MK-3475-U03

1. Must have a histologically confirmed diagnosis of locally advanced/metastatic clear cell RCC (with or without sarcomatoid features), ie, Stage IV ccRCC per AJCC.

2. Have received no prior systemic therapy for advanced RCC. [1L participants] Note: Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed ≥ 12 months prior to randomization.

3. Have measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

4. Have a KPS ≥ 70%.

5. Be able to swallow oral medication.

6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.

7. Have adequate organ function as defined in (Table 1). Specimens must be collected within 10 days prior to the start of study intervention and assessed by central laboratory prior to randomization/allocation.

8. Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to randomization.

9. Have resolution of the toxic effect(s) of the most recent prior therapy to ≤ Grade 1 (except alopecia or Grade 2 hypothyroidism). If participant received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.

10. Is male or female, from 18 years to 120 years of age inclusive, at the time of signing the informed consent.

11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention:

• 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.

• Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.

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 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 study intervention 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, non-compliance, recently initiated) in relationship to the first dose of study intervention.

• A WOCBP must have a negative highly sensitive pregnancy test (urine) 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.

13. The participant (or legally acceptable representative if applicable) provides written informed consent for the study.

Substudy 03B: 2L+ RCC: A participant will be eligible for inclusion in the study if the participant:

1. Must have a histologically confirmed diagnosis of locally advanced/metastatic clear cell RCC (with or without sarcomatoid features), ie, Stage IV RCC per American Joint Committee on Cancer (AJCC).

2. Have experienced disease progression on or after having received systemic treatment for advanced disease with a PD1/L1 checkpoint inhibitor and a VEGF-TKI. The PD1/L1 checkpoint inhibitor and VEGF-TKI may have been received in combination or in sequence. [2L+ post-IO/post-VEGF-TKI participants].

Note: There is no wash out period required.

Treatment progression is defined by meeting all of the following criteria:

(a) Has received an approved VEGF-TKI.

(b) Has received at least 2 doses of an approved anti-PD-1/L1 mAb.

(c) Has demonstrated disease progression as defined by RECIST 1.1. If clinically indicated, the initial evidence of PD is to be confirmed by a second assessment on a scan performed no less than 4 weeks from the date of the first documented PD.

3. Have measurable disease per RECIST 1.1 as assessed BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

4. Have a KPS ≥ 70%.

5. Able to swallow oral medication.

6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.

7. Have adequate organ function as defined in Table 2. Specimens must be collected within 10 days prior to the start of study intervention and assessed by central laboratory prior to randomization/allocation.

8. Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to treatment.

9. Have resolution of the toxic effect(s) of the most recent prior therapy to ≤ Grade 1 (except alopecia or Grade 2 hypothyroidism). If participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.

10. Is male or female, from 18 years to 120 years of age inclusive, at the time of signing the informed consent.

11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention:

• 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.

• Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.

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 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 study intervention 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, non-compliance, recently initiated) in relationship to the first dose of study intervention.

• A WOCBP must have a negative highly sensitive pregnancy test (urine) 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.

13. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. 

Substudy 03A: 1L RCC The participant must be excluded from the study if the participant:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Note: In the event that 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 in order for subject to start receiving study medication.

2. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.

3. Prolongation of QTc interval to > 480 ms.

4. LVEF below the institutional normal range as determined by MUGA or ECHO.

5. 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.

6. Has poorly controlled hypertension, defined as SBP ≥ 150 mm Hg and/or DBP ≥ 90 mm Hg.

7. Proteinuria > 1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥ 1 g/24 h will be ineligible.

8. Has a history of interstitial lung disease.

9. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.

10. Has a history of inflammatory bowel disease.

11. Has pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula.

12. Has malabsorption due to prior GI surgery or GI disease.

13. 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).

14. 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.

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.

16. Is currently participating in a study of an investigational agent or is currently using an investigational device.

Note: Participants who have entered the follow-up phase of an investigational study may participate.

17. Participants who have been previously allocated/randomized to study intervention in any substudy of protocol MK-3475-U03.

18. 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.

19. 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.

20. 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.

21. Has a history of hypersensitivity reaction to any of the investigational agent(s) included this study. For example, but not limited to:

• Has a severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.

• Has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema, or anaphylaxis) to lenvatinib.

• Has had a previous severe hypersensitivity reaction to treatment with an mAb.

22. Has an active autoimmune disease that has required systemic treatment in the 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.

Note: Participants with vitiligo, Sjøgren’s syndrome, Type I diabetes, or resolved childhood asthma/atopy will not be excluded from the study. Participants requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Participants with hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement will not be excluded from the study.

23. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

24. Has an active infection requiring systemic therapy.

25. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.

26. 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.

27. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).

28. 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.

29. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

30. 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 (females) or 180 days (males) after the last dose of study intervention.

31. Has had an allogenic tissue/solid organ transplant.

Substudy 03B: 2L+ RCC

The participant must be excluded from the study if the participant:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Note: In the event that 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 in order for subject to start receiving study medication.

2. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.

3. Prolongation of QTc interval to > 480 ms.

4. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

5. 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.

6. Has poorly controlled hypertension, defined as systolic blood pressure (SBP) ≥ 150 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg.

7. Proteinuria > 1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥ 1 g/24 h will be ineligible.

8. Has a history of interstitial lung disease.

9. Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.

10. Has a history of inflammatory bowel disease.

11. Has pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula.

12. Has malabsorption due to prior GI surgery or GI disease.

13. 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.

14. 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.

15. Has received more than 4 previous systemic anti-cancer treatment regimens.

16. Is currently participating in a study of an investigational agent or is currently using an investigational device.

Note: Participants who have entered the follow-up phase of an investigational study may participate.

17. Participants who have been previously allocated/randomized to study intervention in any substudy of protocol MK-3475-U03.

18. 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.

19. 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.

20. 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.

21. Has a history of hypersensitivity reaction to any of the investigational agent(s) included in this study. For example, but not limited to:

• Has a severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.

• Has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema, or anaphylaxis) to lenvatinib.

• Has had a previous severe hypersensitivity reaction to treatment with an mAb.

22. Has an active autoimmune disease that has required systemic treatment in the 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.

Note: Participants with vitiligo, Sjøgren’s syndrome, Type I diabetes, or resolved childhood asthma/atopy will not be excluded from the study. Participants requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Participants with hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement will not be excluded from the study.

23. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

24. Has an active infection requiring systemic therapy.

25. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.

26. 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.

27. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).

28. 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.

29. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

30. 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 (females) or 180 days (males) after the last dose of study intervention.

31. Has had an allogenic tissue/solid organ transplant. 

Research Nurse: Debbie Whittaker (x4656) Debra-Jane.Whittaker@lthtr.nhs.uk

Administrator: Robert Speirs (x8475)