A Phase 2/3, Adaptive, Randomized, Open-label, Clinical Study to Evaluate Neoadjuvant and Adjuvant Intismeran Autogene (mRNA-4157) in Combination With Pembrolizumab (MK-3475) Versus Standard of Care, and Pembrolizumab Monotherapy in Participants With Resectable Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (INTerpath-007)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 46
- 试验地点
- 212
- 主要终点
- Event Free Survival (EFS)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Pembrolizumab with SOC
Participants will receive pembrolizumab 400 mg IV infusion q6w up to 12 weeks as neoadjuvant therapy prior to surgery.
干预措施: Pembrolizumab (Biological)
Standard of Care (SOC)
Participants will receive surgical resection as per local guidelines with/without adjuvant radiation therapy (RT) at investigator's discretion.
干预措施: Surgery (Procedure)
Pembrolizumab plus Intismeran autogene with SOC
Participants will receive intismeran autogene 1 mg intramuscular (IM) injection every 3 weeks (q3w) for up to 6 weeks and pembrolizumab 400 mg intravenous (IV) infusion every 6 weeks (q6w) up to 12 weeks as neoadjuvant therapy prior to surgery; followed by intismeran autogene 1 mg IM injection q3w up to 21 weeks.
干预措施: Surgery (Procedure)
Pembrolizumab with SOC
Participants will receive pembrolizumab 400 mg IV infusion q6w up to 12 weeks as neoadjuvant therapy prior to surgery.
干预措施: Surgery (Procedure)
Pembrolizumab plus Intismeran autogene with SOC
Participants will receive intismeran autogene 1 mg intramuscular (IM) injection every 3 weeks (q3w) for up to 6 weeks and pembrolizumab 400 mg intravenous (IV) infusion every 6 weeks (q6w) up to 12 weeks as neoadjuvant therapy prior to surgery; followed by intismeran autogene 1 mg IM injection q3w up to 21 weeks.
干预措施: Pembrolizumab (Biological)
Pembrolizumab plus Intismeran autogene with SOC
Participants will receive intismeran autogene 1 mg intramuscular (IM) injection every 3 weeks (q3w) for up to 6 weeks and pembrolizumab 400 mg intravenous (IV) infusion every 6 weeks (q6w) up to 12 weeks as neoadjuvant therapy prior to surgery; followed by intismeran autogene 1 mg IM injection q3w up to 21 weeks.
干预措施: Intismeran autogene (Biological)
结局指标
主要结局
Event Free Survival (EFS)
时间窗: 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.
次要结局
- Overall response rate (ORR)(Up to ~22 months)
- Freedom from surgery (FFS) rate(Up to ~22 months)
- Pathologic complete response (pCR) rate(Up to ~22 months)
- Major pathologic response (mPR) rate(Up to ~22 months)
- Disease-specific survival (DSS)(Up to ~22 months)
- Overall Survival (OS)(Up to ~22 months)
- Percentage of participants who experience an adverse event (AE)(Up to ~22 months)
- Percentage of participants who discontinue study intervention due to AEs(Up to ~22 months)