Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611 (MASTERKEY-318)

• ClinicalTrials.gov Identifier: NCT02509507
• Recruitment Status: Recruiting
• First Posted: July 28, 2015
• Last Update Posted: December 22, 2020
• Sponsor: Amgen
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: July 10, 2015
• First Posted Date: July 28, 2015
• Last Update Posted Date: December 22, 2020
• Actual Study Start Date: February 5, 2016
• Estimated Primary Completion Date: October 25, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 10, 2020)

• Subject incidence DLTs separately in Group A and B observed in monotherapy and combination cohorts and in each tumor type seperately in Part 2 [ Time Frame: 3 year ]
• To evaluate in Part 2 ORR per modified irRC-RECIST separately by tumor type (HR+, TNBC, CRC, BCC, CSCC, HCC) [ Time Frame: 2 years ]

• Original Primary Outcome Measures (submitted: July 24, 2015): Subject incidence of Dose-Limiting Toxicities s in dose-escalation cohorts to determine the Maximum Tolerated Dose. [ Time Frame: 1 year ]

Current Secondary Outcome Measures (submitted: December 4, 2019)

• Safety: Subject incidence of treatment-related and treatment-emergent adverse events in monotherapy and combination of Part 1 and each separate tumour type in Part 2 [ Time Frame: 5 years ]
• Safety: To estimate the incidence of detectable talimogene laherparepvec DNA in blood and urine [ Time Frame: 5 years ]
• Safety: To estimate the incidence of clearance of talimogene laherparepvec DNA from blood and urine [ Time Frame: 5 years ]
• Safety: To estimate the rate of detection and incidence of talimogene laherparepvec DNA and virus at the surface of talimogene laherparepvec injection site, the exterior of the occlusive dressing, and the oral mucosa [ Time Frame: 5 years ]
• Safety: To estimate the incidence of talimogene laherparepvec DNA detection in lesions suspected to be herpetic in origin [ Time Frame: 5 years ]
• Efficacy: Objective response rate (ORR) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Best overall response (BOR) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Durable response rate (DRR) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Duration of response (DOR) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Response in injected and uninjected lesions [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Disease control rate (DCR) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy Progression-free survival (PFS) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Overall survival (OS) [ Time Frame: 5 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)

Original Secondary Outcome Measures (submitted: July 24, 2015)

• Safety: To evaluate the safety of intrahepatic injection of talimogene laherparepvec into liver tumors as assessed by subject incidence of treatment-emergent and treatment-related adverse events [ Time Frame: 3 years ]
• Safety: To estimate the incidence of detectable talimogene laherparepvec DNA in blood and urine [ Time Frame: 3 years ]
• Safety: To estimate the incidence of clearance of talimogene laherparepvec DNA from blood and urine [ Time Frame: 3 years ]
• Safety: To estimate the rate of detection and incidence of talimogene laherparepvec DNA and virus at the surface of talimogene laherparepvec injection site, the exterior of the occlusive dressing, and the oral mucosa [ Time Frame: 3 years ]
• Safety: To estimate the incidence of talimogene laherparepvec DNA detection in lesions suspected to be herpetic in origin [ Time Frame: 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: July 24, 2015)

• Efficacy: Objective response rate (ORR) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Best overall response (BOR) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Durable response rate (DRR) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Duration of response (DOR) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Response in injected and uninjected lesions [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Disease control rate (DCR) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy Progression-free survival (PFS) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Efficacy: Overall survival (OS) [ Time Frame: 3 years ]
  To evaluate the efficacy of intrahepatic injection of talimogene laherparepvec in the overall population and by tumor type (non-hepatocellular carcinoma and hepatocellular carcinoma)
• Exploratory: To assess blood and tumor tissue for potential biomarkers which predict and/or are correlated with clinical outcomes to talimogene laherparepvec [ Time Frame: 3 years ]

