| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Uveal Melanoma |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Uveal Melanoma |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081431 |
| E.1.2 | Term | Uveal melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Primary objective is to evaluate the progression-free survival (PFS) after 27 weeks of treatment as assessed by the investigator using the RECIST v1.1.
Because clinical benefit of pembrolizumab is expected to be influenced by prior treatment by Tebentafusp (better response to Pembrolizumab when previously treated by Tebentafusp), two independent cohorts will be conducted: cohort 1 with Tebentafusp-naive patients, and cohort 2 patients previously treated with Tebentafusp.
In each cohort, we hypothesize that combining pembrolizumab with lenvatinib in metastatic UM will target essential cellular oncogenic pathways while normalizing tumor vascularization, leading to an increase infiltration of the tumor by immune cells and a better control of the disease assessed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) at nine cycles of treatment (third tumor evaluations (27 weeks). Combination effect is expected to be the same in each cohort.
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| E.2.2 | Secondary objectives of the trial |
[1]To evaluate PFS over the entire follow-up
[2]To evaluate the overall survival (OS) for the combination
[3]To evaluate the objective response rate (ORR) according to RECIST 1.1 as assessed by the investigator
[4]To evaluate the safety and tolerability for the combination
[5]To compare the mean change from baseline in the global health status/quality of life (QoL)
[6]To evaluate the 27-weeks PFS per Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST) as assessed by the investigator
[7]To explore biomarkers of response (exploratory)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic uveal melanoma (UM).
2.(i) Not having been treated with Tebentafusp for cohort 1 (Tebentafusp-naive patients) OR
(ii) Having been previously treated with Tebentafusp for cohort 2.
3.Life expectancy > 3 months.
4.Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
5.Male participants:
A male participant must agree to use contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.
6.A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
a.Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b.A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and at least 180 days after the last dose of study treatment.
7.Measurable disease based on RECIST 1.1.
8.The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
9.Have provided a newly obtained (or archival within 90 days before C1D1, FFPE biopsy allowed) core or excisional biopsy of a tumor lesion not previously irradiated.
10.Patients with French Social Security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code).
11.All other relevant medical conditions must be well-managed and stable, in the opinion of the investigator, for at least 28 days prior to first administration of study drug.
12.Have adequate organ function. Specimens must be collected within 10 days prior to the start of study treatment.
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| E.4 | Principal exclusion criteria |
1.A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation
2.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, and CD137) for metastatic UM.
In contrast, prior therapy with Tebentafusp is permitted.
3.Has recently received prior systemic anti-cancer therapy including investigational agents or biological agents [eg cytokines, antibodies or small molecules kinase inhibitors within 3 weeks or nitrosoureas/mitomycin C within 6 weeks] prior to allocation.
4.Has received prior radiotherapy within 2 weeks of start of study intervention.
5.Has received a live vaccine within 30 days prior to the first dose of study drug. Only mRNA vaccines are authorized to prevent SARS-CoV-2 infection (COVID-19) during the trial.
6.Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
7.Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
8.Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
9.Has known active CNS metastases and/or carcinomatous meningitis. Brain imaging is not required at inclusion if asymptomatic. 10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or lenvatinib and/or any of their excipients.
11.Has active autoimmune disease that has required systemic treatment in the past 2 years.
12.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13.Has an active infection requiring systemic therapy.
14.Has a known history of Human Immunodeficiency Virus (HIV) infection. HIV testing is not required at allocation.
15.Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16.Has a known history of active TB (Bacillus Tuberculosis).
17.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study
18.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19.Is pregnant or breastfeeding or expecting to conceive.
20.Has had an allogenic tissue/solid organ transplant.
21.Concurrent or recent (less than 1 week prior inclusion) immunosuppressive médications.
22.Uncontrolled blood pressure.
23.Electrolyte abnormalities that have not been corrected as assessed by the investigator.
24.Significant cardiovascular impairment.
25.Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.
26.Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.
27.Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to starting therapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The progression-free survival (PFS) will be assessed after 9 cycles (i.e. 27 weeks +/- 2 weeks) using the RECIST criteria version 1.1, based on investigator assessment. PFS will be estimated as a crude rate at 27 weeks (+/- 2 weeks, i.e. 14 days) after the start of treatment when patients will be followed at least between 25 and 29 weeks after the start of treatment. Will be considered progression events: objective clinical progression, radiological progression according to RECIST 1.1 criteria and death from any cause.
A sensitive analysis will be performed using Kaplan-Meier method: PFS will be defined as the time from the date of treatment start until the date of first objective clinical disease progression, radiological disease progression based on investigator assessment using the RECIST v1.1 or death. In case of no death and no progression before the 29-weeks after treatment among patients still followed, the patient will be censored at 29 weeks; in case of lost to follow-up or consent withdrawal before the 29 weeks of treatment, the date of last contact will be the censoring date.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 9 cycles (i.e. 27 weeks +/- 2 weeks) |
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| E.5.2 | Secondary end point(s) |
[1]PFS is defined as the time from the date of treatment start until the date of first objective clinical or radiological disease progression (RECIST 1.1) or death. Patients alive and without progression at the date of last contact will be censored at this date.
[2]OS is defined as the time from the start of treatment until the date of death due to any cause. Patients alive at the date of last contact will be censored at this date.
[3]Objective response rate using the RECIST criteria version 1.1 is defined as a confirmed complete response (CR) or partial response (PR) at nine cycles, 27 weeks (+/- 2 weeks, i.e. 14 days)
[4]Adverse events (AEs) and study intervention discontinuation due to AEs.
[5]Quality of life as measured by EORTC QLQ-C30.
[6]27-weeks PFS using the iRECIST criteria, based on investigator assessment.
[7]Immune monitoring and biomarkers of response on blood, archived tumor and biopsy (exploratory |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
[1]Objective clinical or radiological disease progression (RECIST 1.1) or death.
[2]Death
[3] After 9 cycles (i.e. 27 weeks +/- 2 weeks)
[4]All along the study
[5]Every 3 cycles
[6]After 9 cycles (i.e. 27 weeks +/- 2 weeks)
[7]At screening, before first dose at C1 at 9 weeks, before C4, at Follow-up visit 30 days after treatment discontinuation. |
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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 | 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) | 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 | 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| Last follow-up visit, 30 days after the study treatments discontituation |
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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 | |
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