MASTERKEY-318: Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611
Study Details
Study Description
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
- 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase Ib/II Talimogene Laherparepvec Talimogene Laherparepvec |
Drug: Talimogene Laherparepvec
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.
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| Experimental: Phase Ib/II Talimogene Laherparepvec + Pembrolizumab Combination treatment of Talimogene Laherparepvec and Pembrolizumab |
Drug: Talimogene Laherparepvec
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.
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.
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Outcome Measures
Primary Outcome Measures
- Subject incidence DLTs separately in Group A and B observed in monotherapy and combination cohorts and in each tumor type seperately in Part 2 [3 year]
- To evaluate in Part 2 ORR per modified irRC-RECIST separately by tumor type (HR+, TNBC, CRC, BCC, CSCC, HCC) [2 years]
Secondary Outcome Measures
- 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 [5 years]
- Safety: To estimate the incidence of detectable talimogene laherparepvec DNA in blood and urine [5 years]
- Safety: To estimate the incidence of clearance of talimogene laherparepvec DNA from blood and urine [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 [5 years]
- Safety: To estimate the incidence of talimogene laherparepvec DNA detection in lesions suspected to be herpetic in origin [5 years]
- Efficacy: Objective response rate (ORR) [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) [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) [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) [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 [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) [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) [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) [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)
Eligibility Criteria
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.
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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.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | HonorHealth Research Institute | Scottsdale | Arizona | United States | 85258 |
| 2 | University of California Los Angeles | Santa Monica | California | United States | 90404 |
| 3 | Georgetown-Howard University Center for Clinical Translational Science | Washington | District of Columbia | United States | 20007 |
| 4 | University of Louisville James Graham Brown Cancer Center | Louisville | Kentucky | United States | 40202 |
| 5 | Washington University School of Medicine, Center for Advanced Medicine | Saint Louis | Missouri | United States | 63110 |
| 6 | Rutgers Cancer Institute of New Jersey | New Brunswick | New Jersey | United States | 08903 |
| 7 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 8 | University of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15213 |
| 9 | University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 10 | Liverpool Hospital | Liverpool | New South Wales | Australia | 2170 |
| 11 | Melanoma Institute Australia | North Sydney | New South Wales | Australia | 2060 |
| 12 | Tasman Oncology Research | Southport | Queensland | Australia | 4215 |
| 13 | Landeskrankenhaus Salzburg | Salzburg | Austria | 5020 | |
| 14 | Universite Catholique de Louvain Cliniques Universitaires Saint Luc | Bruxelles | Belgium | 1200 | |
| 15 | Universitair Ziekenhuis Antwerpen | Edegem | Belgium | 2650 | |
| 16 | Universitair Ziekenhuis Gent | Gent | Belgium | 9000 | |
| 17 | Charite Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum | Berlin | Germany | 13353 | |
| 18 | Universitätsklinikum Bonn | Bonn | Germany | 53127 | |
| 19 | Kreiskliniken Reutlingen - Klinikum am Steinenberg | Reutlingen | Germany | 72764 | |
| 20 | Universitätsklinikum Tübingen | Tübingen | Germany | 72076 | |
| 21 | Cha Bundang Medical Center, Cha University | Seongnam-si, Gyeonggi-do | Korea, Republic of | 463-712 | |
| 22 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 | |
| 23 | Severance Hospital Yonsei University Health System | Seoul | Korea, Republic of | 120-752 | |
| 24 | Uniwersyteckie Centrum Kliniczne | Gdansk | Poland | 80-214 | |
| 25 | Hospital Universitari Vall d Hebron | Barcelona | Cataluña | Spain | 08035 |
| 26 | Hospital Clinic i Provincial de Barcelona | Barcelona | Cataluña | Spain | 08036 |
| 27 | Hospital General Universitario Gregorio Marañon | Madrid | Spain | 28009 | |
| 28 | Hospital Universitario Madrid Sanchinarro | Madrid | Spain | 28050 | |
| 29 | Hopitaux Universitaires de Geneve | Geneva 14 | Switzerland | 1211 | |
| 30 | Centre Hospitalier Universitaire Vaudois | Lausanne | Switzerland | 1011 | |
| 31 | Kantonsspital Winterthur | Winterthur | Switzerland | 8401 | |
| 32 | Universitaetsspital Zuerich | Zurich | Switzerland | 8091 |
Sponsors and Collaborators
- Amgen
- Merck Sharp & Dohme LLC
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 20140318
- 2014-005386-67