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

Amgen127 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

Talimogene LaherparepvecDRUG

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.

PembrolizumabDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (32)

HonorHealth Research Institute

Scottsdale, Arizona, United States

University of California Los Angeles

Santa Monica, California, United States

Georgetown-Howard University Center for Clinical Translational Science

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

University of Louisville James Graham Brown Cancer Center

Louisville, Kentucky, United States

Washington University School of Medicine, Center for Advanced Medicine

St Louis, Missouri, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Part 1 Only: ORR Per Modified irRC-RECIST

ORR was defined as the percentage of participants with a best overall response of CR or 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.

Time frame: Up to 297 weeks

Best Overall Response (BOR) Per Modified irRC-RECIST

BOR was defined as the number of participants with a best visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE) as per modified irRC-RECIST. * CR: Disappearance of all lesions and confirmation by 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. * SD: Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. * PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented PD. * UE: Any lesion present at baseline which was not assessed or was unable to be evaluated.

Time frame: Up to 297 weeks

Durable Response Rate (DRR) Per Modified irRC-RECIST

DRR per modified irRC-RECIST was defined as the percentage of participants with an objective response (CR/PR) with a duration of response of at least 6 months. * CR: Disappearance of all lesions and confirmation by 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.

Time frame: Up to 297 weeks

Duration of Response (DOR) Per Modified irRC-RECIST

Data from ClinicalTrials.gov

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Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Liverpool Hospital

Liverpool, New South Wales, Australia

...and 22 more locations

DOR per modified irRC-RECIST was defined as the time from the date of an initial response (CR/PR) that was subsequently confirmed to the earlier of PD or death. DOR was estimated using the Kaplan-Meier method. * CR: Disappearance of all lesions and confirmation by 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. * PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented PD.

Time frame: Up to 297 weeks

Disease Control Rate (DCR) Per Modified irRC-RECIST

DCR per modified irRC-RECIST was defined as percentage of participants that had a BOR in 1 of the following: CR, PR or SD. * CR: Disappearance of all lesions and confirmation by 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. * SD: Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.

Time frame: Up to 297 weeks

Progression Free Survival (PFS) Per Modified irRC-RECIST

PFS was defined as the time from first dose to the date of first of PD per modified irRC-RECIST criteria, or death, whichever occurs first. PFS was estimated using the Kaplan-Meier method. Participants that did not have an event of death or disease progression were censored at the latter of their last evaluable tumor assessment date or first dose date. * PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented PD.

Time frame: Up to 297 weeks

Overall Survival (OS)

OS was defined as the time from the date of first dose date to the date of death from any cause. OS time was censored at the last date the participant was known to be alive when the confirmation of death was absent or unknown, or at the date 24 months after the last participant enrolled if the last known to be alive/death date was beyond it. One month = 365.25/12 days. OS was estimated using the Kaplan-Meier method.

Time frame: Up to 297 weeks

Part 1 Only: Number of Participants Who Experienced a TEAE

Time frame: Day 1 to 30 days post-last dose of talimogene laherparepvec or pembrolizumab, whichever is later. The maximum duration of talimogene laherparepvec treatment was 34.1 weeks and pembrolizumab treatment was 98.3 weeks in Part 1.

Percentage of Participants With Detectable Talimogene Laherparepvec Deoxyribonucleic Acid (DNA) in Blood

Blood samples were tested using real-time polymerase chain reaction (qPCR). Detectable DNA was defined as a positive result by qPCR analysis.

Time frame: Week 1 to Week 10

Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Urine

Urine samples were tested using qPCR. Detectable DNA was defined as a positive result by qPCR analysis.

Time frame: Week 1 to Week 10

Percentage of Participants With Clearance of Talimogene Laherparepvec in Blood

Blood samples were tested using qPCR. A participant was defined as having cleared talimogene laherparepvec if a negative qPCR in a sample was obtained following a prior positive test and if there were no subsequent positive test results in the same cycle.

Time frame: Cycles 2, 3 and 4: Day 1 pre-dose. Each cycle was 21 days.

Percentage of Participants With Clearance of Talimogene Laherparepvec in Urine

Urine samples were tested using qPCR. A participant was defined as having cleared talimogene laherparepvec if a negative qPCR in a sample was obtained following a prior positive test and if there were no subsequent positive test results in the same cycle.

Time frame: Cycles 2, 3 and 4: Day 1 pre-dose. Each cycle was 21 days.

Percentage of Participants With Detectable Talimogene Laherparepvec DNA at the Surface of Injection Site

The number of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of skin surface of injections. Detectable DNA was defined as a positive result by qPCR analysis.

Time frame: Week 1 to Week 10

Percentage of Participants With Detectable Talimogene Laherparepvec Virus at the Surface of Injection Site

The percentage of participants with detectable virus were evaluated from swabs of skin surface of injections. Detectable virus was defined as a positive result by TCID50.

Time frame: Week 1 to Week 10

Percentage of Participants With Detectable Talimogene Laherparepvec DNA at the Exterior of the Occlusive Dressing

The percentage of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of the exterior of the occlusive dressing. Detectable DNA was defined as a positive result by qPCR analysis.

Time frame: Week 1 to Week 7

Percentage of Participants With Detectable Talimogene Laherparepvec Virus at the Exterior of the Occlusive Dressing

The percentage of participants with detectable virus were evaluated from swabs of the exterior of the occlusive dressings. Detectable virus was defined as a positive result by TCID50.

Time frame: Week 1 to Week 7

Percentage of Participants With Detectable Talimogene Laherparepvec DNA at the Oral Mucosa

The percentage of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of the oral mucosa. Detectable DNA was defined as a positive result by qPCR analysis.

Time frame: Part 1: Week 1 to Week 37. Part 2: Week 1 to Week 43

Percentage of Participants With Detectable Talimogene Laherparepvec Virus at the Oral Mucosa

The percentage of participants with detectable virus were evaluated from swabs of the oral mucosa. Detectable virus was defined as a positive result by TCID50.

Time frame: Week 1 to Week 7

Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Lesions Suspected to be Herpetic in Origin

The percentage of participants with positive qPCR were evaluated in any swab of a lesion suspected to be herpetic in origin. Detectable DNA was defined as a positive result by qPCR analysis. Participants returned to the clinic within 3 days of the occurrence of reportable lesion suspected to be herpetic in origin such as cold sores or vesicles. The lesion was evaluated by the Investigator and swabbed if herpes simplex virus infection was suspected.

Time frame: Day 1 to 30 days post-last dose of talimogene laherparepvec. The maximum duration of talimogene laherparepvec treatment was 102.4 weeks and pembrolizumab treatment was 109.3 weeks.

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

Overview

Conditions

Interventions

Eligibility

Locations (32)

Outcomes

Primary Outcomes

Secondary Outcomes