| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent/Metastatic Head and Neck Cancer |
|
| 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 | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082179 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck metastatic |
| 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 |
1. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to ORR per RECIST 1.1 as assessed by BICR.
2. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to PFS per RECIST 1.1 as assessed by BICR.
3. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to OS. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate pembrolizumab + lenvatinib and pembrolizumab + placebo with respect to DOR per RECIST 1.1 as assessed by BICR.
2. To assess the safety and tolerability of study intervention with pembrolizumab + lenvatinib and pembrolizumab + placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically confirmed diagnosis of R/M HNSCC that is considered incurable by local therapies.
2. Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.
3. Is male or female, and at least 18 years of age at the time of signing the informed consent.
4. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of lenvatinib/placebo:
- 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) 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.
- Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and
at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib/placebo whichever occurs last. 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 asrequired 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 pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
6. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
7. Has measurable disease per RECIST 1.1 as assessed by BICR.
8. Has provided an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
9. Has a PD-L1 positive (CPS ≥1) tumor as determined by the central laboratory.
10. Participants with oropharyngeal cancer must have results from testing of HPV status defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If HPV status was previously tested using this method, no additional testing is required.
11. Has an ECOG performance score of 0 to 1.
12. Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
13. Has adequate organ function as defined in the protocol. Specimens must be collected within 7 days prior to the start of study intervention. |
|
| E.4 | Principal exclusion criteria |
1. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to randomization.
2. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90 degree abutment or encasement of a major blood vessel.
3. Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer.
4. Has ulceration and/or fungation of disease onto the skin surface.
5. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥Grade 3) or lenvatinib.
6. Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
7. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption.
8. Has clinically significant cardiovascular impairment within 12 months of the first dose of study drug, such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident/TIA/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability.
9. Has disease that is suitable for local therapy administered with curative intent.
10. Had PD within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
11. Has had major surgery within 3 weeks prior to first dose of study interventions.
12. Has difficulty swallowing capsules or ingesting a suspension either orally or by a nasogastric (NG) tube.
13. Has received prior therapy with lenvatinib or pembrolizumab.
14. Received last dose of systemic therapy for locoregionally advanced disease less than 6 months prior to signing consent
15. 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, CD137).
16. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
17. Has received prior radiotherapy within 2 weeks of start of study intervention.
18. Has received a live vaccine within 30 days prior to the first dose of study drug.
19. 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.
20. Has urine protein ≥1 g/24 hours.
21. Has prolongation of QTc interval (calculated using Fridericia’s formula) to >480 msec.
22. Has a LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO.
23. 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 prior the first dose of study drug.
24. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
25. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
26. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
27. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
28. Has an active infection requiring systemic therapy.
29. Has a known history of HIV infection.
30. Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected)
infection.
31. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
32. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's 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.
33. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
34. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention.
35. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Objective Response Rate per RECIST 1.1 as Assessed by BICR.
2. Progression Free Survival per RECIST 1.1 as Assessed by BICR.
3. Overall Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 30 months
3. Up to approximately 44 months |
|
| E.5.2 | Secondary end point(s) |
1. Duration of Response
2. Number of Participants Who Experienced an Adverse Event (AE)
3. Number of Participants Who Discontinued Study Drug Due to an AE |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 44 months
2. Up to approximately 44 months
3. Up to approximately 44 months
|
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| 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 |
| Brazil |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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