN
Exclusion Criteria
- •Inability to understand the aims of the study and/or protocol procedures
- •Hypersensitivity towards pembrolizumab, maraviroc, or any ingredients of the formulations administered
- •History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies
- •Any other concurrent antineoplastic treatment including irradiation (local radiation of single non-target lesions for palliation only allowed)
- •Active autoimmune disease requiring immunosuppressive therapy
- •Any condition requiring continuous systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
- •Secondary malignant disease during the last 5 years (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).
- •Clinical relevant comorbidity also including significant psychiatric disease
- •Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV
- •Cardiocirculatory insufficiency with hypotension (systolic blood pressure \<100 mmHg)
Arms & Interventions
Single arm, prospective, open-label trial
Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22).
Intervention: Pembrolizumab
Single arm, prospective, open-label trial
Eligible subjects will receive pembrolizumab beginning on Day 1 of each 3-week dosing cycle (d1, qd22) together with maraviroc administered perorally on day 1 to 21 of each cycle (d1-21; qd22).
Intervention: Maraviroc
Outcomes
Primary Outcomes
Feasibility Rate of a Combined Therapy
Time Frame: After core treatment period of 8 cycles (each cycle is 21 days)
Defined as the rate of patients receiving the protocol treatment according to the planned schedule without occurrence of at least one of the following events: Study treatment-related Grade ≥ 3 immune-related abnormalities; Study treatment-related Grade ≥ 4 AEs of any aetiology; Any toxic event leading to the premature withdrawal of protocol treatment
Secondary Outcomes
- Efficacy Endpoint: Progression-free Survival(through study completion (20 months))
- Efficacy Endpoint: Objective Response Rate(through study completion (20 months))
- Overall Survival(through study completion (20 months))
- Safety and Toxicity of a Combined Therapy Based on Subjects Who Experienced Toxicities(After core treatment period of 8 cycles (each cycle is 21 days))
- Efficacy Endpoint: Disease Control Rate(through study completion (20 months))