| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Stage IIIB to IVM1c Melanoma |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| 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 |
Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in subjects with previously untreated, unresectable, stage IIIB to IVM1c melanoma.
Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors 1.1 [RECIST]) and overall survival (OS). |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
• evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab, as assessed by:
− ORR,BOR,DRR,DOR,DCR,&PFS
− OS
• evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as assessed by incidence of treatment-emergent and -related AEs, and abnormal laboratory tests.
Phase 3:
• Evaluate efficacy of talimogene laherparepvec with pembrolizumab, versus placebo with pembrolizumab, as assessed by:
- iCRR by blinded independent central assessed modified irRC-RECIST
- iPFS by blinded independent central assessed modified irRC-RECIST
- OS in subjects excluding stage IVM1c per CRF
- ORR, BOR, DRR, DOR, DCR, iORR, iBOR, iDRR, iDOR, and iDCR
• Evaluate safety of talimogene laherparepvec with pembrolizumab, versus placebo with pembrolizumab, as assessed by incidence of treatment -emergent and -related AEs and abnormal laboratory tests.
• Evaluate patient reported outcomes (PRO) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1b and Phase 3:
• Male or female age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to IVM1c for whom surgery in not recommended.
• Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
• Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, renal, and coagulation function.
Phase 1b only:
• Subjects enrolled in phase 1b must be treatment naïve (i.e., must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy) given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.
• Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that prior adjuvant therapy with inhibitors of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) is not allowed. However, if the subject received adjuvant therapy, the
subject must have completed therapy at least 3 months prior to enrolment.
Phase 3 only:
• Subjects enrolled in phase 3 with serine/threonine protein kinase B-Raf V600 (BRAFV600) wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.
• Subjects enrolled in phase 3 with BRAFV600 mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as their only prior systemic therapy are eligible for the phase 3 of this study. Subjects with BRAFV600 mutant melanoma or unknown BRAFV600 mutation status who have not received a BRAF inhibitor are also eligible for the phase 3 of this study as first-line treatment if they meet the following criteria: lactate dehydrogenase (LDH) < upper limit of normal (ULN), no clinically significant tumor related symptoms, and absence of rapidly progressing metastatic melanoma. Subjects (BRAF mutant, wildtype and UNK) who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that prior adjuvant therapy with inhibitors of PD-1 OR PD-L1 is not allowed. However, if the subject received adjuvant therapy, the subject must have completed therapy at least 28 days prior to enrolment.
• Subjects must have a tumor sample (archival sample or newly obtained biopsy) that is adequate for PD-L1 assessment prior to randomization. |
|
| E.4 | Principal exclusion criteria |
Phase 1b and Phase 3:
• Subjects must not have clinically active cerebral metastases and/or carcinomatous meningitis.
• Subjects with up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or Gamma Knife therapy, with no evidence of progression, and not requiring steroids, for at least 2 months prior to enrolment. Carcinomatous meningitis is excluded regardless of clinical stability.
• Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states (e.g., hereditary immune deficiency, organ transplant, or leukemia), or history of other malignancy within the past 3 years with the exceptions of the prior malignancies noted in Section 4.1.2.
• Subjects may not have been previously treated with talimogene laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or programmed cell death ligand 2 (PD-L2). Prior treatment with other immunotherapies ( e.g., anti-CD137, or cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibitor, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways), is allowed only in the adjuvant setting.
• Subjects must not have history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.
• Subjects must not have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
• Incidence of DLT
Phase 3:
• PFS (response evaluation by blinded independent central review assessed using modified RECIST 1.1) and OS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary completion: The date when the last subject is assessed or receives an intervention for the primary endpoint(s), for the purpose of conducting the primary analysis, whether the study concluded as planned in the protocol or was terminated early.
End of Trial: The date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), following any additional parts in the study (eg, long-term follow-up), as applicable. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b:
• Confirmed ORR (CR+PR) (response evaluation by investigator using modified irRC).
• BOR, DRR, DOR, PFS and DCR (response evaluation by investigator using modified irRC).
• OS.
• Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest), and abnormal laboratory tests.
Phase 3:
• iCRR by blinded independent central review using modified irRC-RECIST
• iPFS by blinded independent central review using modified irRC-RECIST (PFS2)
• OS in subjects excluding stage IVM1c per CRF
• ORR (CR+PR), BOR, DRR, DOR, and DCR (response evaluation by blinded independent central review assessed using modified RECIST 1.1 and iORR (iCR + iPR), iBOR, iDRR, iDOR, and iDCR (response evaluation by blinded independent central review assessed
using modified irRC-RECIST)
• Incidence of treatment-emergent and treatment-related AEs (all AEs, grade ≥ 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest), and abnormal laboratory tests
• Changes in EORTC QLQ-C30 GHS/QoL subscale. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The clinical study report (CSR) will be written based on the results from the OS primary analysis for phase 3, which will also include safety data from subjects in phase 1b. However, a CSR will be prepared should there be a decision for unblinding the study team based on early stopping for safety, efficacy, or futility (Section 10.4.1). Amgen senior management will make the decision to unblind the study team based on the DMC’s recommendations; however, only a subset of the study team will be unblinded prior to the OS 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 |
| Phase 1b to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| South Africa |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), following any additional parts in the study (eg, long-term follow-up), as applicable. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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