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 informed
consent with histologically or cytologically confirmed TNBC (Cohort 1), NSCLC (Cohort
2), or solid tumors other than TNBC and NSCLC (Cohort 3) with brain metastasis and
with or without active extracranial disease will be enrolled in this study.
2. Has at least 1 measurable brain metastasis: Presence of at least 1 independently
verified measurable brain metastasis in accordance with mRECIST (Appendix 1) that can
be accurately assessed at baseline and suitable for accurate repeated measurements 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 3
weeks prior to study treatment initiation, provided that neurologic sequelae have
completely resolved and measurable untreated lesion(s) remain.
If the patient had
prior whole brain radiation therapy or SRS, progression in any measurable brain
metastasis must have occurred at least 1 month after the end of radiation therapy
for the irradiated lesion to be counted as measurable.
- - Patients can have asymptomatic (no neurologic signs or symptoms, not requiring
immediate local intervention [surgery or radiosurgery] or systemic glucocorticoid
therapy [within 10 days prior to study treatment initiation]) OR minimally
symptomatic brain metastases (requiring ≤10 mg prednisone or equivalent per day
and not requiring immediate surgical or radiation therapy in the opinion of the
treating investigator and a radiation therapy or neurosurgical consultant).
3. Extracranial disease is not required and if present, it can be measurable or
non-measurable (RECIST v1.1).
4. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR. 2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 during the
treatment period and for at least 120 days after the last dose of study
treatment.
5. A male patient must agree to use contraception as detailed in Appendix 6 of this
protocol during the treatment period and for at least 120 days after the last dose of
study treatment and refrain from donating sperm during this period.
6. The patient (or legally acceptable representative if applicable) provides written
informed consent for the study.
7. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix
7).
8. Has a life expectancy ≥12 weeks.
9. Has adequate organ function within 28 days of study treatment initiation as defined
below:
- - Absolute neutrophil count ≥1000/µL (without granulocyte colony-stimulating factor
support within 2 weeks of laboratory test used to determine eligibility)
- Platelet count ≥100 000/µL (without transfusion within 2 weeks of laboratory test
used to determine eligibility)
- Hemoglobin ≥9.0 g/dL.
- - Total bilirubin ≤1.5 × upper limit of normal (ULN); if hepatic metastases are
present, ≤2.0 × ULN.
- - Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN; if
hepatic metastases are present, ≤5.0 × ULN.
- - Creatinine clearance ≥50 mL/min.
- - International normalized ratio (INR) OR prothrombin time (PT) and activated
partial 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 in antihypertensive
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 HBV
antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior
to randomization.
- - Participants should remain on anti-viral therapy throughout study intervention
and follow local guidelines for HBV anti-viral therapy post completion of study
intervention.
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 BRAF
V600E; 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 brain
metastasis are excluded from this trial because the dose of lenvatinib approved for
this disease is different than the ones used in this trial.
3. Has symptomatic or untreated spinal cord compression. Patients with clinical or
radiographic evidence of leptomeningeal metastases or other metastatic systemic
disease are not allowed. In cases where brain metastases are superficially located
(cortical-based brain metastasis) and leptomeningeal spread is suspected, a work-up
for leptomeningeal disease (LMD) should be performed (MRI and lumbar puncture with CSF
cytology). If LMD is not confirmed, the treating physician, neuro-oncologist, or brain
metastasis multidisciplinary team should make a clinical call and exclude the patient
if LMD dissemination is likely.
4. Has received prior therapy with lenvatinib or other antiangiogenic tyrosine kinase
inhibitor alone or in combination with a PD-1/PD-L1 inhibitor. Prior therapy with an
anti-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 agents within
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. Patients with
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 major
surgery.
Withhold lenvatinib treatment for at least 1 week prior to elective
surgery. Do not administer lenvatinib for at least 2 weeks following major
surgery 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 require corticosteroids
in dosing exceeding 10 mg daily of prednisone equivalent, and not have had radiation
pneumonitis. Any radiation to the brain or spinal cord/cauda equina 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 study
treatment initiation. Administration of killed vaccines is allowed.
8. Is currently participating in or has participated in a study of an investigational
agent 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 may
participate as long as it has been 28 days after the last dose of the previous
investigational 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 of
immunosuppressive therapy within 7 days prior to study treatment initiation.
12. Has a known additional malignancy that is progressing or has required active treatment
within the past 5 years.
Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded.
13. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or lenvatinib and/or any of
their excipients.
14. Has a condition requiring systemic treatment with either corticosteroids (>10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days of study
treatment initiation. Inhaled or topical steroids, and adrenal replacement steroid
doses ≤10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.
15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
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 laboratory abnormality
that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator.
21. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study.
22. 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 study treatment.
23. GI tract disease causing the inability to take oral medication, malabsorption
syndrome, a requirement for IV alimentation, prior surgical procedures affecting
absorption, 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 of congestive
heart failure greater than New York Heart Association Class II (Appendix 8), unstable
angina, myocardial infarction or stroke within previous 6 months, or cardiac
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 0.5
teaspoon) with 28 days of enrollment.
29. Has bleeding or thrombotic disorder(s) or uses anticoagulants such as warfarin or
similar agents requiring therapeutic INR monitoring. Treatment with low molecular
weight heparin is allowed.
30. Electrolyte abnormalities that have not been corrected.
31. Patients having >1+ proteinuria on urine dipstick testing unless a 24-hour urine
collection for quantitative assessment indicates that the urine protein is <1 g/24
hours.
32. Has had an allogeneic tissue/solid organ transplant.
33. Has radiographic evidence of intratumoral cavitation, encasement, or invasion of a
major blood vessel.
