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A Phase 3, Randomized, Placebo-controlled, Double-blind Clinical Study of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) to Evaluate the Safety and Efficacy of Pembrolizumab and Lenvatinib as 1L Intervention in a PD-L1 Selected Population of Participants With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) - MK-7902-010 (LEAP-010).

Studio Clinico

Patologia: Tumori della testa e del collo

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: III

Richiesta mandatoria di tessuto: 

Linee di trattamento: Prima linea

Criteri di inclusione: 

1. Has histologically confirmed diagnosis of R/M HNSCC that is considered incurable by local therapies.
Note: Participants with newly-diagnosed HNSCC must have distant metastases and be Stage M1 at study entry.
2. Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.
Note: Other primary tumor sites of HNSCC, including nasopharynx (any histology) or unknown primary tumor are not eligible.
3. Is male or female, and at least 18 years of age at the time of signing the informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
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 [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.
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male
condom during each episode of penile-vaginal penetration.
    - Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
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), as described in Appendix 5 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.
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 pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    - Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2.
    - The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
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.
Note: Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Has provided an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
Note: Details pertaining to tumor tissue submission can be found in the Procedures Manual.
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.
Note: If local p16 testing results are not available or cannot be assessed using this method, a tumor tissue sample must be submitted for p16 testing at the designated central laboratory, and results must be received prior to randomization.
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 following table (Table 3). Specimens must be collected within 7 days prior to the start of study intervention.
Table 3 Adequate Organ Function Laboratory Values System Laboratory Value:
    - Hematological
Absolute neutrophil count (ANC) ≥1500/μL
Platelets ≥100 000/μL
Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L
Renal Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
International normalized ratio (INR) OR prothrombin time (PT)
Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

Criteri di esclusione: 

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.
Note: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy.
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.
Note: Medically controlled arrhythmia that is stable with medication is permitted.
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.
Note: Prior systemic therapy administered in the recurrent or metastatic setting is not permitted, unless it was given as part of a multimodal treatment for locally advanced
disease.
11. Has 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.
12. Has difficulty swallowing capsules or ingesting a suspension either orally, by a nasogastric (NG) tube, or by a gastrostomy tube.
Note: Gastrostomy tube (PVC, greater than or equal to 6 Fr) can be used to administer lenvatinib suspension.
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.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
17. Has received prior radiotherapy within 2 weeks of start of study intervention.
Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
18. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (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 (eg, FluMist®) are live attenuated vaccines and are not allowed.
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.
Note: Participants who have entered the follow-up phase of an investigational study may participate if it has been 4 weeks since the last dose of the previous
investigational agent.
20. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria >1+ on urine dipstick testing/urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria.
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.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
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 (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 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.
Note: No HIV testing is required unless mandated by local health authority.
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.
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
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.

Trattamento sperimentale: 

Pembrolizumab + Lenvatinib/Placebo

Trattamento di controllo: 

NA

Obiettivi primari dello studio: 

- Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR). [ Time Frame: Up to approximately 24 months ]
    ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experience a CR or PR based on modified RECIST 1.1 will be presented.

- Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR). [ Time Frame: Up to approximately 30 months ]
    PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions is also considered PD.

- Overall Survival (OS) [ Time Frame: Up to approximately 44 months ]
    OS is the time from randomization to death due to any cause.

Centri partecipanti

Nord Italia

Azienda Spedali Civili di Brescia
Piazzale Spedali Civili 1 - 25123 Brescia - BS
Oncologia

Riferimento: Prof. Paolo Bossi
Telefono: 03039951
Email: paolo.bossi@unibs.it

 

Azienda Ospedaliera San Paolo
Via Antonio di Rudinì 8 - 20142 Milano - MI
UO Oncologia Medica

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
Struttura di Oncologia Medica dei Tumori Testa e collo

Riferimento: Dr.ssa Laura Locati
Telefono: 0223902150
Email: laura.locati@istitutotumori.mi.it

 

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI
Oncologia Medica Urogenitale e Cervico Facciale

Riferimento: Dr. Franco Nolè
Telefono: 0257489460
Email: franco.nole@ieo.it

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD
UOC Oncologia 2

Riferimento: Dr.ssa Maria Grazia Ghi
Telefono: 049215931
Email: oncologia2@iov.veneto.it

 

Ospedale San Paolo di Savona ASL 2 Savonese
Via Genova 30 - 17021 Savona - SV
S.C. Oncologia

Riferimento: Dr. Marco
Telefono: 0198404436
Email: m.benasso@asl2.liguria.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2019-003717-34

Data di inserimento: 19.04.2021

Promotore

Merck Sharp & Dohme Corp.

CRO

NA

Principal Investigator ITALIA

Istituto Europeo di Oncologia, Milano

Riferimento: Dr. Franco Nolè

Telefono: 0257489460

Email: franco.nole@ieo.it

Localita: Milano

 

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