Patient case: 64-year-old male with head and neck squamous cell carcinoma; genetic feature: CDKN2A

Clinical trial: Trial of Lenvatinib Plus Pembrolizumab in Subjects With Selected Solid Tumors

Summary: This is an open-label Phase 1b study designed to confirm the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with selected solid tumors (non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma [excluding uveal melanoma]).


Eligibility: Inclusion Criteria:
  -  Histologically and/or cytologically confirmed selected solid tumor types that have progressed after treatment with standard therapies or for which there are no other appropriate 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.
  The selected tumor types are: non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma)
  -  At least 1 measurable target lesion according to modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
  -  Participants must have an Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) of 0 to 1.
  -  Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week prior to the Cycle 1/Day 1 (C1D1)
  -  Adequate renal function defined as creatinine ≤1.5 times the upper limit of normal (ULN) or calculated creatinine clearance ≥40 milliliters per minute (mL/min) per the Cockcroft and Gault formula with creatinine levels >1.5×ULN
  -  Adequate bone marrow function:
  -  Absolute neutrophil count (ANC) ≥1500/mm^3 (≥1.5×10^3/microliters [μL])
  -  Platelets ≥100,000/mm^3 (≥100×10^9/liters [L])
  -  Hemoglobin ≥9.0 grams per deciliter (g/dL)
  -  Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤1.5
  -  Adequate liver function as evidenced by bilirubin ≤1.5×ULN and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN). In case ALP is >3×ULN (in the absence of liver metastases) or >5×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.
  -  Males or females age ≥20 years at the time of informed consent
  -  Life expectancy of 12 weeks or more
  -  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.
  -  Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
  -  Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose of study drug for biomarker analysis. 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:
  -  Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 28 days prior to the first dose of study drugs. All toxicities related to prior treatments must be resolved to Grade ≤1 (except alopecia).
  Note: Refer to the inclusion criteria regarding hypertension.
  -  Biologic response modifiers (e.g., 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 the first dose of study treatment.
  -  Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, excluding cancer types such as melanoma and non-small cell lung cancer where prior treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed
  -  Participants must have recovered adequately from any complications from major surgery prior to starting therapy.
  -  Participants having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 hour will be ineligible.
  -  Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  -  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
  -  Prolongation of QTc (Fridericia formula) interval to >480 milliseconds (ms)
  -  Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
  -  Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g., carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
  -  Active infection (any infection requiring systemic treatment)
  -  Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C
  -  Serious nonhealing wound, ulcer, or bone fracture
  -  Known intolerance to either of the study drugs (or any of the excipients)
  -  History of organ allograft
  -  Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial
  -  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
  -  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 7.5 milligrams per day [mg/d] of prednisone or equivalent) may be approved after consultation with the sponsor.
  -  Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine [T4], insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  -  Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or has a history of interstitial lung disease
  -  Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
  -  Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International units per liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
  -  Females of childbearing potential who:
  -  do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study drug discontinuation, i.e.:
  -  total abstinence (if it is their preferred and usual lifestyle)
  -  an intrauterine device (IUD) or hormone releasing system (intrauterine system [IUS])
  -  a contraceptive implant
  -  an oral contraceptive (with additional barrier method); or
  -  do not have a vasectomized partner with confirmed azoospermia.
  For sites outside of the European Union (EU), it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, ie double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
  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 (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
  Participants 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.
  - Male participants who are partners of women of childbearing potential must use a condom plus spermicide, and their female partners, if of childbearing potential, must use a highly effective method of contraception (see methods described in Exclusion Criterion #23) 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.

Relevance to patient case: not relevant