MC# 20-38 - A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) in Previously Treated Subjects with Selected Solid Tumors

  • Agent(s): Lenvatinib/Pembrolizumab
  • Disease Type(s): Colorectal, Gastric, Ovarian, Pancreatic, Glioblastoma, Cholangiocarcinoma, Breast- Triple Negative, Gastroesophageal Junction
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): MET, VEGFR, RTK

Mechanism of Action

Lenvatinib (E7080) is an orally available potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1/VEGFR-1 and KDR/VEGFR-2.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of Lenvatinib and Pembrolizumab when given together
  • The effects of Lenvatinib (good and bad) when given in combination with Pembrolizumab
  • How much of Lenvatinib is absorbed into the blood and how fast it is removed when given in combination with Pembrolizumab
  • If Lenvatinib prevents or delays tumor growth or shrinks existing tumors
  • If research tests can be used in the future to predict who will benefit from Lenvatinib in combination with Pembrolizumab
Inclusion Criteria
  1. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard systemic therapy has failed in one of the following cohorts:

Cohort A

Triple-Negative Breast Cancer (TNBC)

Cohort B

Ovarian Cancer

Cohort C

Gastric Cancer

Cohort D

Colorectal Cancer

Cohort E

Glioblastoma (GBM)

Cohort F

Biliary Tract Cancer (BTC) (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder cancer; excludes Ampulla of Vater)

  1. Participants must have fulfilled cohort-specific requirements regarding prior (line of therapy) treatments
    • Note: Merck will be utilizing American Joint Committee on Cancer (AJCC) Staging manual 8th edition to review tumor node metastasis (TNM) staging classification to ensure consistency of participant enrollment
  2. Participants must have progressed on or since the last treatment
  3. Have measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by the local site investigator/radiology and confirmed by BICR.  Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  4. Have provided a PD-L1 evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.  Note: If participants have only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from a nontarget lesion or archival tissue.
  5. Participant are at least 18 years of age; male or female for gastric cancer, GBM, TNBC, CRC and BTC cohorts; female only for ovarian cancer
  6. Life expectancy of 12 weeks or more
  7. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of lenvatinib:
    • 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) 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.
      • Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed
  8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
    • Is not a woman of childbearing potential (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 post pembrolizumab or 30 days post lenvatinib, whichever occurs last.  The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) 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
  9. The participant (or legally acceptable representative if applicable) provides written informed consent for the study
  10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 7 days of treatment initiation
  11. Have adequate organ function as defined in the following table. Samples must be collected within 7 days prior to the start of study intervention

Table 1: Adequate Organ Function Laboratory Values

System

Laboratory Value

Hematological

Absolute neutrophil count (ANC)

≥1500/µL

Platelets

≥100,000/µL

Hemoglobin

≥9.0 g/dL or ≥5.6 mmol/L1

Renal

Creatinine OR

Measured or calculated2 creatinine clearance (GFR can also be used in place of creatinine or CrCl)

≤1.5 × ULN OR

≥30 mL/min for participant with creatinine levels

>1.5 × institutional ULN

Hepatic

Total bilirubin

≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN

AST (SGOT) and ALT (SGPT)

≤2.5 × ULN (≤5 × ULN for participants with liver metastases and biliary tract cancer)

Coagulation

International normalized ratio (INR) OR prothrombin time (PT)

Activated partial thromboplastin time (aPTT)

≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal

1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks

2Creatinine clearance (CrCl) should be calculated per institutional standard

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies

  1. Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization

Triple Negative Breast Cancer Specific Inclusion Criteria

  1. Have received one or 2 prior lines of therapy.  Study medication will treat TNBC (2L/3L).
    • Note: Participants must have been treated with a taxane and anthracycline at some time during their course of treatment to meet eligibility
    • Note: Prior surgery +/- adjuvant chemotherapy is not considered a line of therapy unless such treatments were completed within 6 months prior to the current tumor recurrence
    • Note: Prior therapy of metastatic or unresectable disease is considered a line of therapy
    • Note: Definitive surgery with curative intent and radiation therapy or systemically administered radiopharmaceutical therapy are NOT considered prior lines of therapy
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions (eg, oxaliplatin in FOLFOX) will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
    • Note: Maintenance regimens administered with the purpose of maintaining response following treatment will not be considered lines of therapy
  2. Have Lactate Dehydrogenase (LDH) <2.0 × ULN
  3. Have locally determined results for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 tumor analyses

Ovarian Cancer Specific Inclusion Criteria

  1. Have received 3 prior lines of therapy.  Study medication will treat ovarian cancer (4L).
    • Note: The initial 30 participants in this cohort included patients with primary ovarian cancer.  The expanded cohort will include patients with primary ovarian cancer, fallopian tube, and peritoneal ovarian cancer.
    • Note: Neoadjuvant/adjuvant systemic cytotoxic chemotherapy used in the initial treatment is considered prior line of therapy
    • Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a cytotoxic warhead, are considered prior lines of therapy
    • Note: Definitive surgery with curative intent and radiation therapy or systemically administered radiopharmaceutical therapy are NOT considered prior lines of therapy
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions will NOT be considered a line of therapy change (unless the interruption is ≥2 months, eg, re-challenge with platinum in ovarian cancer).
    • Note: Maintenance regimens administered with the purpose of maintaining response following  treatment will not be considered lines of therapy

