This is a phase 1b/2, multicenter, open-label trial to evaluate the safety of talimogene
laherparepvec injected intrahepatically into liver tumors with known progression alone and in
combination with systemic IV administration of pembrolizumab, in subjects with non-HCC liver
metastases from BC, CRC, GEC, melanoma, NSCLC, RCC, and subjects with HCC. The study consists
of 2 parts and 2 groups, and Part 2 includes 2 stages. 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 six 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.
Summary of Subject Eligibility Criteria:
Key Inclusion Criteria:
Subjects must be age ≥ 18 years at the time of informed consent. They must have
histologically or cytologically confirmed BC, CRC, GEC, melanoma, NSCLC, or RCC with liver
metastases or HCC.
Part 2 Group B is restricted to HCC (fibrolamellar and mixed
hepatocellular/cholangiocarcinoma subtypes are not 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
metastatic melanoma or NSCLC do not need to have received prior therapy.
Subjects must have measurable liver tumors and lesions that are suitable for injection.
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 to B7.
Key Exclusion Criteria:
Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors
with curative intent or planned immediate systemic anti-cancer therapy, with the exception
of immunotherapy in the combination cohorts (Cohorts 5 and 6 in Part 1 and all subjects in
Liver tumors must not be estimated to invade approximately more than one-third of the
Liver tumor-directed therapy, hepatic 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 have no central nervous system (CNS) metastasis, or carcinomatous
meningitis, or if CNS metastasis is present, must have stable treated cerebral metastases
from BC, NSCLC, RCC, CRC, GEC, or melanoma.
Subjects must not have symptomatic auto-immune disease or be immunosuppressed. They must
not have a history of solid organ transplantation.
For non-HCC, there must not be acute or chronic active 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 real time polymerase chain reaction (qPCR) must be undetectable, and they
must not have had recent treatment within 12 weeks for HBV or HCV with certain antiviral
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 oral or
intravenous systemic antiherpetic drug; have received live-virus vaccination within 30 days
of planned treatment start; have previous therapy with talimogene laherparepvec, oncolyic
viruses, or tumor vaccine.
They must not require concomitant treatment with warfarin. 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.