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

Study Overview
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Brief Summary
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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 intravenous (IV) administration of pembrolizumab, in subjects with non-hepatocellular carcinoma (HCC) liver metastases from breast adenocarcinoma (BC), colorectal adenocarcinoma (CRC), gastroesophageal cancer (GEC), melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (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 triple negative breast cancer (TNBC), hormone receptor positive breast cancer, CRC, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (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. As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study. Enrollment for this study has stopped.

Official Title
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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)

Conditions
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Hepatocellular Carcinoma, Liver Metastases, Cutaneous or Subcutaneous Lymph Node, Liver Tumors

Intervention / Treatment
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* Drug: Talimogene Laherparepvec
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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 hepatitis B virus (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. NOTE: as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study, enrollment for this study has stopped. 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 (NOTE: as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study, enrollment for this study has stopped), 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.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib/II Talimogene Laherparepvec<br>Talimogene Laherparepvec | Drug: Talimogene Laherparepvec<br>* Talimogene laherparepvec (T-VEC) administered by intralesional injection into liver tumors, with ultrasound/computed tomography (US/CT) guidance. Part 1: initial dose of T-VEC is 10^6 plaque forming unit (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. NOTE: as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.<br>|
| Experimental: Phase Ib/II Talimogene Laherparepvec + Pembrolizumab<br>Combination treatment of Talimogene Laherparepvec and Pembrolizumab | Drug: Talimogene Laherparepvec<br>* Talimogene laherparepvec (T-VEC) administered by intralesional injection into liver tumors, with ultrasound/computed tomography (US/CT) guidance. Part 1: initial dose of T-VEC is 10^6 plaque forming unit (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. NOTE: as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.<br>Drug: Pembrolizumab<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | All toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 1: Mild Grade 2: Moderate Grade 3: Severe or medically significant but not immediately life threatening Grade 4: Life threatening consequences Grade 5: Death related to adverse event (AE) The occurrence of specific pre-defined toxicities during the DLT evaluation period were considered a DLT if judged by the investigator to be related to talimogene laherparepvec and/or pembrolizumab. All Grade 5 toxicities, intolerable toxicities that lead to permanent discontinuation of talimogene laherparepvec and/or pembrolizumab and Grade 3 or higher AEs related to talimogene laherparepvec and/or pembrolizumab that resulted in a study treatment delay by > 2 weeks were considered DLTs. | Cycle 1 and Cycle 2: Day 1 to Day 21 | 
| Part 2 Only: Objective Response Rate (ORR) | ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) per modified irRC-RECIST. CR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. | Week 10, then every 9 weeks thereafter. The maximum duration of talimogene laherparepvec treatment at data cut off was 61.0 weeks and pembrolizumab treatment at data cut off was 98.3 weeks. | 
| Part 2 Only: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as an event that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state. A treatment-related TEAE was defined as a TEAE that was suspected to be related to the study treatment. | Day 1 to 30 days post-last dose of talimogene laherparepvec. The maximum duration of talimogene laherparepvec treatment at data cut off was 61.0 weeks and pembrolizumab treatment at data cut off was 98.3 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver tumours