Hepatocellular CarcinomaPhase 1/2MASTERKEY-318NCT02509507
Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611
A Phase 1/2 study testing Talimogene Laherparepvec and Pembrolizumab in people with Hepatocellular Carcinoma and Liver Metastases, run by Amgen at 32 sites in 9 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma, Liver Metastases, Cutaneous or Subcutaneous Lymph Node
- What is being tested?
- Talimogene Laherparepvec and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 127 participants
- Where
- 32 sitesin 9 countries
- Study dates
- 5 Feb 2016to 11 Jul 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
32 sites in 9 countries.
32 sites in 9 countries
United States9 sites
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
University of Louisville James Graham Brown Cancer Center
Louisville, Kentucky, 40202
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
University of California Los Angeles
Santa Monica, California, 90404
HonorHealth Research Institute
Scottsdale, Arizona, 85258
Washington University School of Medicine, Center for Advanced Medicine
St Louis, Missouri, 63110
Georgetown-Howard University Center for Clinical Translational Science
Washington D.C., District of Columbia, 20007
Germany4 sites
Charite Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum
Berlin, 13353
Universitätsklinikum Bonn
Bonn, 53127
Kreiskliniken Reutlingen - Klinikum am Steinenberg
Reutlingen, 72764
Universitätsklinikum Tübingen
Tübingen, 72076
Spain4 sites
Hospital Universitari Vall d Hebron
Barcelona, Catalonia, 08035
Hospital Clinic i Provincial de Barcelona
Barcelona, Catalonia, 08036
Hospital General Universitario Gregorio Marañon
Madrid, 28009
Hospital Universitario Madrid Sanchinarro
Madrid, 28050
Switzerland4 sites
Hopitaux Universitaires de Geneve
Geneva, 1211
Centre Hospitalier Universitaire Vaudois
Lausanne, 1011
Kantonsspital Winterthur
Winterthur, 8401
Universitaetsspital Zuerich
Zurich, 8091
Australia3 sites
Liverpool Hospital
Liverpool, New South Wales, 2170
Melanoma Institute Australia
North Sydney, New South Wales, 2060
Tasman Oncology Research
Southport, Queensland, 4215
Belgium3 sites
Universite Catholique de Louvain Cliniques Universitaires Saint Luc
Brussels, 1200
Universitair Ziekenhuis Antwerpen
Edegem, 2650
Universitair Ziekenhuis Gent
Ghent, 9000
South Korea3 sites
Cha Bundang Medical Center, Cha University
Seongnam-si, Gyeonggi-do, 463-712
Seoul National University Hospital
Seoul, 03080
Severance Hospital Yonsei University Health System
Seoul, 120-752
About this study
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)
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
- Being tested
- Talimogene Laherparepvec, Pembrolizumab
- Keywords
- Liver tumours
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
| Study group | Role | What they receive |
|---|---|---|
| Phase Ib/II Talimogene Laherparepvec | Experimental | Talimogene Laherparepvec Receives: Drug: Talimogene Laherparepvec |
| Phase Ib/II Talimogene Laherparepvec + Pembrolizumab | Experimental | Combination treatment of Talimogene Laherparepvec and Pembrolizumab Receives: Drug: Talimogene Laherparepvec; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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
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.
Measured: 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.
Measured: 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.
Measured: Up to 297 weeks
Duration of Response (DOR) Per Modified irRC-RECIST
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to 297 weeks
Part 1 Only: Number of Participants Who Experienced a 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2015 (estimated)
- Study start5 Feb 2016
- Primary completion14 Feb 2022
- Study completion11 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 127 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02509507
- Sponsor's protocol ID
- 20140318
- Other IDs
- 2014-005386-67, 2014
- Acronym
- MASTERKEY-318
- Status last verified
- Jul 2024
- First submitted
- 10 Jul 2015
- Last updated
- 6 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Publications
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.
PubMed 40156118
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02509507
- Acronym / sponsor ID
- MASTERKEY-318 / 20140318
- Conditions
- Hepatocellular Carcinoma, Liver Metastases, Cutaneous or Subcutaneous Lymph Node, Liver Tumors
- Keywords
- Liver tumours
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 127 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 5 Feb 2016 (actual)
- Primary completion
- 14 Feb 2022 (actual)
- Study completion
- 11 Jul 2023 (actual)
- First posted
- 28 Jul 2015 (estimated)
- Results
- Posted 30 Dec 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phase Ib/II Talimogene Laherparepvec | Experimental | Drug: Talimogene LaherparepvecTalimogene Laherparepvec |
| Phase Ib/II Talimogene Laherparepvec + Pembrolizumab | Experimental | Drug: Talimogene Laherparepvec, Drug: PembrolizumabCombination treatment of Talimogene Laherparepvec and Pembrolizumab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Talimogene LaherparepvecTalimogene 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 | Phase Ib/II Talimogene Laherparepvec, Phase Ib/II Talimogene Laherparepvec + Pembrolizumab |
| PembrolizumabPembrolizumab 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. | Drug | Phase Ib/II Talimogene Laherparepvec + Pembrolizumab |
Primary outcome
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Time frame: Cycle 1 and Cycle 2: Day 1 to Day 21
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.
Part 2 Only: Objective Response Rate (ORR) Per Modified Immune-related Response Criteria Simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST).
Time frame: Up to 154 weeks
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.
Part 2 Only: Number of Participants Who Experienced a Treatment-emergent Adverse Event (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 102.4 weeks and pembrolizumab treatment was 109.3 weeks in Part 2.
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.
19 secondary outcomes
Part 1 Only: ORR Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Best Overall Response (BOR) Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Durable Response Rate (DRR) Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Duration of Response (DOR) Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Disease Control Rate (DCR) Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Progression Free Survival (PFS) Per Modified irRC-RECIST
Time frame: Up to 297 weeks
Overall Survival (OS)
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
Time frame: Week 1 to Week 10
Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Urine
Time frame: Week 1 to Week 10
Percentage of Participants With Clearance of Talimogene Laherparepvec in Blood
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
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
Time frame: Week 1 to Week 10
Percentage of Participants With Detectable Talimogene Laherparepvec Virus at the Surface of Injection Site
Time frame: Week 1 to Week 10
Percentage of Participants With Detectable Talimogene Laherparepvec DNA at the Exterior of the Occlusive Dressing
Time frame: Week 1 to Week 7
Percentage of Participants With Detectable Talimogene Laherparepvec Virus at the Exterior of the Occlusive Dressing
Time frame: Week 1 to Week 7
Percentage of Participants With Detectable Talimogene Laherparepvec DNA at the Oral Mucosa
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
Time frame: Week 1 to Week 7
Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Lesions Suspected to be Herpetic in Origin
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40156118Hecht 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.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
32 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Talimogene Laherparepvec and Pembrolizumab in people with Hepatocellular Carcinoma and Liver Metastases, run by Amgen at 32 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 32 sites in United States, Germany, Spain, Switzerland, Australia and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) (time frame: Cycle 1 and Cycle 2: Day 1 to Day 21). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02509507, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2024.