Phase II Study of Pembrolizumab in Combination With Lenvatinib in Patients With TNBC, NSCLC, and Other Tumor Types and Brain Metastases

Inclusion Criteria:

Patients are eligible to be included in the study only if all the following criteria apply:

1. Male/female patients who are at least 18 years of age on the day of signing informedconsent with histologically or cytologically confirmed TNBC (Cohort 1), NSCLC (Cohort 2), or solid tumors other than TNBC and NSCLC (Cohort 3) with brainmetastasis and with or without active extracranial disease will be enrolled in thisstudy.

2. Has at least 1 measurable brain metastasis: Presence of at least 1 independentlyverified measurable brain metastasis in accordance with mRECIST (Appendix 1) thatcan be accurately assessed at baseline and suitable for accurate repeatedmeasurements and with a tumor diameter of 0.5-3 cm on magnetic resonance imaging [MRI]).

• Previous SRS and excision of up to 5 brain metastases are permitted at least 3weeks prior to study treatment initiation, provided that neurologic sequelaehave completely resolved and measurable untreated lesion(s) remain. If thepatient had prior whole brain radiation therapy or SRS, progression in anymeasurable brain metastasis must have occurred at least 1 month after the endof radiation therapy for the irradiated lesion to be counted as measurable.

• Patients can have asymptomatic (no neurologic signs or symptoms, not requiringimmediate local intervention [surgery or radiosurgery] or systemicglucocorticoid therapy [within 10 days prior to study treatment initiation]) ORminimally symptomatic brain metastases (requiring ≤10 mg prednisone orequivalent per day and not requiring immediate surgical or radiation therapy inthe opinion of the treating investigator and a radiation therapy orneurosurgical consultant).

3. Extracranial disease is not required and if present, it can be measurable ornon-measurable (RECIST v1.1).

4. A female patient is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:

5. Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR

6. A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 duringthe treatment period and for at least 120 days after the last dose of studytreatment.

7. A male patient must agree to use contraception as detailed in Appendix 6 of thisprotocol during the treatment period and for at least 120 days after the last doseof study treatment and refrain from donating sperm during this period.

8. The patient (or legally acceptable representative if applicable) provides writteninformed consent for the study.

9. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 7).

10. Has a life expectancy ≥12 weeks.

11. Has adequate organ function within 28 days of study treatment initiation as definedbelow:

• Absolute neutrophil count ≥1000/µL (without granulocyte colony-stimulatingfactor support within 2 weeks of laboratory test used to determine eligibility)

• Platelet count ≥100 000/µL (without transfusion within 2 weeks of laboratorytest used to determine eligibility)

• Hemoglobin ≥9.0 g/dL

• Total bilirubin ≤1.5 × upper limit of normal (ULN); if hepatic metastases arepresent, ≤2.0 × ULN

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN; ifhepatic metastases are present, ≤5.0 × ULN

• Creatinine clearance ≥50 mL/min

• International normalized ratio (INR) OR prothrombin time (PT) and activatedpartial thromboplastin time (aPTT) ≤1.5 × ULN.

10. Adequately controlled blood pressure with 0 or 1 antihypertensive medication (defined as blood pressure ≤150/90 mmHg at screening and no changes inantihypertensive medication within 7 days of Day 1 of Cycle 1).

11. Hepatitis B and C screening tests are not required unless:

• Known history of HBV or HCV infection

• As mandated by local health authority 11.1 Hepatitis B positive subjects

• Participants who are HBsAg positive are eligible if they have received HBVantiviral therapy for at least 4 weeks and have undetectable HBV viral loadprior to randomization.

• Participants should remain on anti-viral therapy throughout study interventionand follow local guidelines for HBV anti-viral therapy post completion of studyintervention

11.2 Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.

• Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.

Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply, unless medically indicated and after approval by study chair/IRB office:

1. Has NSCLC with an oncogenic driver mutation (mutation[s] in EGFR, ERBB2, or BRAFV600E; fusion/rearrangement[s] in ALK, ROS1, NTRK, or RET; or MET amplification).KRAS or PIK3CA mutation are allowed.

2. Has hepatocellular carcinoma. NOTE: patients with hepatocellular carcinoma and brainmetastasis are excluded from this trial because the dose of lenvatinib approved forthis disease is different than the ones used in this trial.

3. Has symptomatic or untreated spinal cord compression. Patients with clinical orradiographic evidence of leptomeningeal metastases or other metastatic systemicdisease are not allowed. In cases where brain metastases are superficially located (cortical-based brain metastasis) and leptomeningeal spread is suspected, a work-upfor leptomeningeal disease (LMD) should be performed (MRI and lumbar puncture withCSF cytology). If LMD is not confirmed, the treating physician, neuro-oncologist, orbrain metastasis multidisciplinary team should make a clinical call and exclude thepatient if LMD dissemination is likely.