Gastric Cancer Specific Inclusion Criteria

  1. Have received 2 prior lines of therapy.  Study medication will treat gastric cancer (3L).
    • Note: Gastric cancer will include participants with both gastric and gastroesophageal junction (GEJ) adenocarcinoma.  Participants with squamous cell carcinoma histology are not eligible.
    • Note: Prior neoadjuvant or adjuvant systemic cytotoxic chemotherapy used in the initial treatment is not considered a prior line of therapy, unless such treatments were completed within 12 months prior to the current tumor recurrence
    • Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a cytotoxic warhead, are considered prior lines of therapy
    • Note: Definitive surgery with curative intent and radiation therapy or systemically administered radiopharmaceutical therapy are NOT considered prior lines of therapy
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
    • Note: Maintenance regimens administered with the purpose of maintaining response following treatment will not be considered lines of therapy

Colorectal Cancer Specific Inclusion Criteria

  1. Have received 2 prior lines of therapy.  Study medication will treat CRC (3L).
    • Note: Participants must have received oxaliplatin and irinotecan in separate lines of therapy, these are usually provided with fluoropyrimidine (eg, FOLFOX and FOLFIRI)
    • Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior therapy (XOLFOX, XOLFIRI)
    • Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and irinotecan as part of the same and only chemotherapy regimen, eg, FOLFOXIRI or FOLFIRINOX, will be considered 2L patients, and do not qualify for the study
    • Note: Adjuvant chemotherapy counts as a first line of prior systemic therapy if there is documented disease progression within 6 months of chemotherapy completion
    • Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a cytotoxic warhead, are considered prior lines of therapy
    • Note: Definitive surgery with curative intent and radiation therapy or systemically administered radiopharmaceutical therapy are NOT considered prior lines of therapy
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
    • Note: Maintenance regimens administered with the purpose of maintaining response following treatment will not be considered lines of therapy
    • Note: Hyperthermic intraperitoneal chemotherapy (HIPEC) or other locoregional therapies are allowed, but will not be counted as prior lines of therapies

GBM Specific Inclusion Criteria

  1. Have failed initial systemic therapy for newly diagnosed GBM.  Study medication will treat GBM (2L).
    • Note: Previous first line therapy with at least radiotherapy utilizing standard dosing of CNS radiation including 60 Gy in 30 fractions, 59.4 Gy in 1.8 Gy per fraction or equivalent
    • Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy)
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
  2. Have the following time periods elapsed before the projected start of scheduled study treatment:
    • At least 3 weeks from prior surgical resection
      • Participants  having  undergone  recent  resection  of  recurrent or progressive tumor will be eligible  as  long  as  they have  recovered from the effects of surgery and have measurable residual disease prior to starting study therapy
    • At least 1 week from stereotactic biopsy
    • At least 6 months from completion of prior radiotherapy
      • If participants have not passed an interval of at least 6 months, they may still be eligible if they meet the following criteria:
        1. New area of enhancement outside the 80% isodose line of the original radiation field as determined by the treating investigator
    • At least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent
    • At least 4 weeks from cytotoxic therapy
      • Exceptions:
        1. At least 23 days for temozolomide
        2. At least 6 weeks from nitrosoureas
      • At least 4 weeks (or 5 half-lives, whichever is shorter) for daily administered chemotherapeutics
    • At least 6 weeks from antibodies
    • At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies and 1 week for cancer vaccines
  3. Be neurologically stable (eg, without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable
  4. Has histologically confirmed World Health Organization (WHO) Grade IV glioblastoma
  5. Has locally determined result for O6-methylguanine–DNA methyltransferase (MGMT) analysis

Biliary Tract Cancer Specific Inclusion Criteria

  1. Have received 1 prior line of therapy.  Study medication will treat BTC (2L).
    • Note: Prior adjuvant systemic cytotoxic chemotherapy used in the initial treatment is not considered a prior line of therapy, unless such treatments were completed within 6 months prior to the current tumor recurrence
    • Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a cytotoxic warhead, are considered prior lines of therapy
    • Note: Definitive surgery with curative intent and radiation therapy or systemically administered radiopharmaceutical therapy are NOT considered prior lines of therapy
    • Note: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy.  Switching (eg, cisplatin to carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay in treatment is required for ≥2 months).  Switching for toxicity will be considered a line of therapy change if there is a change in mechanism of action between the therapies.  Interruptions (eg, oxaliplatin in FOLFOX) will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
    • Note: Maintenance regimens administered with the purpose of maintaining response following treatment will not be considered lines of therapy
    • Note: TACE or other locoregional therapies are allowed, but will not be counted as prior lines of therapies
  2. Has Child-Pugh Score, Class A: well-compensated disease. Child-Pugh Score of 5 to 6
Exclusion Criteria
  1. Has presence of gastrointestinal condition including malabsorption that might affect the absorption of lenvatinib
  2. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment.  The participant can receive diuretic drugs as needed per the treating physician, outside of the above mentioned conditions.  Consult with the sponsor if the participant has more than trivial/trace fluid accumulation.
    • Note: This exclusion applies to all cohorts except the ovarian cancer cohort
  3. Has radiographic evidence of major blood vessel invasion/infiltration.  The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
    • Note: Participants with portal vein invasion (Vp4), inferior vena cava, or cardiac involvement based on imaging in the BTC cohort are excluded
  4. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
  5. Has significant cardiovascular impairment within 12 months of the first dose of study drug: such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA), or cardiac arrhythmia associated with hemodynamic instability
    • Note: Medically controlled arrhythmia would be permitted
  6. Has a history of arterial thromboembolism within 12 months of start of study drug
  7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.  Exceptions include early stage cancers (carcinoma in situ or stage 1, non-ulcerated primary melanoma <1 mm in depth with no nodal involvement) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
  8. Serious nonhealing wound, ulcer or bone fracture
  9. 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
  10. Has 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.
  11. Has preexisting ≥Grade 3 gastrointestinal (GI) or non-gastrointestinal fistula

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03797326

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Re: MC# 20-38