| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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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 | 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 |
| To evaluate objective response rate (ORR) as assessed by BICR per RECIST 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate progression-free survival (PFS) as assessed by BICR per RECIST 1.1
2) To evaluate overall survival (OS)
3) To evaluate the duration of response (DOR) per RECIST 1.1
4) To assess safety and tolerability of treatment with lenvatinib in combination with pembrolizumab
5) To characterize the population PK of lenvatinib when co-administered with pembrolizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed melanoma
2. Have unresectable Stage III or Stage IV melanoma, per American Joint Committee on Cancer (AJCC) staging system version 8, not amenable to local therapy
3. Have the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 as confirmed by BICR. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions
4. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
a. Received at least 2 doses of an anti-PD-1/L1 mAb
b. Has demonstrated disease progression after PD-1/L1 as defined by RECIST 1.1. The initial evidence of RECIST 1.1 disease progression is to be confirmed using iRECIST by a second assessment no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression
c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb
5. Have submitted initial imaging
6. Have an ECOG performance status 0 to 1
7. Have provided a baseline tumor biopsy
8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention
9. Be Male or Female and is at least 18 years of age at the time of providing the informed consent
10. Male participants are eligible to participate if they agree to the following during the intervention period andfor at least 95 days, corresponding to time needed to eliminate study interventions (eg, 5 terminal half-lives) after the last dose of study intervention:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
- Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5] as detailed below.
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
- Male participants must also agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
11. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
OR
b. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with lower user dependency, or be abstinent from heterosexual intercourse as their perferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 95 days, corresponding to the time needed to eliminate any study interventions (eg, 5 terminal half-lives) after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum; as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum test is required. In such cases, the participants must be excluded from participation if the serum pregnancy test result is positive.
12. Have provided documented informed consent for the study
13. Have adequately controlled BP, with or without antihypertensive medications, defined as BP ≤150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1
14. Have adequate organ function
|
|
| E.4 | Principal exclusion criteria |
1. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention.
2. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks before the first dose of study intervention and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before study intervention.
4. Has ocular melanoma
5. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody
6. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
7. Has an active infection requiring systemic therapy
8. Has known history of HIV (HIV 1/2 antibodies). No testing of HIV is required unless mandated by local health authority
9. Has known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA [qualitative] is detected). No testing of hepatitis B or C is required unless mandated by local health authority
10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
11. Has a history of active tuberculosis
12. Has presence of a gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
13. Had had major surgery within 3 weeks prior to first dose of study interventions. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
14. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
15. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
16. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
17. Has clinically significant cardiovascular disease within 12 months from first dose of study drug, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
18. Has urine protein ≥1 g/24-hour
19. Has prolongation of QTc interval (calculated using Fridericia’s formula) of >480 msec
20. Has LVEF below the institutional normal range as determined by MUGA or echocardiogram
21. Has received prior radiotherapy within 2 weeks of Cycle 1 Day 1. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
22. Has received a live vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
23. 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.
24. Had a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
25. Has had an allogeneic tissue/solid organ transplant
26. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response (OR): Complete Respons or Partial Response, per RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, by BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Approximately 12 months after the allocation of last participant. No planned interim analyses will be performed. |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS) per RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, assessed by BICR; PFS is defined as The time from first day of study intervention to the first documented disease progression or death due to any cause, whichever occurs first.
2. overall survival (OS), defined as The time from first day of study intervention to death due to any cause.
3. Duration of response (DOR) per RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, assessed by BICR; For participants who demonstrate CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Approximately 12 months after the allocation of last participant. No planned interim analyses will be performed. |
|
| 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 | 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.8.3 |
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 | 8 |
| 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 |
| Canada |
| Spain |
| Sweden |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
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