PD-1 in Patients With Advanced Basal Cell Carcinoma Who Experienced Progression of Disease on Hedgehog Pathway Inhibitor Therapy, or Were Intolerant of Prior Hedgehog Pathway Inhibitor Therapy

• ClinicalTrials.gov Identifier: NCT03132636
• Recruitment Status: Completed
• First Posted: April 28, 2017
• Results First Posted: July 26, 2022
• Last Update Posted: June 18, 2023
• Sponsor: Regeneron Pharmaceuticals
• Collaborator: Sanofi
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: April 24, 2017
• First Posted Date: April 28, 2017
• Results First Submitted Date: May 17, 2022
• Results First Posted Date: July 26, 2022
• Last Update Posted Date: June 18, 2023
• Actual Study Start Date: June 29, 2017
• Actual Primary Completion Date: May 20, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 17, 2022)

Objective Response Rates (ORR) as Assessed by Independent Central Review (ICR) [ Time Frame: Up to 1422 days ]

ORR was defined as percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1 assessed as per ICR assessment. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm) (< 1 centimeter [cm]). PR: At least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. ORR was determined by Clopper-Pearson method.

Original Primary Outcome Measures (submitted: April 24, 2017)

• Overall Response Rate (ORR) for metastatic Basal Cell Carcinoma (BCC) [ Time Frame: Baseline to 93 weeks ]
  ORR for metastatic BCC measured by RECIST version 1.1
• ORR for unresectable locally advanced BCC [ Time Frame: Baseline to 93 weeks ]
  ORR for unresectable locally advanced BCC measured by Composite Response Criteria

Current Secondary Outcome Measures (submitted: June 30, 2022)

• Duration of Response (DOR) Per ICR [ Time Frame: Up to 40 months ]
  DOR per ICR was determined for participants with best overall response of CR or PR. DOR was measured from the time measurement criteria are first met for CR/PR (whichever was first recorded) until the first date of recurrent or progressive disease (PD) (photographic or radiographic), or death due to any cause. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). DOR was determined by Kaplan-Meier estimate.
• Duration of Response (DOR) Per Investigator Assessment [ Time Frame: Up to 40 months ]
  DOR per investigator assessment was determined for participants with best overall response of CR or PR. DOR was measured from the time measurement criteria are first met for CR/PR (whichever was first recorded) until the first date of recurrent or progressive disease (PD) (photographic or radiographic), or death due to any cause. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). DOR was determined by Kaplan-Meier estimate.
• Progression Free Survival (PFS) Determined by ICR [ Time Frame: Up to 40 months ]
  PFS was defined as the time from start of treatment until the first date of recurrent or PD (photographic or radiographic), or death due to any cause, whichever occurred first, was determined by IRC. PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). PFS was determined by Kaplan-Meier estimate.
• Progression Free Survival (PFS) Determined by Investigator Assessment [ Time Frame: Up to 40 months ]
  PFS was defined as the time from start of treatment until the first date of recurrent or PD (photographic or radiographic), or death due to any cause, whichever occurred first, was determined by IRC. PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). PFS was determined by Kaplan-Meier estimate.
• Overall Survival (OS) [ Time Frame: Up to 40 months ]
  OS was measured as time from the start of treatment until death due to any cause. Participants who do not die was censored at the last date that participant was documented to be alive. OS was calculated based on Kaplan-Meier method.
• Percentage of Participants With Complete Response (CR) Rate Assessed by ICR [ Time Frame: Up to 1422 days ]
  CR rate by ICR was determined by the percentage of participants with best overall response of CR. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm).
• Change From Baseline of Patient-reported Outcomes in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: Baseline (Day 1 of Cycle 1); Day 1 of Cycles 2 to 9 (Cycles 1-5 [Each cycle of 9 weeks], Cycles 6 to 9 [Each cycle of 12 weeks]) ]
  The EORTC QLQ-C30 is a 30-item questionnaire used to assess the overall QoL in cancer participants. It consists of 15 domains: 1 Global Health Status (GHS)/QoL scale, 5 functional scales (Physical, role, cognitive, emotional, social), 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). Most items are scored 1 ("not at all") to 4 ("very much") except for the items contributing to the GHS/QoL, which are scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that all transformed scores lie between 0 to 100. For the GHS/QoL and 5 functional scales a higher score indicates higher ("better") quality of life/functioning and a positive change from baseline indicates improvement. For the symptom scales/items, a higher score indicates a higher ("worse") level of symptoms/problems, and a negative change from baseline indicates improvement.
• Change From Baseline of Patient-reported Outcomes in Skindex-16 Questionnaire [ Time Frame: Baseline (Day 1 of Cycle 1); Day 1 of Cycles 2 to 9 (Cycles 1-5 [Each cycle of 9 weeks], Cycles 6 to 9 [Each cycle of 12 weeks]) ]
  Skindex-16 questionnaire contains 16 questions related to quality of life in cancer participants. It consisted of a short 16-item assessment completed by the participant, with each item rated on a 7-point Likert scale (0=never bothered to 6=always bothered). Each raw score is multiplied by 16.667 to transform all responses to a linear scale from 0 (no effect) to 100 (effect experienced all the time). Responses to the Skindex-16 are categorized into 3 subscales: symptom, emotional & functional; their respective scores are expressed in a linear scale from 0 to 100. Symptoms scale score was an average of items 1 to 4 expressed in a linear scale from 0 to 100, Emotions scale score was an average of items 5 to 11 expressed in a linear scale from 0 to 100 and Functioning scale score was an average of items 12 to 16 expressed in a linear scale from 0 to 100. A negative change from baseline indicates an improvement in the participants condition compared to the baseline.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Up to 1422 days ]
  An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as AEs that developed or worsened during the on-treatment period and treatment-related AEs that occur during post-treatment period. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious TEAEs.
• Serum Concentration at End of Infusion (Cmax) of Cemiplimab [ Time Frame: At end-of-infusion (within 10 minutes after the end of infusion) on Cycle 1 Day 1 and Cycle 3 Day 1 (Each cycle of 9 weeks) ]
  Cmax of cemiplimab was reported.
• Serum Concentration at Pre-infusion (Ctrough) of Cemiplimab [ Time Frame: At pre-infusion on Cycle 1 Day 22 and Cycle 3 Day 1 (Each cycle of 9 weeks) ]
  Ctrough of cemiplimab was reported.
• Number of Participants With Anti-Drug Antibody (ADA) Status [ Time Frame: Cycle 1: Days 1 and 43; Cycles 3 and 5: Day 1 (Each cycle of 9 weeks) ]
  Immunogenicity was characterized by ADA responses & titers. Responses categories: Negative - ADA negative response at all time points, regardless of missing samples; Pre-existing immunoreactivity - ADA positive response at baseline with all post first dose negative results or positive response at baseline with all post first dose ADA responses < 9-fold over baseline titer levels; Treatment-boosted response - positive response in the assay post first dose, ≥ 9-fold over baseline titer levels, when baseline results are positive; Treatment-emergent response - ADA positive response in the cemiplimab ADA assay post first dose when baseline results = negative or missing.

Original Secondary Outcome Measures (submitted: April 24, 2017)

• Duration of Response (DOR) [ Time Frame: Time from the first observed confirmed response to disease progression or death, up to approximately 119 weeks ]
  DOR assessed by time from the first observed confirmed response (CR or PR) to disease progression or death, up to approximately 119 weeks (from first response assessment until end of post-treatment follow up)
• Complete Response (CR) Rate [ Time Frame: From date of treatment until best overall response of CR after starting REGN2810, up to approximately 119 weeks ]
  CR rate (per central review) assessed from date of treatment until best overall response of CR after starting REGN2810 treatment, up to approximately 119 weeks (from first response assessment until end of post-treatment follow up).
• Progression Free Survival (PFS) [ Time Frame: From date of treatment until date of death up to approximately 119 weeks ]
  PFS assessed from date of treatment until date of death, up to approximately 119 weeks
• Overall Survival (OS) [ Time Frame: From date of treatment until date of death, up to approximately 119 weeks ]
  OS assessed from date of treatment until date of death, up to approximately 119 weeks
• Change in scores of patient-reported outcomes in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: From date of treatment until date of first documented progression or date of death, up to approximately 93 weeks ]
  Change in scores of patient-reported outcomes in EORTC QLQ-C30 assessed from date of treatment until date of first documented progression or date of death, up to approximately 93 weeks
• Change in scores of patient-reported outcomes in Skindex-16 [ Time Frame: From date of treatment until date of first documented progression or date of death, up to approximately 93 weeks ]
  From date of treatment until date of first documented progression or date of death, assessed up to approximately 93 weeks

