| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent/metastatic head and neck squamous cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) which has progressed after treatment with both platinum therapy and most recently immunotherapy |
|
| 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 | 27.0 |
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 lenvatinib (MK-7902/E7080) + pembrolizumab (MK-
3475) combination therapy and standard of care (SOC) chemotherapy with respect to objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by blinded independent central review. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare lenvatinib + pembrolizumab combination therapy and standard of care (SOC) chemotherapy with respect to progression-free survival (PFS) per modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by blinded independent central review.
2. To compare lenvatinib + pembrolizumab combination therapy and standard of care (SOC) chemotherapy with respect to overall survival (OS).
3. To compare lenvatinib + pembrolizumab combination therapy and standard of care (SOC) chemotherapy with respect to duration of response (DOR) per modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by blinded independent central review.
4. To assess the safety and tolerability of lenvatinib + pembrolizumab combination therapy, standard of care (SOC) chemotherapy, and lenvatinib monotherapy.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female and at least 18 years of age on the day of providing documented informed consent
2.Have pathologically confirmed recurrent or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
3.Experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab
4.Disease progression on or after treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Anti-PD-1/PD-L1 treatment progression is defined by meeting all the following criteria:
-Treatment with an anti-PD-1/PD-L1 mAb
-Received at least 2 doses of an anti-PD-1/PD-L1 mAb
-Demonstrated disease progression on or after an anti-PD-1/PD-L1 mAb as defined by RECIST 1.1
-Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb
5.Submitted pre-study imaging that demonstrates evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor
6.Documentation of results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using the CINtec® p16 Histology assay and a 70% cutoff point. If HPV status has previously been tested using this procedure, no retesting is required
7. Provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not adequate) not previously irradiated.
Repeat samples may be required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior to start of study treatment)
is strongly preferred, but an archival sample is acceptable
8.Measurable disease by CT or MRI based on RECIST 1.1 as verified by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
9.ECOG performance status of 0 or 1 assessed within 7 days of the first dose
10.Male participants are eligible to participate if they agree to the following during the intervention period and for at least: 1 week after the last dose of lenvatinib; 3 months after the last dose of capecitabine and paclitaxel; and 6 months after the last dose of docetaxel. No male contraception is needed for pembrolizumab and cetuximab.
-Refrain from donating sperm
PLUS either:
-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
11.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 randomized to lenvatinib + pembrolizumab (Arm 1) or lenvatinib monotherapy (Arm 3) 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 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 1 month post lenvatinib, whichever occurs last.
-A WOCBP randomized to SOC chemotherapy is eligible to participate if she is using a contraceptive method that is highly effective with low user
dependency or abstinent from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate or freeze/store eggs during
the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of
cetuximab.
-A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose
-If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
-Abstains from breastfeeding during the study intervention period and for at least 180 days after the last dose of chemotherapy, 1 month after the last dose of lenvatinib, or 120 days after the last dose of pembrolizumab.
12.Provides documented informed consent for the study
13.Adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications for at least 1 week prior to randomization
14.Adequate organ function
15.Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV
viral load prior to randomization.
16.Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. |
|
| E.4 | Principal exclusion criteria |
1. Removed, redundant with Inclusion Criterion #2.
2. 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
3. Has disease that is suitable for local therapy administered with curative intent
4. Has a life expectancy of less than 3 months and/or has rapidly progressing disease, in the opinion of the treating investigator
5. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to randomization
6. Has ulceration and/or fungation of disease onto the skin surface
7. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90 degree abutment or encasement of a major blood vessel
8. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease
9. Has an active infection requiring systemic therapy
10. 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 to the first dose of study drug
11. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
12. Has a known additional malignancy that is progressing or has required active systemic treatment within the past 3 years
13. Has an active autoimmune disease that has required systemic treatment in the past 2 years
14. Has had an allogeneic tissue/solid organ transplant
15. Has a known history of HIV infection
16. Removed, not relevant due to addition of Inclusion Criteria #15 and #16
17. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥Grade 3), lenvatinib or SOC chemotherapy
18. Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
19. Has a history of a gastrointestinal malabsorption or any other
condition or procedure that may affect oral study drug absorption
20. Has had major surgery within 3 weeks prior to first dose of study interventions
21. 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 /transient ischemic attack /stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability
22. Has active tuberculosis
23. Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding tube
24. Patients previously treated to one of the 4 SOC agents in this trial may not receive the same agent if randomized to the SOC chemotherapy arm
25. Has had prior treatment with lenvatinib as monotherapy or in combination with an PD-1/PD-L1 inhibitor or other therapies
26. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered from AEs due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.
27. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention.
28. Was previously treated with 4 or more systemic regimens given for R/M disease
29. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
30. Has urine protein ≥1 g/24 hours
31. Has prolongation of QTc interval to >480 msec
32. Has a LVEF below the institutional (or local laboratory) normal
range, as determined by MUGA or ECHO
33. Has a history or current evidence of any condition, therapy, or laboratory abnormality that may 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, in the opinion of the treating investigator
34. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 4 years |
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review
2. Overall Survival (OS)
3. Duration of Response (DOR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review
4. Number of Participants Who Experienced One or More Adverse Events (AEs)
5. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 years
2. Up to approximately 4 years
3. Up to approximately 4 years
4. Up to approximately 4 years
5. Up to approximately 4 years
|
|
| 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 | Yes |
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Taiwan |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| United Kingdom |
| United States |
| Denmark |
| France |
| Norway |
| Portugal |
| Romania |
| Spain |
|
| 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
|
| receipt of the last laboratory result or LVLS, whichever comes last |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 51 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 51 |
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