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 IV administration of pembrolizumab, in subjects with non-HCC liver metastases
from BC, CRC, gastroesophageal cancer (GEC), melanoma, NSCLC, 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
TNBC, hormone receptor positive breast cancer, CRC, CSCC, and 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.
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
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 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.
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, 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.