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A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Lenvatinib (E7080/MK-7902) Versus Pembrolizumab and Placebo as First Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express PD-L1, and in Participants Ineligible for Any Platinum-containing Chemotherapy Regardless of PD-L1 Expression - LEAP-011 - MK-7902-011 - AIOM
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A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Lenvatinib (E7080/MK-7902) Versus Pembrolizumab and Placebo as First Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express PD-L1, and in Participants Ineligible for Any Platinum-containing Chemotherapy Regardless of PD-L1 Expression - LEAP-011 - MK-7902-011

Studio Clinico

Patologia: Carcinoma della vescica

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: III

Richiesta mandatoria di tessuto: 

Linee di trattamento: Prima linea

Criteri di inclusione: 

1. Have a histologically or cytologically confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter (upper urinary tract), bladder, or urethra. Both transitional cell and mixed transitional/nontransitional cell histology are allowed, but transitional cell carcinoma must be the predominant histology.
2. Have at least 1 measurable target lesion per RECIST 1.1 as assessed by the local site investigator/radiologist, per the following criteria:
    1) lymph node (LN) lesion measuring ≥15 mm in the short axis;
    2) non-nodal lesion measuring ≥10 mm in the longest diameter;
    3) lesion suitable for repeat measurement with CT/MRI imaging. Lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
3. Have provided an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated and adequate for PD-L1 evaluation. Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. PD-L1 status (CPS ≥10 or CPS <10) must be obtained by the central laboratory during the screening period prior to enrollment.
• Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date they are cut (details pertaining to tumor submission are in the Procedures Manual).
• Note: If PD-L1 is not evaluable (eg, not enough tissue is provided or the tissue is of poor quality, such that assessment of PD-L1 status is not possible) the participant will be excluded.
4. Have received no prior systemic chemotherapy for advanced or metastatic UC with the following exceptions:
• Neoadjuvant platinum-based chemotherapy for treatment of muscle-invasive bladder cancer with recurrence >12 months from completion of the therapy is permitted.
• Adjuvant platinum-based chemotherapy following radical cystectomy, with recurrence >12 months from completion of the therapy, is permitted.
Note: Low-dose chemotherapy (eg, low-dose cisplatin, cisplatin plus 5-FU, mitomycin plus 5-FU, or cisplatin plus paclitaxel), given concurrently with radiation to the primary tumor site for curative intent treatment of muscle-invasive bladder cancer, is not considered systemic therapy. In the clinical setting, chemotherapy is given with the sole purpose of sensitizing the tumor to local radiation, and is not administered at doses with any systemic efficacy. Surgery is not considered 1L therapy following diagnosis of advanced/metastatic disease.
5. Meet criteria for either option a or option b (below):
    a. Have a tumor(s) with PD-L1 CPS ≥10 and be considered ineligible to receive cisplatin-based combination therapy, based on 1 of the following:
• ECOG PS 2 (Appendix 9) within 7 days prior to randomization
• CrCl (calculated or measured using the institutional standard) ≥30 to ≤60 mL/min
• NCI CTCAE Version 4.0 Grade ≥2 audiometric hearing loss (25 dB in 2 consecutive frequency ranges)
• NCI CTCAE Version 4.0 Grade ≥2 peripheral neuropathy
OR
    b.In the opinion of the investigator, be considered ineligible to receive any platinum-based chemotherapy (ie, ineligible for cisplatin and carboplatin) based on:
• ECOG PS 2 within 7 days prior to randomization.
and at least 1 of the following:
• Documented visceral metastatic disease
• CrCl ≥30 to ≤60 mL/min
• NCI CTCAE Version 4.0 Grade ≥2 audiometric hearing loss
• NCI CTCAE Version 4.0 Grade ≥2 peripheral neuropathy
• Other reason, identified on the case report form (CRF), for the participant’s being unable to receive carboplatin safely. Additional criteria for platinum ineligibility will be considered and allowed on a case-by-case basis, following consultation with the Sponsor.
Note: Participants considered ineligible for any platinum-based chemotherapy are eligible for this study regardless of their tumor PD-L1 status.
Note: The reason(s) for ineligibility for cisplatin or any platinum-based chemotherapy must be documented in the participant’s medical record and on the electronic case report form (eCRF).
6. Be male or female and ≥18 years of age and considered an adult per local regulations on the day of signing the informed consent.
7. Have ECOG PS 0, 1, or 2 within 7 days prior to randomization and a life expectancy of ≥3 months.
8. 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 her 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 after the last dose of pembrolizumab or lenvatinib/placebo. 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 72 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.

Criteri di esclusione: 

1. Has disease that is suitable for local therapy administered with curative intent (eg, chemotherapy and radiation for Stage 3 disease).
2. Has tumor with any neuroendocrine or small cell component.
3. Has a history of a gastrointestinal condition or procedure (eg, gastric bypass, malabsorption) that, in the opinion of the investigator, may affect oral drug absorption.
4. Has had major surgery within 4 weeks prior to the first dose of study intervention.
Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
5. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
6. Has radiographic evidence of major blood vessel invasion/infiltration, or has had clinically significant hemoptysis (at least 0.5 teaspoon of bright red blood) or tumor bleeding within 2 weeks prior to the first dose of study intervention. 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.
7. Has had significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of NYHA >Class II congestive heart failure, unstable angina, myocardial infarction or cerebrovascular accident (CVA)/stroke, cardiac revascularization procedure, or cardiac arrhythmia associated with hemodynamic instability.
8. Has known intolerance or severe hypersensitivity (Grade ≥3) to pembrolizumab or lenvatinib or any of their excipients
9. Has received lenvatinib as monotherapy or in combination with a PD-1/PD-L1 inhibitor or has previously been enrolled in a clinical study evaluating lenvatinib for bladder cancer, regardless of the treatment received.
10. Is a WOCBP who has a positive urine pregnancy test within 72 hours before randomization (see Appendix 5). If the urine test is positive or 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 test result is positive. If >72 hours have elapsed between the screening pregnancy test and the first dose of study intervention, another pregnancy test (urine or serum) must be performed and must be negative for the participant to start receiving study intervention.
Prior/Concomitant Therapy
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor, indoleamine-pyrrole 2,3 dioxygenase (IDO1) inhibitor, or agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting T-cell costimulatory pathways in the adjuvant or advanced/metastatic setting.
12. Has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities, and must not require corticosteroids.
13. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (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.
14. In the investigator’s judgment, has not recovered from toxicity or other complications from any major surgery prior to starting study intervention.
15. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
16. Has an LVEF below the institutional normal range, as determined by MUGA or ECHO.
17. Has history or presence of an abnormal ECG that, in the investigator’s opinion, is clinically meaningful. Participants with QTcF >480 msec are excluded. If a single QTcF is >480 msec, the participant may be enrolled if the average QTcF for 3 ECGs is <480 msec.
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
19. Has had an active malignancy (except locally advanced or metastatic UC) within the past 36 months.
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) who have undergone potentially curative therapy are not excluded.
• A history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry is acceptable, provided that the participant is considered prostate cancer-free and the following criteria are met:
• Participants who have undergone radical prostatectomy must have undetectable prostate-specific antigen (PSA) for >1 year and at screening.
• Participants who have had radiation must have a PSA doubling time >1 year (based on at least 3 values determined >1 month apart) and a total PSA value which does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL above nadir).
• Participants with untreated low-risk prostate cancer (Gleason score ≤6) on active surveillance with PSA doubling time >1 year (based on at least 3 values determined >1 month apart) are also eligible.
20. Has central nervous system (CNS) metastases, unless the participant has completed local therapy (eg, whole brain radiation therapy, surgery, or radiosurgery) and has discontinued use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study intervention.
21. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Brief (<7 days) use of systemic corticosteroids is allowed when use is considered SOC.
• Participants with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will be an exception to this rule.
• Participants requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded.
• Participants with hypothyroidism that is stable with hormone replacement or Sjøgren’s syndrome will not be excluded. 22.Has a history of (non-infectious) pneumonitis that required systemic steroids, or current pneumonitis.
23. Has an active infection requiring systemic therapy.
24. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
25. Has a known history of or is positive for active hepatitis B (hepatitis B surface antigen [HbsAg] reactive) or has active hepatitis C (HCV RNA). Testing is not required unless mandated by the local health authority.
26. Has active tuberculosis.
27. 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.
28. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
29. Is receiving hemodialysis.
30. A participant with >1+ proteinuria on urinalysis at screening will undergo 24-hour urine collection for quantitative assessment of proteinuria. A participant with urine protein ≥1 g/24 h will be excluded.
31. 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 pembrolizumab and lenvatinib/placebo.
32. Has had an allogeneic tissue/solid organ transplant.

Trattamento sperimentale: 

Pembrolizumab+Lenvatinib

Trattamento di controllo: 

Pembrolizumab+Placebo

Obiettivi primari dello studio: 

- 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 40 months ]
    PFS is defined as the time from randomization to the first documented progressive disease (PD) or death from 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 ≥1 new lesions is also considered PD.
 
- Overall Survival (OS) [ Time Frame: Up to approximately 40 months ]
    OS is defined as the time from randomization to the date of death from any cause.

Centri partecipanti

Nord Italia

Ospedale S.Orsola Malpighi, Università di Bologna
Via Pietro Albertoni 15 - 40138 Bologna - BO

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr.ssa Elena Verzoni
Telefono: 0223904449
Email: elena.verzoni@istitutotumori.mi.it

 

Ospedale Niguarda Ca' Granda
Piazza dell'Ospedale Maggiore 3 - 20162 Milano - MI

 

Centro di Riferimento Oncologico
Via Franco Gallini 2 - 33081 Aviano - PN

 

AOUI Verona - Borgo Trento
Piazzale Aristide Stefani 1 - 37126 Verona - VR

 

Centro Italia

AO S. Maria Terni
Via Tristano di Joannuccio 1 - 05100 Terni - TR

Riferimento: Dr. Sergio Bracarda
Telefono: 0744205631
Email: s.bracarda@aospterni.it

 

Sud Italia e isole

Istituto Tumori “Giovanni Paolo II” IRCCS
Viale Orazio Flacco 65 - 70124 Bari - BA

 

A.O. per l’Emergenza Cannizzaro di Catania
Via Messina 829 - 95126 Catania - CT

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2018-003752-21

Data di inserimento: 16.04.2021

Promotore

Merck Sharp & Dohme Corp.

CRO

NA

Principal Investigator ITALIA

Azienda Ospedaliera Santa Maria, Terni

Riferimento: Dr. Sergio Bracarda

Telefono: 0744205631

Email: s.bracarda@aospterni.it

Localita: Terni

 

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