4. Has received prior therapy with lenvatinib or other antiangiogenic tyrosine kinaseinhibitor alone or in combination with a PD-1/PD-L1 inhibitor. Prior therapy with ananti-PD-1, anti-PD-L1, anti-PD L2, or anti-CTLA-4 agent or chemotherapy is allowed.

5. Has received prior systemic anticancer therapy including investigational agentswithin 28 days prior to study treatment initiation.

• Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Patients with ≤ Grade 2 neuropathy may be eligible. Patientswith immunotherapy-related AEs of a permanent nature but manageable (hypothyroidism on thyroid hormone replacement, vitiligo, etc.) are eligible.

• Patients must have recovered adequately from any complications from majorsurgery. Withhold lenvatinib treatment for at least 1 week prior to electivesurgery. Do not administer lenvatinib for at least 2 weeks following majorsurgery and until adequate wound healing.

6. Has received radiotherapy within 14 days prior to study treatment initiation.Patients must have recovered from all radiation-related toxicities, not requirecorticosteroids in dosing exceeding 10 mg daily of prednisone equivalent, and nothave had radiation pneumonitis. Any radiation to the brain or spinal cord/caudaequina must have been completed within >3 weeks from study treatment initiation.

7. Has received a live vaccine or live-attenuated vaccine within 30 days prior to studytreatment initiation. Administration of killed vaccines is allowed.

8. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 28 days or 5 half-lives,whichever is shorter, prior to study treatment initiation. Note: Patients who have entered the follow-up phase of an investigational study mayparticipate as long as it has been 28 days after the last dose of the previousinvestigational agent.

9. Contraindications to MRI (implanted metal device or foreign bodies) or MRI contrast (insufficient renal function or allergy).

10. A WOCBP who has a positive screening serum pregnancy test within 7 days prior to Day 1 of Cycle 1 (see Appendix 6).

11. 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 ofimmunosuppressive therapy within 7 days prior to study treatment initiation.

12. Has a known additional malignancy that is progressing or has required activetreatment within the past 5 years. Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) thathave undergone potentially curative therapy are not excluded.

13. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or lenvatinib and/or any oftheir excipients.

14. Has a condition requiring systemic treatment with either corticosteroids (>10 mgdaily prednisone equivalent) or other immunosuppressive medications within 14 daysof study treatment initiation. Inhaled or topical steroids, and adrenal replacementsteroid doses ≤10 mg daily prednisone equivalent, are permitted in the absence ofactive autoimmune disease.

15. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

16. Has an active infection requiring systemic therapy.

17. Has a known history of human immunodeficiency virus.

18. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA)and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)infection. Note: Hepatitis B and C screening tests are not required unless:

• Known history of HBV and HCV infection

• As mandated by local health authority

19. Active tuberculosis (Bacillus Tuberculosis).

20. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thepatient's participation for the full duration of the study, or is not in the bestinterest of the patient to participate, in the opinion of the treating investigator.

21. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the study.

22. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of study treatment.

23. GI tract disease causing the inability to take oral medication, malabsorptionsyndrome, a requirement for IV alimentation, prior surgical procedures affectingabsorption, or uncontrolled inflammatory GI disease (e.g., Crohn's disease,ulcerative colitis).

24. Unable to swallow and retain oral medications.

25. Has significant cardiac impairment including but not limited to history ofcongestive heart failure greater than New York Heart Association Class II (Appendix 8), unstable angina, myocardial infarction or stroke within previous 6 months, orcardiac arrhythmia requiring medical treatment at the time of screening.

26. Has prolongation of QTc using Fridericia's formula (QTcF) to >480 ms.

27. Has gastric or esophageal varices that may require treatment.

28. Having a GI bleeding event or active hemoptysis (bright red blood of at least 0.5teaspoon) with 28 days of enrollment.

29. Has bleeding or thrombotic disorder(s) or uses anticoagulants such as warfarin orsimilar agents requiring therapeutic INR monitoring. Treatment with low molecularweight heparin is allowed.

30. Electrolyte abnormalities that have not been corrected.

31. Patients having >1+ proteinuria on urine dipstick testing unless a 24-hour urinecollection for quantitative assessment indicates that the urine protein is <1 g/24hours.

32. Has had an allogeneic tissue/solid organ transplant.

33. Has radiographic evidence of intratumoral cavitation, encasement, or invasion of amajor blood vessel.