Inclusion Criteria:
1. Phase 1b: Histologically and/or cytologically confirmed metastatic selected solid
tumor types that have progressed after treatment with approved therapies or for which
there are no standard effective therapies available. If nivolumab or pembrolizumab is
an approved therapy for the participant's tumor type, but the participant has not been
treated with it, the Investigator may enroll the participant in this study.
Phase 2: Histologically and/or cytologically confirmed metastatic selected solid tumor
types with 0-2 prior lines of systemic therapy (unless discussed with the sponsor).
For the non-small cell lung cancer (NSCLC) and melanoma cohorts, participants must
have progressed on or after prior treatment with one anti-PD-1, anti-PD-L1, or
anti-PDL2 agent. For the renal cell carcinoma (RCC) cohort, participants must have
progressed on treatment with an anti- programmed death receptor-1 /programmed death
receptor-ligand 1 monoclonal antibody (anti-PD-1/PD-L1 mAb) administered either as
monotherapy, or in combination with other checkpoint inhibitors or other therapies,
the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy. Selected
tumor types of both phases: NSCLC, predominantly clear cell renal cell carcinoma,
endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and
neck, or melanoma (excluding uveal melanoma)
2. Life expectancy of 12 weeks or more
3. Phase 2: Measurable disease meeting the following criteria:
1. At least 1 lesion of greater than or equal to 10 mm in the longest diameter for a
non-lymph node or greater than or equal to 15 mm in the short-axis diameter for a
lymph node that is serially measurable according to irRECIST (immune-related
RECIST) using computerized tomography/magnetic resonance imaging (CT/MRI)
2. Lesions that have had external beam radiotherapy (EBRT) or loco-regional
therapies such as radiofrequency (RF) ablation must show subsequent evidence of
substantial size increase to be deemed a target lesion
4. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status
of 0 to 1
5. Adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP less than or equal to 150/90 mmHg at screening and no
change in antihypertensive medications within 1 week prior to the Cycle 1 Day 1
6. Adequate renal function defined as creatinine less than or equal to 1.5 X ULN (upper
limit of normal) or calculated creatinine clearance greater than or equal to 40 mL/min
per the Cockcroft and Gault formula with creatinine levels greater than 1.5 X ULN
7. Adequate bone marrow function:
1. Absolute neutrophil count (ANC) greater than or equal to 1500/mm3 (greater than
or equal to 1.5 X 103/uL)
2. Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 X
109/L)
3. Hemoglobin greater than or equal to 9.0 g/dL
8. Adequate blood coagulation function as evidenced by an International Normalized Ratio
(INR) less than or equal to 1.5
9. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the
ULN and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) less than or equal to 3 X ULN (in the case of liver metastases
less than or equal to 5 X ULN). In case ALP is greater than 3 X ULN (in the absence of
liver metastases) or greater than 5 X ULN (in the presence of liver metastases) AND
the participant also is known to have bone metastases, the liver specific ALP must be
separated from the total and used to assess the liver function instead of the total
ALP
10. Males or females age greater than or equal to 18 years at the time of informed consent
11. Participants with known brain metastases will be eligible if they have completed the
primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or
complete surgical resection) and if they have remained clinically stable, asymptomatic
and off of steroids for at least 28 days before starting study treatment.
12. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the
Screening Visit and the Baseline Visit. A pregnancy test needs to be performed within
72 hours of the first dose of study drug. Females of childbearing potential must agree
to use a highly effective method of contraception for the entire study period and for
120 days after study discontinuation, ie
- total abstinence (if it is their preferred and usual lifestyle)
- an intrauterine device (IUD) or hormone-releasing system (IUS)
- a contraceptive implant
- an oral contraceptive** (with additional barrier method) OR
- have a vasectomized partner with confirmed azoospermia.
NOTES:
- All females will be considered to be of childbearing potential unless they are
postmenopausal (amenorrheic for at least 12 consecutive months, in the
appropriate age group, and without other known or suspected cause) or have been
sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or
bilateral oophorectomy, all with surgery at least 1 month before dosing).
- Must be on a stable dose of the same oral hormonal contraceptive product for at
least 4 weeks before dosing with study drug and for the duration of the study
13. Male participants who are partners of women of childbearing potential must use a
condom + spermicide and their female partners if of childbearing potential must use a
highly effective method of contraception (see methods described in Inclusion Criterion
#12) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout
the entire study period, and for 120 days after the last dose of study drug, unless
the male participants are totally sexually abstinent or have undergone a successful
vasectomy with confirmed azoospermia or unless the female partners have been
sterilized surgically or are otherwise proven sterile.
14. Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol
15. Archival tumor tissue or a newly obtained biopsy must be available prior to the first
dose of study drug for biomarker analysis. In the case archival tissue cannot be
provided, participants with inaccessible tumors for biopsy specimens can be enrolled
without a biopsy upon consultation and agreement by the sponsor Note: In case of
submitting unstained cut slides, freshly cut slides should be submitted to the testing
laboratory within 14 days from when the slides are cut.
Exclusion Criteria:
1. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is
shorter) or any investigational agent within 30 days prior to the first dose of study
drugs. All acute toxicities related to prior treatments must be resolved to Grade less
than or equal to 1
2. Participants must have recovered adequately from any toxicity and/or complications
from major surgery prior to starting therapy
3. Participants having greater than 1+ proteinuria on urinalysis will undergo 24-h urine
collection for quantitative assessment of proteinuria. Participants with urine protein
greater than or equal to 1 g/24-hour will be ineligible.
4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
that might affect the absorption of lenvatinib
5. New York Heart Association congestive heart failure of grade II or above, unstable
angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia
associated with significant cardiovascular impairment within the past 6 months
6. Prolongation of QTc interval to greater than 480 msec
7. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
the first dose of study drug
8. Active infection (any infection requiring systemic treatment)
9. Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis
B, or Hepatitis C
10. Serious nonhealing wound, ulcer, or bone fracture
11. Known intolerance to either of the study drugs (or any of the excipients)
12. History of organ allograft (Participant has had an allogenic tissue/solid organ
transplant)
13. Biologic response modifiers (eg, granulocyte colony-stimulating factor) 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
14. Any medical or other condition which, in the opinion of the investigator, would
preclude participation in a clinical trial
15. Females who are pregnant or breastfeeding
16. Excluding the primary tumor leading to enrollment in this study, any other active
malignancy (except for definitively treated melanoma in-situ, basal or squamous cell
carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past
24 months
17. Prior treatment with lenvatinib or any PD-1, anti-PD-L1, or anti-PD-L2 agent,
excluding melanoma and NSCLC where prior treatment with one PD-1, anti-PD-L1, or
anti-PD-L2 agent is allowed, and excluding RCC where prior treatment with one regimen
containing an anti-PD-1/PD-L1 mAb is required.
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment. The use of physiologic doses of corticosteroids (up to 7.5mg/d of
prednisone or equivalent) may be approved after consultation with the sponsor.
19. No 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, etc.) is not considered a form of
systemic treatment.
20. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis
21. Has received a live-virus vaccination within 30 days of planned treatment start.
Seasonal flu vaccines that do not contain live virus are permitted.