Descriptive Information

• Brief Title: Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611
• Official Title: A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Liver Tumors Alone and in Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate the Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination With Systemic Pembrolizumab to Treat Subjects With Advanced Solid Tumors in Phase 2 (MASTERKEY-318)
• Brief Summary: This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of talimogene laherparepvec injected intrahepatically into liver tumors alone and in combination with systemic IV administration of pembrolizumab, in subjects with non-HCC liver metastases from BC, CRC, gastroesophageal cancer (GEC), melanoma, NSCLC, RCC in Part 1 Group A, and subjects with HCC with and without viral hepatitis in Part 1 Group B (viral hepatitis is only applicable in combination setting), and to evaluate the efficacy and safety of intratumoral talimogene laherparepvec in combination with systemic pembrolizumab in subjects with advanced TNBC, hormone receptor positive breast cancer, CRC, CSCC, and BCC in Part 2 Group A and subjects with HCC with and without viral hepatitis in Part 2 Group B. The objective of Part 1 is to evaluate the safety of intrahepatic injection of talimogene laherparepvec into liver tumors alone and in combination with systemically administered pembrolizumab for the non-HCC (Group A) and HCC (Group B) cohorts separately. Part 2 consists of 2-stage design to evaluate the efficacy and safety of talimogene laherparepvec in combination with systemic pembrolizumab. Efficacy and safety will be evaluated in each of the five non-HCC tumor types from Group A separately. Similarly, the efficacy and safety of the combination treatment will be determined for Group B HCC subjects.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hepatocellular Carcinoma
• Liver Metastases
• Cutaneous or Subcutaneous Lymph Node
• Liver Tumors

Intervention

• Drug: Talimogene Laherparepvec
  Talimogene laherparepvec (T-VEC) administered by intralesional injection into liver tumors, with US/CT guidance. Part 1: initial dose of T-VEC is 10^6 PFU/mL up to 4mL in Cohorts 1 & 2, up to 8mL in Cohorts 3 & 4 of the Group A & Group B. The 1st cycle of T-VEC will be 21 (+3) days (from the 1st dose at 10^6 PFU/mL to the 2nd dose at 10^7 or 10^8 PFU/mL). Subsequent cycles of T-VEC will be 21 (±3) days. Max. volume of T-VEC administered at any dose is 4mL (Cohorts 1, 2, 5, and 6) or 8mL (Cohorts 3 & 4) for any individual lesion or for all lesions combined. Part 2: Initial dose of T-VEC is 10^6 PFU/mL followed by subsequent T-VEC doses at a concentration of 10^8 PFU/mL. T-VEC volume is up to 8mL based on the size of the inejected lesions.
• Drug: Pembrolizumab
  Pembrolizumab is a non-Amgen Investigational product that is manufactured by Merck. Pembrolizumab will be labeled, packaged, and distributed by Amgen (or designee) using Amgen (or designee) clinical study drug distribution procedures. Pembrolizumab is supplied as pembrolizumab 100 mg/4 mL vials (25 mg/mL) solution for IV infusion. The trial treatment will consist of a total dose of 200mg administered intravenously every 3 weeks (day 1 of each cycle) for up to 35 cycles.

Study Arms

• Experimental: Phase Ib/II Talimogene Laherparepvec
  Talimogene Laherparepvec
  Intervention: Drug: Talimogene Laherparepvec
• Experimental: Phase Ib/II Talimogene Laherparepvec + Pembrolizumab
  Combination treatment of Talimogene Laherparepvec and Pembrolizumab
  Intervention: Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 6, 2020): 206
• Original Estimated Enrollment (submitted: July 24, 2015): 100
• Estimated Study Completion Date: April 4, 2024
• Estimated Primary Completion Date: October 25, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Summary of Subject Eligibility Criteria:

Key Inclusion Criteria:

Subjects must be age ≥ 18 years at the time of informed consent. Subjects must have histologically or cytologically confirmed disease.

Part 1 is restricted to BC, CRC, GEC, melanoma, NSCLC, or RCC with liver metastases or HCC.

Part 2 Group A is restricted to advanced hormone receptor positive BC, CRC, TNBC, CSCC, and BCC with or without liver metastases.

• Part 2 Hormone receptor positive Breast Cancer Arm only: Histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER) positive and/or progesterone receptor (PrR) positive breast cancer.
• Triple negative breast cancer: Histologically and/or cytologically confirmed diagnosis of ER negative, PrR negative, human epidermal growth factor receptor 2 (HER2)-Neu negative.

Part 2 Group B is restricted to HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).

For HCC subjects with a diagnosis of hepatitis B, they must be on antiviral therapy for at least 4 weeks prior to enrollment and HBV viral load by real-time polymerase chain reaction (qPCR) must be < 100 IU/mL. HCC subjects with past or ongoing hepatitis C infection must have completed treatment for hepatitis C at least 1 month prior to study enrollment and hepatitis C viral load must be undetectable; subjects with hepatitis B and C must fulfill the eligibility criteria for hepatitis B and hepatitis C. Subjects with unresectable locally recurrent TNBC are eligible.

Non-HCC subjects must have received at least 1 prior standard of care systemic anti-cancer therapy for their locally advanced or metastatic disease. For the combination cohorts (Cohorts 5 and 6 in Part 1) and Part 2, subjects with melanoma CSCC or NSCLC do not need to have received prior therapy. In Part 1, subjects must have measurable liver tumors and liver tumors that are suitable for injection. In Part 2, subjects must have measurable disease and cutaneous, subcutaneous, lymph node, or liver tumors suitable for injection. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1, and life expectancy should be approximately 5 months or more. Adequate hematological, renal, hepatic, and coagulation function is required. Liver function tests may be mildly abnormal but within the parameters. Child-Pugh score must be A.

Key Exclusion Criteria:

Subjects must not be candidates for surgery or locoregional therapy with curative intent or planned systemic anti-cancer therapy, with the exception of immunotherapy in the combination cohorts (Cohorts 5 and 6 in Part 1 and all subjects in Part 2). Liver tumors must not be estimated to invade approximately more than one-third of the liver. Liver tumor-directed therapy, hepatic surgery or major surgery, antibody-based therapy, or immunotherapy must not have been performed < 28 days, chemotherapy < 21 days, and targeted small molecule therapy or hormonal therapy < 14 days prior to enrollment. Subjects must either (1) have no central nervous system (CNS) metastasis, or carcinomatous meningitis, or (2) if CNS metastasis is present, must have stable treated cerebral metastases. Subjects must not have symptomatic auto-immune disease or be symptomatically immunosuppressed. They must not have a history of solid organ transplantation. For non-HCC, there must not be acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. For HCC with prior hepatitis B and/or C infection, HBV and/or HCV viral load by qPCR must be undetectable, and they must not have had recent treatment within 12 weeks for HBV or HCV with certain antiviral medications in Part 1 Group B cohorts 1-5 and 6a, and Part 2 Group B HCC without viral hepatitis. For all patients in Part 1 and for patients in Part 2 where intrahepatic liver injection is planned, there should be no macroscopic intravascular invasion of tumors into the main portal vein, hepatic vein, or vena cava. Subjects must not: have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis); require treatment with an antiherpetic drug; have received live-virus vaccination within 30 days of planned treatment start; have previous therapy with talimogene laherparepvec, oncolytic viruses, or tumor vaccine. Subjects in the combination treatment cohort must not have: a history or evidence of psychiatric, substance abuse, or any other clinically significant disorder; toxic effects of the most recent prior chemotherapy not resolved to grade 1 or less (except alopecia); or expected other cancer therapy while on study with the exception of local radiation to the site of bone or other metastasis for palliative treatment. Male subjects of reproductive potential in the combination treatment must be willing to use acceptable methods of effective contraception during treatment and through 4 months after the last dose of pembrolizumab.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Amgen Call Center; 866-572-6436; medinfo@amgen.com

• Listed Location Countries: Australia, Austria, Belgium, Germany, Korea, Republic of, Poland, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT02509507
• Other Study ID Numbers: 20140318; 2014-005386-67 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• URL: https://www.amgen.com/datasharing

• Responsible Party: Amgen
• Study Sponsor: Amgen
• Collaborators: Merck Sharp & Dohme Corp.

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: December 2020