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PD-1 in Patients With Advanced Basal Cell Carcinoma Who Experienced Progression of Disease on Hedgehog Pathway Inhibitor Therapy, or Were Intolerant of Prior Hedgehog Pathway Inhibitor Therapy
• Official Title: A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to Programmed Death-1, in Patients With Advanced Basal Cell Carcinoma Who Experienced Progression of Disease on Hedgehog Pathway Inhibitor Therapy, or Were Intolerant of Prior Hedgehog Pathway Inhibitor Therapy
• Brief Summary: The primary objective is to estimate the objective response rate (ORR) for metastatic Basal Cell Carcinoma (BCC) (group 1) and for unresectable locally advanced BCC (group 2) when treated with cemiplimab as a monotherapy
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Basal Cell

Intervention

Drug: cemiplimab

Regimen as per protocol

Other Names:

• REGN2810
• Libtayo

Study Arms

• Experimental: Group 1- metastatic BCC
  Administration of cemiplimab in accordance with protocol dosing regimen
  Intervention: Drug: cemiplimab
• Experimental: Group 2 - unresectable locally advanced BCC
  Administration of cemiplimab in accordance with protocol dosing regimen
  Intervention: Drug: cemiplimab

Publications *

• Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Kaatz M, Lewis KD, Basset-Seguin N, Chang ALS, Dalle S, Orland AF, Licitra L, Robert C, Ulrich C, Hauschild A, Migden MR, Dummer R, Li S, Yoo SY, Mohan K, Coates E, Jankovic V, Fiaschi N, Okoye E, Bassukas ID, Loquai C, De Giorgi V, Eroglu Z, Gutzmer R, Ulrich J, Puig S, Seebach F, Thurston G, Weinreich DM, Yancopoulos GD, Lowy I, Bowler T, Fury MG. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):848-857. doi: 10.1016/S1470-2045(21)00126-1. Epub 2021 May 14.
• Li R, Lee G, Huang M, El-Sherief A. Rare basal cell metastasis of a basal-squamous skin collision tumour to the lung and axillary lymph node. BMJ Case Rep. 2019 Oct 3;12(10):e231487. doi: 10.1136/bcr-2019-231487.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 17, 2022): 138
• Original Estimated Enrollment (submitted: April 24, 2017): 137
• Actual Study Completion Date: April 27, 2023
• Actual Primary Completion Date: May 20, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Confirmed diagnosis of invasive BCC
• Progression of disease on hedgehog inhibitor (HHI) therapy or intolerance of prior HHI therapy
• At least 1 measurable lesion
• ≥18 years of age
• Hepatic function, renal function, bone marrow function in defined lab-value-ranges
• Anticipated life expectancy >12 weeks
• Consent to provide archived tumor biopsy material (all patients)
• Group 2: consent to undergo research biopsies
• Group 2: must not be a candidate for radiation therapy or surgery
• Comply with study procedures and site visits
• Sign Subject Information Sheet and Informed Consent Form

Key Exclusion Criteria:

• Ongoing or recent significant autoimmune disease
• Prior treatment with specific pathway-blockers (PD-1/PD-L1)
• Prior treatment with immune-modulating agents within 28 days before cemiplimab
• Untreated brain metastasis that may be considered active
• Immunosuppressive corticosteroid doses (>10mg prednisone) within 28 days prior to treatment with cemiplimab
• Active infections requiring therapy, including HIV, hepatitis
• Pneumonitis within the last 5 years
• Cancer treatment other than radiation therapy, including investigational or standard of care, within 30 days prior to treatment with cemiplimab
• Documented allergic reactions or similar to antibody treatments
• Concurrent malignancies other than BCC, other than those with negligible risk of metastases or death
• Any acute or chronic psychiatric problems
• Having received a solid organ transplantation
• Inability to undergo contrast radiological assessments
• Breastfeeding, pregnant, women of childbearing potential not using contraception

Note: Other protocol-defined inclusion/exclusion criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, France, Germany, Greece, Italy, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT03132636
• Other Study ID Numbers: R2810-ONC-1620; 2016-003122-16 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Regeneron Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Regeneron Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Sanofi

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: June 2023