Patologia: Tumori dell’esofago
Fase di studio: III
Linee di trattamento: Prima linea
Criteri di inclusione:
1. The participant must have a histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus.
2. The participant must have measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment. A lesion(s) situated in a previously irradiated area can be considered a target lesion(s) if progression has been demonstrated and the lesion(s) is considered measurable per RECIST 1.1 criteria.
Note: The same image acquisition and processing parameters should be used throughout the study for a given participant.
3. Participants are at least 18 years of age on the day 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 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
• 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 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only and is greater than 90 days post chemotherapy, no male contraception measures are needed.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• Refrain from donating sperm during the chemotherapy treatment period and for at least 90 days after the last dose of chemotherapy.
• Refer to Appendix 7 for country-specific requirements.
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
• 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 after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever occurs last, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction
during this period. 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 within 72 hours (serum) or 24 hours (urine) (as required by local regulations) before starting 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 Section 8.3.6.
• 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.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• Refer to Appendix 7 for country-specific requirements.
6. The participant (or legally acceptable representative) provides documented informed consent/assent for the study. Refer to Appendix 7 for country-specific requirements.
7. Has an ECOG performance score of 0 to 1 assessed 0 to 3 days before randomization.
8. Has submitted a tumor tissue sample that meet the acceptance criteria (as defined in the Study Manual) for PD-L1 analysis before randomization. In addition, the PD-L1 composite score (CPS) result must be determined by the central laboratory before randomization. Newly obtained biopsies are preferred to archived tissue.
Note: Archival tumor tissue or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been provided. Details pertaining to tumor tissue submission can be found in the Study Manual.
9. 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.
10. Has adequate organ function as defined in the following table (Table 2). Specimens must be collected within 7 days prior to the start of study intervention.
Criteri di esclusione:
1. Has had previous therapy for locally advanced unresectable or metastatic esophageal cancer. Participants may have received prior neoadjuvant or adjuvant therapy in consideration of the following:
a. Assessment of disease progression should be confirmed by CT scan. In certain situations, clinical evidence of disease progression such as any new or worsening malignant effusion (documented by ultrasound) and confirmation by pathologic
criteria (histology and/or cytology) may be acceptable for assessment.
b. Treatment with curative intent, including neoadjuvant/adjuvant treatment, given as chemotherapy or chemoradiotherapy, using standard of care agents or definitive chemoradiation, will count as a line of therapy if disease progression occurs during
treatment or within 6 months of cessation of treatment.
c. Dose reduction and/or switching of one or more agents due to toxicity/intolerability as deemed clinically appropriate by the investigator will not constitute a new line of therapy.
2. Has locally advanced esophageal carcinoma.
3. Has metastatic adenocarcinoma of the esophagus.
4. Has direct invasion into adjacent organs such as the aorta or trachea (T4b disease).
5. Has radiographic evidence of >90-degree encasement of a major blood vessel, or of intratumoral cavitation.
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.
6. Has perforation risks or significant GI bleeding, such as:
- Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to randomization
- Has significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to randomization
- Has pre-existing ≥Grade 3 GI or non-GI fistula
7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug or tumor bleeding within 2 weeks prior to the first dose of study intervention.
8. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of randomization).
9. Has GI obstruction, poor oral intake, or difficulty in taking oral medication. Participants with existing esophageal stent are not eligible. Also, participants with known gastrointestinal malabsorption or any other condition that may affect the absorption of
10. Has had major surgery, open biopsy, or significant traumatic injury within 3 weeks prior to the first dose of study interventions, or anticipation of the need for major surgery during the course of study intervention.
Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention. Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
11. 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) or has previously participated in a pembrolizumab clinical study.
12. Has received prior therapy with anti-VEGF TKI or anti-VEGF mAb.
13. Is currently receiving brivudine, sorivudine analogs, or other inhibitors of the enzyme dihydropyrimidine dehydrogenase. Refer to Appendix 7 for country-specific requirements.
14. Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis.
Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
15. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
Note: Administration of killed vaccines is allowed.
Prior/Concurrent Clinical Study Experience
16. 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
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
17. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
18. Has inadequate cardiac function assessed as:
QTcF value >470 msec for males and >480 msec for females (mean of 3 measurements corrected for HR using Fridericia's formula).
Cardiac function will be assessed using 12-lead ECG scan and ECHO performed by the investigator or other qualified person prior to enrollment in the study.
19. Has an LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO.
20. 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 intervention, or has a history of organ transplant, including allogeneic stem cell transplant.
21. 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.
22. 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.
23. Has severe hypersensitivity (≥Grade 3) to treatment with an mAb or known sensitivity or intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum containing products.
24. 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. Brief (ie, <7 days) use of systemic corticosteroids is allowed when use is considered standard of care by investigator.
25. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
26. Has an active infection requiring systemic therapy.
27. Has poorly controlled diarrhea (eg, watery stool, uncontrollable bowel movement with drugs, ≥Grade 2 and number of defecations, ≥5/day).
28. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, 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.
Note: Medically controlled arrhythmia would be permitted.
29. Has a history or current evidence of any condition (eg, but not limited to, known deficiency of the enzyme DPD), therapy, or laboratory abnormality (eg., hypokalemia, hypomagnesemia, or hypocalcemia) 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 investigator (refer to Appendix 7 for country-specific requirements).
30. Has peripheral neuropathy ≥Grade 2.
31. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority. Refer to Appendix 7 for country-specific requirements.
32. 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. Refer to Appendix 7 for country-specific requirements.
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. Has weight loss of >20% within the last 3 months.
Pembro+Lenva+FP or FOLFOX6
Trattamento di controllo:
Pembro+FP or FOLFOX6
IRCCS - IRST Meldola Dino Amadori
Via P. Maroncelli 40 - 47014 Meldola - FC
Riferimento: Dr. Luca Frassineti
IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
Riferimento: Dr.ssa Maria Di Bartolomeo
Ospedale San Raffaele di Milano
Via Olgettina 60 - 20132 Milano - MI
Riferimento: Dr.ssa Elena Mazza
Istituto Clinico Humanitas Rozzano
Via Manzoni 56 - 20089 Rozzano - MI
Riferimento: Prof. Armando Santoro
A.O.U. Policlinico di Modena
Via del Pozzo 71 - 41100 Modena - MO
Riferimento: Dr. Andrea Spallanzani
Azienda Ospedaliera Santa Maria della Misericordia
Piazzale Santa Maria della Misericordia 15 - 33100 Udine - UD
Largo Brambilla 3 - 50134 Firenze - FI
Riferimento: Prof. Lorenzo Antonuzzo
AOU Pisana - Santa Chiara
Via Roma 67 - 56126 Pisa - PI
Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM
Riferimento: Prof. Giampaolo Tortora
Università degli Studi Magna Græcia
Viale Europa - 88100 Germaneto - CZ
AOU Renato Dulbecco
AOU degli studi della Campania Luigi Vanvitelli
Piazza Luigi Miraglia 2 - 80138 Napoli - NA
Riferimento: Prof. Ferdinando De Vita
Numero di iscrizione a registro: 2020-001911-26
Data di inserimento: 12.05.2022
Data di aggiornamento: 23.11.2023
Merck Sharp & Dohme LLC
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Riferimento: Prof. Giampaolo Tortora