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

NCT02509507 | Completed Phase 1 Results

• 2 other identifiers: 201403182014-005386-67
• Study Type: interventional
• Target: 127
• Locations: 8 countries
• Sites: 31

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 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.

Conditions

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

Keywords

Liver tumours

Outcome Measures

Primary Outcomes (3)

• 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) Per Modified Immune-related Response Criteria Simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST).

  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.

  Up to 154 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 or pembrolizumab, whichever is later. The maximum duration of talimogene laherparepvec treatment was 102.4 weeks and pembrolizumab treatment was 109.3 weeks in Part 2.

Secondary Outcomes (19)

• Part 1 Only: ORR Per Modified irRC-RECIST

  Up to 297 weeks

• Best Overall Response (BOR) Per Modified irRC-RECIST

  Up to 297 weeks

• Durable Response Rate (DRR) Per Modified irRC-RECIST

  Up to 297 weeks

• Duration of Response (DOR) Per Modified irRC-RECIST

  Up to 297 weeks

• Disease Control Rate (DCR) Per Modified irRC-RECIST

  Up to 297 weeks

Study Arms (2)

Phase Ib/II Talimogene Laherparepvec

EXPERIMENTAL

Talimogene Laherparepvec

Drug: Talimogene Laherparepvec

Phase Ib/II Talimogene Laherparepvec + Pembrolizumab

EXPERIMENTAL

Combination treatment of Talimogene Laherparepvec and Pembrolizumab

Drug: Talimogene Laherparepvec; Drug: Pembrolizumab

Interventions

Talimogene Laherparepvec DRUG

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.

Phase Ib/II Talimogene Laherparepvec; Phase Ib/II Talimogene Laherparepvec + Pembrolizumab

Pembrolizumab DRUG

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.

Phase Ib/II Talimogene Laherparepvec + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amgen: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (32)

HonorHealth Research Institute

Scottsdale, Arizona, 85258, United States

Location

University of California Los Angeles

Santa Monica, California, 90404, United States

Location

Georgetown-Howard University Center for Clinical Translational Science

Washington D.C., District of Columbia, 20007, United States

Location

University of Louisville James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Washington University School of Medicine, Center for Advanced Medicine

St Louis, Missouri, 63110, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

Melanoma Institute Australia

North Sydney, New South Wales, 2060, Australia

Location

Tasman Oncology Research

Southport, Queensland, 4215, Australia

Location

Landeskrankenhaus Salzburg

Salzburg, 5020, Austria

Location

Universite Catholique de Louvain Cliniques Universitaires Saint Luc

Brussels, 1200, Belgium

Location

Universitair Ziekenhuis Antwerpen

Edegem, 2650, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

Location

Charite Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Universitätsklinikum Bonn

Bonn, 53127, Germany

Location

Kreiskliniken Reutlingen - Klinikum am Steinenberg

Reutlingen, 72764, Germany

Location

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-214, Poland

Location

Cha Bundang Medical Center, Cha University

Seongnam-si, Gyeonggi-do, 463-712, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital Yonsei University Health System

Seoul, 120-752, South Korea

Location

Hospital Universitari Vall d Hebron

Barcelona, Catalonia, 08035, Spain

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, Catalonia, 08036, Spain

Location

Hospital General Universitario Gregorio Marañon

Madrid, 28009, Spain

Location

Hospital Universitario Madrid Sanchinarro

Madrid, 28050, Spain

Location

Hopitaux Universitaires de Geneve

Geneva, 1211, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, 1011, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

Universitaetsspital Zuerich

Zurich, 8091, Switzerland

Location

Related Publications (1)

• Hecht JR, Oberoi A, Garralda Cabanas E, Jae Chon H, Digklia A, Rottey S, Martin Jimenez M, Chaney M, Hippenmeyer J, Lawrence T, Liu K, Hamidi A, Chesney J. Phase Ib/II trial of talimogene laherparepvec alone and with pembrolizumab in advanced solid tumors with liver metastases and hepatocellular carcinoma. Oncologist. 2025 Mar 10;30(3):oyae203. doi: 10.1093/oncolo/oyae203.

  PMID: 40156118 DERIVED

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

talimogene laherparepvec; pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2015
• First Posted: July 28, 2015
• Study Start: February 5, 2016
• Primary Completion: February 14, 2022
• Study Completion: July 11, 2023
• Last Updated: August 6, 2024
• Results First Posted: December 30, 2022

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

AU (3); CH (4); KR (3); ES (4); BE (3); US (9); PL (1); DE (4)