E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable/Metastatic Stage IIIB-IVM1d Melanoma |
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E.1.1.1 | Medical condition in easily understood language |
A type of cancer that develops from the pigment-containing cells known as melanocytes |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To evaluate the efficacy of Talimogene laherparepvec in combination with pembrolizumab as assessed by objective response rate (ORR) in subjects with unresectable/metastatic stage IIIB-IVM1d melanoma who have progressed on prior anti-PD-1 therapy |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab, as assessed by: o Complete response rate (CRR), best overall response, (BOR) durable response rate, (DRR) duration of response, (DOR) and disease control rate, (DCR) o ORR using modified irRC-RECIST o Progression free survival (PFS) o Overall survival (OS) -To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as assessed by incidence of treatment-emergent and treatment-related adverse events, and abnormal laboratory tests in patients who have progressed on prior anti-PD-1 therapy -To evaluate time to subsequent anti-cancer therapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
This study will enroll subjects -who are male or female age > 18 years at the time of informed consent -with histologically confirmed diagnosis of melanoma (unresectable or metastatic stage IIIB, IIIC, IIID, IVM1a, IVM1b, IVM1c, or IVM1d melanoma). - Subjects with stage IVM1d and 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 enrollment. -Subjects must have measurable disease and be a candidate for intralesional therapy. -Subjects must have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 -Adequate hematologic, hepatic, renal, and coagulation function. - Subject must also have received prior anti-PD-1 therapy for at least 2 to 3 consecutive cycles within an 8 week period and have disease progression as defined by RECIST v1.1 criteria. Note: subjects with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy are excluded. |
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E.4 | Principal exclusion criteria |
-Subjects must not have clinically active cerebral melanoma metastases and/or carcinomatous meningitis. -Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia), or history of other malignancy within the past 3 years with the exceptions noted in Section 6.2 of the protocol. -Subjects must not have been previously treated with talimogene laherparepvec, any other oncolytic viruses, or tumor vaccine (unless administered in the adjuvant setting). -Subjects must not have a history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. -Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. -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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response (complete response [CR]+partial response [PR]) (by investigator assessment using modified Response Evaluation Criteria in Solid Tumor [RECIST v1.1]) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Efficacy analysis will be performed on the Full Analysis Set (FAS) defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination and the Per Protocol Analysis Set (PPAS). The PPAS is a subset of the FAS and includes subjects who do not have important protocol deviations that are considered to have an impact on efficacy outcomes. |
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E.5.2 | Secondary end point(s) |
- Complete response, BOR, durable response, DOR, and disease control, (investigator assessment using modified RECIST v1.1 and modified irRCRECIST) and overall response using modified irRC-RECIST by investigator assessment -PFS (by investigator assessment using modified RECIST v1.1 and modified irRC-RECIST) -OS -Incidence of treatment-emergent and treatment-related adverse events (all adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse events, adverse events defined as events of interest), and abnormal laboratory tests -Time to subsequent anti-cancer therapy |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Efficacy analysis will be performed on the Full Analysis Set (FAS) defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination and the Per Protocol Analysis Set (PPAS). The PPAS is a subset of the FAS and includes subjects who do not have important protocol deviations that are considered to have an impact on efficacy outcomes. - The Safety Analysis Set (SAS), defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec or pembrolizumab, will be used in the analysis of the safety endpoints. |
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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 | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
Greece |
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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
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The end of study date is defined as 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. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |