Nivolumab Alone or Plus Relatlimab or Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma

Study Overview
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Brief Summary
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This is a phase 2 trial assessing the efficacy of nivolumab, alone or in combination with relatlimab or ipilimumab in treating patients with locally-advanced unresectable or metastatic basal cell carcinoma.

Detailed Description
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This is an open-label, phase 2 signal-seeking study. Screening will begin by establishing a participant's initial eligibility and signing of the informed consent document. Eligible, enrolled patients will be assigned to one of 3 cohorts in a non-randomized fashion according to prior treatment history. Cohort A: Patients who have not received prior systemic therapy to treat BCC (e.g., anti-PD-1 therapy or hedgehog signaling pathway inhibitors) will receive nivolumab 480 mg IV every 4 weeks for up to 48 weeks. Cohort B: Patients who have refractory BCC to anti-PD-(L)1 monotherapy (Cohort A or off study) and nivolumab + relatlimab (Cohort C). Patients who have received prior hedgehog pathway inhibitors are eligible. If Cohort C is filled, the nivolumab + relatlimab requirement listed above no longer applies. Patients will receive nivolumab 240mg IV + ipilimumab 1mg/kg IV every 3 weeks x 4 doses, then nivolumab 480mg IV every 4 weeks x 7 doses starting 6 weeks after the final dose of ipilimumab + nivolumab. Cohort C: Patients who have anti-PD-(L)1-refractory BCC (defined as PD or ongoing SD at 36 weeks) BCC after receiving anti-PD-(L)1 monotherapy on Cohort A or outside the study, without prior hedgehog pathway inhibitor treatment. Patients will receive nivolumab 480mg IV + relatlimab 480mg IV every 4 weeks for up to 48 weeks. Patients enrolled on Cohort A who demonstrate PD after nivolumab monotherapy may, if appropriate in the opinion of the investigator, move to Cohort B or Cohort C. Discontinuation of nivolumab or ipilimumab +nivolumab or relatlimab + nivolumab may be at the discretion of the investigator under circumstances including but not limited to the following: A complete response to therapy. A severe IMAR, defined as Grade 3 or greater. Documented disease progression warranting alternative systemic therapy Intercurrent illness that prevents further administration of study treatment Noncompliance with trial treatment or procedure requirements, or administrative reasons

Official Title
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Nivolumab Alone or Plus Relatlimab or Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma

Conditions
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Basal Cell Carcinoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Relatlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Written Informed Consent Subjects must have signed and dated an Institutional Review Board (IRB)-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study Type of Participant and Target Disease Characteristics Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Participants with histologically confirmed Basal Cell Carcinoma with disease that is considered by the investigator to be unresectable or metastatic. i. COHORT A: Patients with advanced BCC who have not received prior systemic therapy to treat BCC (e.g., hedgehog pathway inhibitors and T cell modulating agents). ii. COHORT B: Patients who have refractory BCC (defined as PD or ongoing SD at 36 weeks) after receiving anti-PD-(L)1 monotherapy on CA209-8DP (i.e., on Cohort A) or outside the study, and refractory BCC (defined as above) after relatlimab + nivolumab. Patients who have received prior hedgehog pathway inhibitors are eligible. If Cohort C is filled, the relatlimab + nivolumab requirement listed above no longer applies. iii. COHORT C: Patients with anti-PD-(L)1-refractory BCC (defined as PD or ongoing SD at 36 weeks) after receiving anti-PD-(L)1 monotherapy on CA209-8DP (Cohort A) or outside the study, without prior hedgehog pathway inhibitor treatment. c. Patients may not have received prior T cell modulating agents (e.g., anti-CTLA-4, anti-PD-L1, anti-LAG-3, anti-KIR, etc.), except anti-PD-1 per ARM B specifications, above. d. At least one measurable lesion by the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1) e. Participants with Gorlin syndrome will be permitted to enroll in the study. f. Male or female, aged 18 years or older Laboratory Testing Requirements Screening laboratory values obtained within -28 +/- 3 days of first dose must meet the following criteria: White Blood Cells greater than or equal to 2000/μL Neutrophils greater than or equal to 1500/μL Platelets greater than or equal to 100 x 10³/μL Hemoglobin greater than or equal to 9.0 g/dL Serum creatinine less than or equal to 1.5 x Upper Limit of Normal (ULN)or creatinine clearance (CrCl) greater than or equal to 40 mL/minute (using Cockcroft/Gault formula) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN, except in patients with liver metastases whose values may be less than or equal to 5 x ULN Total Bilirubin less than or equal to 1.5 x ULN (except subjects with Gilbert Syndrome who may have total bilirubin less than or equal to 3.0 mg/dL) Reproductive Status Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the initial administration of study drug, then every 4 weeks +/- 1 week thereafter for the duration of treatment with study drug(s). Women must not be breastfeeding. WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus approximately 5 half-lives of study drug(s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment completion. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus approximately 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion. Azoospermic males and those who are continuously not heterosexually active are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, however they must still undergo pregnancy testing as described in this section. Exclusion Criteria: Medical Conditions Pregnant or nursing women Central nervous system metastases, unless stable for at least 4 weeks and no longer requiring steroid therapy. Patients with an autoimmune disease or with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications may be permitted to enroll only after discussion with the study P.I. Participants with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) Viral hepatitis i. Participants with active hepatitis B (positive hepatitis B surface antigen [HBsAg] or hepatitis C virus (HCV) (positive HCV RNA) are excluded ii. Patients with past Hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and the absence of HBsAg) are not ineligible, but HBV DNA quantification must be performed and results discussed with the P.I. iii. HBV carriers or those participants requiring antiviral therapy are not eligible to participate. iv. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA after discussion with the study P.I. f. Participants with a prior malignancy active within the previous 2 years may be permitted to enroll only after discussion with the study P.I. Examples might include locally curable cancers that have been apparently cured, such as squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. g. Organ transplant recipients with a functioning allograft will be excluded from this study. h. For Cohorts B and C, patients may be excluded from the study if they previously experienced a toxicity to immunotherapy that, in the opinion of the investigator, would make it unsafe to restart therapy. Examples may include a Grade 3 or greater immune mediated adverse event that was considered related to previous immunotherapy and required immunosuppressive therapy, or an immune mediated adverse event that was considered related to previous immunotherapy and is still > grade 1 despite administration of immunosuppressive therapy. Exceptions may include Grade 3 ophthalmologic immune-mediated events that improved to Grade 1 within 2 weeks after topical therapy only, or Grade 3 endocrine immune-mediated events that did not result in symptoms lasting >6 weeks and are not requiring >7.5mg prednisone or equivalent per day. Allergies and Adverse Drug Reaction History of severe allergy or hypersensitivity to study drug components. Patients with a history of a severe toxicity to an immune checkpoint blocking drug may be permitted to enroll only after discussion with the study P.I. Other Exclusion Criteria Prisoners or participants who are incarcerated may be permitted to enroll only after discussion with the study P.I. Participants who are detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Patients from Arm A can crossover to Arm B or Arm C
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Previous Systemic Therapy Patients<br>Cohort A: Nivolumab 480mg IV q4weeks for up to 48 weeks (six 8-week cycles) | Drug: Nivolumab<br>* 480mg IV every 4 weeks<br>* Other names: Opdivo;|
| Experimental: Progression after anti-PD-1 therapy (Cohort A) and Cohort C<br>Cohort B: Nivolumab 240mg IV + ipilimumab 1mg/kg IV q3 weeks x 4 doses, then nivolumab 480mg IV q4 weeks x 7 doses for up to 48 total weeks of therapy. | Drug: Nivolumab<br>* 480mg IV every 4 weeks<br>* Other names: Opdivo;Drug: Ipilimumab<br>* 1mg/kg IV every 4 weeks for 4 doses<br>* Other names: Yervoy;|
| Experimental: Progression after anti-PD-1 therapy (Cohort A)<br>Cohort C: Nivolumab 480 mg IV q4 weeks plus relatlimab 480 mg IV q4 weeks for up to 48 weeks. | Drug: Nivolumab<br>* 480mg IV every 4 weeks<br>* Other names: Opdivo;Drug: Relatlimab<br>* 480 mg IV q4wks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective response rate per the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival | duration of time from start of treatment to time of progression or Basal Cell Carcinoma specific death, whichever occurs first | 5 years | 
| duration of response | duration of time that measurement criteria are met for Complete Response or Partial Response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented | 5 years | 
| overall survival | measured from the time of enrollment until death | 5 years |