| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010036 |
| E.1.2 | Term | Colorectal carcinoma |
| 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 lenvatinib+pembrolizumab combination therapy to standard of care (SOC) with respect to overall survival (OS). |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare lenvatinib+pembrolizumab combination therapy to SOC with respect to 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)
2. To compare lenvatinib+pembrolizumab combination therapy to SOC with respect to objective response rate (ORR) per RECIST 1.1 as assessed by BICR
3. To assess the efficacy of lenvatinib+pembrolizumab combination therapy and SOC with respect to duration of response (DOR) per RECIST 1.1 by BICR
4. To evaluate the safety and tolerability of pembrolizumab+lenvatinib versus SOC
5. To compare the change from baseline in global health status/quality of life (QoL), physical functioning, appetite loss and bloating for lenvatinib+pembrolizumab combination therapy to SOC
6. To compare the time to deterioration (TTD) in global health status/QoL, physical functioning, appetite loss and bloating for lenvatinib+pembrolizumab combination therapy to SOC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically or cytologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma (Stage IV A, B and C as defined by AJCC 8th edition).
2. Has been previously treated for their disease and progressed on or after or could not tolerate standard treatment, which must include ALL of the following agents if approved and locally available in the country where the participant is randomized:
a. Fluoropyrimidine, irinotecan and oxaliplatin
b. With or without an anti-VEGF monoclonal antibody (bevacizumab)
c. With anti-EGFR mAbs (cetuximab or panitumumab) for RAS (KRAS/NRAS) WT participants
d. BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E mutated mCRC
3. Has measurable disease per RECIST 1.1 assessed by the investigator.
4. Has provided to a designated central laboratory an archival tumor tissue sample or newly obtained core, incisional or excisional biopsy of a tumor lesion which has not been previously irradiated. Formalin-fixed, paraffin embedded tissue blocks are preferable to slides. Newly obtained biopsies are preferable to archived tissue.
5. Has an ECOG performance status of 0 to 1 within 3 days prior to randomization.
6. Has a life expectancy of at least 3 months, based on the investigator assessment.
7. Has the ability to swallow capsules or ingest a suspension orally or by a feeding tube.
8. 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.
9. Has adequate organ function. Specimens must be collected within 3 days prior to the start of study intervention.
10. Is male or female ≥18 years of age at the time of providing documented informed consent.
11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of regorafenib or TAS-102 and at least 7 days after the last dose of lenvatinib:
-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 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.
• 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 drugs is more stringent than the requirements above, the local label requirements should be followed.
12. 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 low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least 30 days after the last dose of lenvatinib, 120 days after the last dose of pembrolizumab (whichever is last), and 180 days after the last dose of regorafenib or TAS-102 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 in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention.
- 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.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to dein crease 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.
13. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. |
|
| E.4 | Principal exclusion criteria |
1. Has a tumor that is MSH-H/dMMR per local testing.
2. Has presence of gastrointestinal condition, that might affect the absorption of study drug.
3. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment. The participant can receive diuretic drugs as needed per the treating physician, outside of the above-mentioned conditions.
4. Has radiographic evidence of encasement or invasion of a major blood vessel invasion, or of intratumoral cavitation.
5. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
6. 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.
7. Has a history of arterial thromboembolism within 12 months of start of study drug.
8. Has urine protein ≥1 g/24h.
9. Has prolongation of QTcF interval to >480 ms.
10. Has LVEF below the institutional (or local laboratory) normal range as determined by MUGA or ECHO.
11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions include early stage cancers treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
12. Has serious nonhealing wound, ulcer or bone fracture.
13. Has had major surgery within 3 weeks prior to first dose of study interventions.
14. Has received biologic response modifiers within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided that no dose adjustments were made within 2 months before first dose of study treatment.
15. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
16. Has received prior treatment with a combination of an anti-PD-1, anti-PD-L1, or anti PDL2 agent with anti-VEGF mAbs or VEGFR inhibitors.
17. Has previously received regorafenib or TAS-102.
18. Has received prior systemic anti-cancer therapy including investigational agents within 28 days prior to randomization.
19. Has received prior radiotherapy within 2 weeks of start of study intervention. 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. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
20. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines are allowed.
21. Has known intolerance to lenvatinib, regorafenib or TAS-102 and/or any of their excipients.
22. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study intervention.
23. Has known CNS metastases and/or carcinomatous meningitis.
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
25. 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.
26. 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 medication.
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. No HIV testing is required unless mandated by local health authority.
30. Has a known history of Hepatitis B or known active Hepatitis C virus infection.
31. 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.
32. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
33. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 40 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
3. Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
4. Number of Participants Who Experience an Adverse Event (AE)
5. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
6. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
7. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning (Items 1-5) Score
8. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Appetite Loss (Item 13) Score
9. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
10. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
11. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning (Items 1-5) Score
12. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Appetite Loss (Item 13) Score
14. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 40 months
2. Up to approximately 40 months
3. Up to approximately 40 months
4. Up to approximately 40 months
5. Up to approximately 40 months
6. Baseline and up to approximately 40 months
7. Baseline and up to approximately 40 months
8. Baseline and up to approximately 40 months
9. Baseline and up to approximately 40 months
10. Up to approximately 40 months
11. Up to approximately 40 months
12. Up to approximately 40 months
13. Up to approximately 40 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
| Denmark |
| Germany |
| Spain |
| United Kingdom |
| Argentina |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 40 |
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