A Randomised Phase II Study of Pembrolizumab With or Without Bevacizumab in Platinum-resistant Recurrent/Metastatic Nasopharyngeal Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- pembrolizumab
- Conditions
- Locally Recurrent Cancer
- Sponsor
- National University Hospital, Singapore
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Primary endpoint of ORR
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a single center, randomized, phase Ib/II open-label study of pembrolizumab (pembro or MK-3475) with or without bevacizumab in patients with recurrent non-curable or metastatic nasopharyngeal carcinoma (NPC).
Detailed Description
The study will consist of 2 treatment arms. In Treatment Arm A, patients will be treated with intravenous pembrolizumab alone, 21-day cycle. For Treatment Arm B, patients will receive intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle). Each treatment cycle is 3 weeks. Up to 48 patients will be enrolled in this study in 2 stages. The first stage will consist of 30 patients and the remaining 18 patients will be added if interim data looks promising. Eligible patients will be randomized 1:1 into either Treatment Arm A or Arm B. Treatment will continue until tumor progression, intolerance to treatment, or up to 2 years (32 doses of pembrolizumab/bevacizumab). For patients who have progressed on pembrolizumab alone, cross over to Arm B is allowed, with repeat biopsy of the lesions before and 1 week after starting bevacizumab. Patients who discontinue from the trial will not be replaced. The study will collect serial samples of tumor tissue and blood to determine the PD biomarkers of immune activation, in the tumor and systemically, following treatment. This is expected to provide preliminary evidence for immune stimulation using both pembrolizumab and bevacizumab in NPC. The tumor biopsies will also present an opportunity to determine the molecular details of tissue and tumor response to anti-angiogenic therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants are eligible to be included in the study only if all of the following criteria apply:
- •The participant (or legally acceptable representative if applicable) provides written consent for the trial.
- •Participants who are at least 21 years of age on the day of signing informed consent with histologically or cytologically confirmed diagnosis of non-keratinizing nasopharyngeal carcinoma (NPC) that has recurred at loco regional and/or distant sites will be enrolled in this study.
- •Have measurable disease based on RECIST 1.
- •Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Have locally or centrally determined EBV-positive NPC by EBV-encoded small RNA in situ hybridization (EBER in situ hybridization \[ISH\]) assay. If EBV-positive status has been previously determined by EBER ISH assay, then no re-testing is required. Note: If EBV status by EBER ISH assay has not been previously determined, tumor tissue from archival tissue may be submitted for EBV determination.
- •Received one or more lines of chemotherapy, which must include prior treatment with a platinum agent and must not be amenable to potentially curative radiotherapy or surgery.
- •Have provided archival tumor tissue sample of newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
- •Willingness to donate blood and tissue for mandatory translational research studies.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion Criteria
- •Participants are excluded from the study if any of the following criteria apply:
- •Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. Note: Participants must have recovered from all AEs to previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
- •Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study treatment.
- •Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
- •Has a condition requiring systemic steroid therapy (\> 10 mg daily prednisone equivalents) or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \< or = 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayedtype hypersensitivity reaction caused by contact allergen) is permitted.
- •Has a known history of active TB (Bacillus Tuberculosis).
- •Has had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, antiCTLA-4 antibody.
- •Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
- •Has hypersensitivity to bevacizumab or any of its components.
- •Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
Arms & Interventions
Treatment Arm A
Intravenous pembrolizumab alone,D8 of 21-day cycle.
Intervention: pembrolizumab
Treatment Arm B
Intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle).
Intervention: pembrolizumab
Treatment Arm B
Intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle).
Intervention: bevacizumab
Outcomes
Primary Outcomes
Primary endpoint of ORR
Time Frame: 2 years
Comparison of the two treatment arms will be evaluated using the Fisher's exact test. The treatment effect will be quantified via the relative risk estimate and its associated 95% confidence interval (CI).
Progression free survival (PFS)
Time Frame: 2 years
This is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging assessment or death due to any cause, whichever occurs earlier.
The secondary endpoint of PFS
Time Frame: 2 years
This will be summarized using the Kaplan-Meier survival estimate for each group. As an exploratory analysis, the log-rank test will be used for comparing differences in PFS, with its effect quantified based on hazard ratio and its 95% CI.