Carcinoma, Squamous Cell, Skin Neoplasms
Conditions
Keywords
pembrolizumab
Brief summary
This is a two-part (Phase 2/Phase 3) study of intismeran autogene, an individualized neoantigen therapy (INT), plus pembrolizumab in participants with locally resectable advanced cutaneous squamous cell carcinoma (LA cSCC). Phase 2 has three arms intismeran autogene plus pembrolizumab given as neoadjuvant and adjuvant treatment with standard of care (SOC), standard of care (surgical resection with/without adjuvant radiation therapy (RT) only at investigator's discretion) and pembrolizumab monotherapy given as neoadjuvant and adjuvant treatment with SOC. This phase will assess the safety and efficacy of intismeran autogene in combination with pembrolizumab as neoadjuvant and adjuvant therapy in participants with resectable LA cSCC as compared to standard of care SOC only. The primary hypothesis is that intismeran autogene plus pembrolizumab with SOC is superior to SOC only with respect to event free survival (EFS) as assessed by the investigator. Phase 3 expansion will be determined by prespecified Go-No-Go decision in which 412 additional participants will be randomized to intismeran autogene plus pembrolizumab with SOC and SOC only, without changing the inclusion/exclusion criteria for the additional enrollment or study endpoints. As of Amendment 04, enrollment was stopped and there will be no Phase 3 expansion.
Interventions
BIOLOGICALPembrolizumab
IV Infusion
BIOLOGICALIntismeran autogene
IM injection
PROCEDURESurgery
Local resection of cancerous lesions of the skin
Sponsors
Merck Sharp & Dohme LLC
ModernaTX, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically confirmed diagnosis of resectable cSCC as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted). * Has LA Stage II-IV (M0) cSCC without distant metastases. * cSCC must be amenable to surgery (resectable) with curative intent. * Has a formalin-fixed, paraffin-embedded (FFPE) tumor sample available or is able to provide one that is suitable for the Next-generation Sequencing (NGS) required for this study. * For males, agrees to be abstinent from penile-vaginal intercourse OR agrees to use a highly effective contraceptive method while receiving adjuvant radiation therapy (RT), and for ≥3 months after the last dose of study intervention * Is female and not pregnant/breastfeeding and at least one of the following applies during the study : is not a woman of childbearing potential (WOCBP), is a WOCBP and uses highly effective contraception (low user dependency method OR a user dependent hormonal method in combination with a barrier method) at least during use of intismeran autogene: 15 days, Pembrolizumab: 120 days, Adjuvant RT, if performed: 90 days after last exposure or is a WOCBP who is abstinent from heterosexual intercourse. * Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. * Has a life expectancy of \>3 months per investigator assessment. * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 14 days before randomization. * Has adequate organ function. * If hepatitis B surface antigen (HBsAg) positive, must have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization * If there is a history of hepatitis C virus (HCV) infection, HCV viral load must be undetectable at screening * If human immunodeficiency virus (HIV)-infected, must have well controlled HIV on antiretroviral therapy (ART)
Exclusion criteria
* Has any other histologic type of skin cancer other than invasive cSCC as well as mixed histology, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen's disease, Merkel cell carcinoma (MCC), or melanoma * Has distant metastatic disease (M1), visceral and/or distant nodal * Has received prior therapy with an anti-programmed cell death receptor 1 (anti-PD-1), anti-programmed cell death receptor ligand 1 (anti-PD-L1), or anti-programmed cell death receptor ligand 2 (anti-PD-L2) agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte associated protein 4 (CTLA-4), OX-40, CD137) * Has received prior systemic anticancer therapy including investigational agents for cSCC before randomization * Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention * Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 2 weeks of the screening blood sample (including the NGS blood sample) * Has received prior treatment with another cancer vaccine * Has received prior radiotherapy to the index lesion (in-field lesion). Must have recovered from all radiation-related toxicities prior to randomization and not have had radiation pneumonitis * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration * 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 7 days prior the first dose of study medication * Has a known additional malignancy that is progressing or has required active treatment within the past 2 years * History of chronic lymphocytic leukemia (CLL) * History of central nervous system (CNS) metastases and/or carcinomatous meningitis * Has severe hypersensitivity (≥Grade 3) to either intismeran autogene or pembrolizumab and/or any of its excipients * Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed * History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * Has an active infection requiring systemic therapy * Has HIV with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease * Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection * Has had a myocardial infarction within 6 months of randomization * History of allogeneic tissue/solid organ transplant * Has not adequately recovered from major surgery or have ongoing surgical complications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) | Up to ~22 months | EFS is defined as the time from randomization to any of the following events as assessed by the investigator: progression of disease that precludes surgery, or inability to undergo R0 or R1 surgical resection; disease recurrence (local, regional, or distant); new primary high-risk cSCC; death due to any cause. EFS will be presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | Up to ~22 months | ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR). ORR will be presented. |
| Freedom from surgery (FFS) rate | Up to ~22 months | FFS rate is defined as the proportion of participants with clinical CR with no residual tumor on clinical exam and imaging with the confirmation of negative biopsy. FFS rate will be presented. |
| Pathologic complete response (pCR) rate | Up to ~22 months | pCR rate is defined as the proportion of participants who have complete absence of viable tumor in the surgical resection specimen. The pCR rate will be presented. |
| Major pathologic response (mPR) rate | Up to ~22 months | mPR rate is defined as the proportion of participants who have ≤10% of viable tumor cells in the surgical resection specimen. The mPR rate will be presented. |
| Disease-specific survival (DSS) | Up to ~22 months | DSS is defined as time from randomization to death due to progression of cancer under study. DSS will be presented. |
| Overall Survival (OS) | Up to ~22 months | OS is defined as the time from the date of randomization to death due to any cause. The OS will be reported for all participants. |
| Percentage of participants who experience an adverse event (AE) | Up to ~22 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be reported. |
| Percentage of participants who discontinue study intervention due to AEs | Up to ~22 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue intervention due to an AE will be reported. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, Colombia, Czechia, France, Germany, Hungary, Israel, Italy, New Zealand, Norway, Poland, Romania, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed