Phase II Neoadjuvant Study of PD-1 Inhibitor Pembrolizumab in PD-1 Naive Cutaneous Squamous Cell Carcinoma (cSCC)
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab Injection
- Conditions
- Squamous Cell Carcinoma
- Sponsor
- Diwakar Davar
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Pathologic Response
- Status
- Active, not recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
This phase II single-arm two-stage neoadjuvant study of pembrolizumab in patients with PD-1 naïve high-risk resectable cutaneous squamous cell carcinoma (cSCC) will be conducted over a 52-week period. The study will include patients who have not undergone surgery to remove disease, to formally evaluate whether both biologically and clinically high-risk disease may benefit from neoadjuvant anti-PD-1 therapy. Response to neoadjuvant anti-PD-1 therapy will be evaluated for association with improved landmark Relapse-free Survival (RFS).
Detailed Description
Patients with high-risk resectable cSCC who have yet to undergo definitive surgery will be eligible to enroll. Patients with nodal and/or in-transit relapse including those who have received prior adjuvant RT are eligible to enroll. This trial excludes patients who have received either nivolumab or pembrolizumab or other anti-PD-(L)1 therapy. Suitable patients will be identified pre-operatively. Patients will undergo a 28-day screening evaluation consisting of systemic staging scans, tumor biopsy, and blood studies to confirm suitability. Once enrolled, patients will receive pembrolizumab peri-operatively for 6 weeks (200mg Q3Wq3; 2 cycles) prior to definitive surgery (Neoadjuvant Phase). Following peri-operative therapy, patients will undergo restaging scans and surgical evaluation followed by definitive surgical resection (Surgical Phase). Post-operatively, patients will receive 15 further cycles of pembrolizumab over a 45-week period (200mg q3Q3W) (Adjuvant Phase). In the post-operative period, if patients are deemed eligible for RT, this will be administered concurrently with pembrolizumab. The total duration of pembrolizumab therapy is 1 year (52 weeks).
Investigators
Diwakar Davar
Assistant Professor of Medicine
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of high-risk localized or locooregional cSCC as defined below may be enrolled in this study.
- •NOTE: Patients are eligible for this trial either at initial presentation for cSCC with locally advanced and/or concurrent regional nodal metastasis; or at the time of recurrence with locally advanced and/or concurrent regional nodal metastasis assuming following criteria are met per the cSCC-specific AJCC UICC 8th edition staging classification
- •i. T2 and Nx and M0 (tumor \>2 cm and ≤4 cm in greatest dimension) OR;
- •ii. T3 and Nx and M0 (tumor \>4 cm or minor bone erosion or perineural invasion or deep invasion) OR;
- •Deep invasion is defined as invasion beyond the subcutaneous fat or \>6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor).
- •Perineural invasion is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.
- •iii. T4 and Nx and M0 (tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion if deemed surgically resectable) OR;
- •iv. Tx and N1-3 and M0 (if deemed surgically resectable) OR;
- •i. If T2, tumors must possess ≥2 NCCN/BWH clinical or pathologic risk factor(s) as stated below.
- •ii. NCCN/BWH clinical risk factors:
Exclusion Criteria
- •Diagnosis of immunodeficiency, immunosuppression and/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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
- •Prior chemotherapy, targeted small molecule 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.
- •Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- •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 the first dose of study intervention.
- •A WOCBP who has a positive urine pregnancy test at Screening. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Has received a live vaccine within 30 days prior to the first dose of study drug.
- •Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
- •Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug.
Arms & Interventions
Pembrolizumab
Neoadjuvant Phase: 200 mg IV infusion, every 3 weeks (Day 1 of each 3-week cycle, 2 cycles) Adjuvant Phase: Day 1 of each 3-week cycle, 15 cycles
Intervention: Pembrolizumab Injection
Outcomes
Primary Outcomes
Pathologic Response
Time Frame: At time of surgery, up to 6 weeks post-baseline
Percentage of patients with either pathologic complete response (pCR) or partial pathologic response (pPR) per Immune-Related Pathologic Response Criteria (immunotherapy-specific pathologic response criteria (irPRC) criteria. Per (irPRC), pCR = 0% residual viable tumor (RVT) remaining in post-therapy specimen (no signs of cancer) in tissue samples removed during surgery, and pPR = \>10% but ≤50% RVT remaining in post-therapy specimen in tissue samples removed during surgery.
Response Assessment Per Immune-Related Pathologic Response Criteria (irPRC)
Time Frame: At time of surgery
Number of patients with pathologic complete response (pCR), partial pathologic response (pPR), pathologic non-response (pNR) per Immune-Related Pathologic Response Criteria ((irPRC) criteria. Per (irPRC), pCR = 0% residual viable tumor (RVT) (no signs of cancer), pPR = \>10% but ≤50% RVT, or pNR = \>50% RVT remaining in post-therapy specimen tissue samples removed during surgery.
Secondary Outcomes
- Overall Survival (OS)(Up to 84 months)
- Progression-free Survival (PFS)(Up to 60 months)
- 1-year PRS(Up to 12 months)
- 6-month PFS(Up to 6 months)
- 2-year PFS(Up to 24 months)
- 3-year PFS(Up to 36 months)
- 1-year OS(Up to 12 months)
- 2-year OS(Up to 24 months)
- Pathologic Response(From start of treatment, up to 24 months)