| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatocellular carcinoma (HCC) and metastatic liver tumors (non-HCC) |
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| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025628 |
| E.1.2 | Term | Malignant liver tumour non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To evaluate the following, as assessed by the incidence of dose-limiting toxicities (DLTs), in subjects with liver metastases (non-hepatocellular carcinoma [HCC]) and subjects with primary HCC in:
• Monotherapy Cohorts: the maximum tolerated volume and concentration (MTV and MTC) of intrahepatic injection of talimogene laherparepvec into liver tumors in subjects with non-HCC and subjects with primary HCC without active viral hepatitis
• Combination Cohorts: the MTC of intrahepatic injection of talimogene laherparepvec into liver tumors in combination with systemic intravenous (IV) administration of pembrolizumab in subjects with non-HCC, and subjects with primary HCC with or without viral hepatitis
Part 2:
• To evaluate the efficacy, as assessed by objective response rate (ORR) of intratumoral injection of talimogene laherparepvec in combination with systemic IV administration of pembrolizumab, separately, for each non-HCC tumor type... |
|
| E.2.2 | Secondary objectives of the trial |
Part 1: To evaluate the efficacy separately by monotherapy versus combination for non-HCC tumors and HCC with and without viral hepatitis when applicable as assessed by:
• ORR, best overall response (BOR), durable response rate (DRR), duration of response (DOR), response in injected and uninjected lesions, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS)
Part 2:
• To evaluate the efficacy in individual tumor types in the non-HCC group and HCC group with and without viral hepatitis as assessed by:
o BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS by primary tumor type (TNBC, Hormone receptor positive BC, CRC, CSCC, BCC, and HCC with and without viral hepatitis)
SAFETY (Parts 1 and 2)
• To evaluate the safety in each monotherapy and combination cohorts in Part 1 and each arm separately in Part 2, as assessed by subject incidence of treatment-emergent and treatment-related adverse events
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
o 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 (ER ≥ 1%, PrR ≥ 1%) breast cancer.
o Triple negative breast cancer: Histologically and/or cytologically confirmed diagnosis of ER negative, PR negative, human epidermal growth factor receptor 2 (HER2)-Neu negative (ER <1%; PR <1%; HER2-Neu < 3+ by immunohistochemistry or fluorescence in situ hybridization ratio ≤ 2.2 or < 6 copies HER2 gene copies/nucleus).
• 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 hepatitis 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 enrolment and hepatitis C viral load must be undetectable; subjects with hepatitis B and C must fulfil 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 defined in the protocol. Child-Pugh score must be A. |
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| E.4 | Principal 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 from BC, NSCLC, RCC, CRC, GEC, or melanoma. 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. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
Monotherapy cohorts 1-4: Subject incidence of DLTs with intrahepatic injection of talimogene laherparepvec into liver tumors in subjects with non-HCC with liver metastases and subjects with HCC without active viral hepatitis.
Combination cohorts 5 and 6: Subject incidence of DLTs with intrahepatic injection into liver tumors of talimogene laherparepvec in combination with systemic IV administration of pembrolizumab in subjects with non-HCC with liver metastases and subjects with HCC with and without viral hepatitis.
Part 2:
• ORR per the modified immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors version 1.1 (irRC-RECIST) with intralesional injection of talimogene laherparepvec into cutaneous, subcutaneous, lymph node, and liver tumors in combination with systemic IV administration of pembrolizumab separately by tumor type arm (TNBC, Hormone receptor positive BC, CRC, CSCC, BCC, and HCC with and without viral hepatitis)
• Subject incidence for each tumor type of treatment-emergent and treatment-related adverse events, including DLTs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When all subjects in each tumour type have a min. of 29 weeks of treatment in each arms of Part 2 |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
Part 1:
• ORR, BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS separately for non-HCC and HCC tumors in monotherapy and combination cohorts
Part 2:
• BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS by primary tumor type arm (TNBC, Hormone receptor positive BC, CRC, CSCC, BCC, and HCC with and without viral hepatitis)
Safety:
Parts 1 and 2:
• Subject incidence of treatment-related and treatment-emergent adverse events (monotherapy and combination cohorts in Part 1, and each tumor type separately in Part 2, and HCC with and without viral hepatitis)
• Subject incidence of detectable talimogene laherparepvec DNA in blood and urine
• Incidence of clearance of talimogene laherparepvec DNA from blood and urine
• Subject incidence (per subject) and rate of detection (per sample) of talimogene laherparepvec DNA and virus at the surface of injection site, the exterior of occlusive dressing, and the oral mucosa
• Subject incidence of talimogene laherparepvec DNA detection in lesions suspected to be herpetic in origin |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Will be evaluated at Interim and Primary Analysis |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| evaluate safety of talimogene laherparepvec alone and in combo with Pembrolizumab |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Poland |
| Spain |
| Switzerland |
| Germany |
| Belgium |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will occur when the last subject discontinues talimogene laherparepvec and/or pembrolizumab (whichever is later) and has had the opportunity to complete both the safety follow-up visit and the long-term survival follow-up. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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