Clinical Trials /

Pembrolizumab and Lenvatinib in Patients With Brain Metastases From Melanoma or Renal Cell Carcinoma



This is a phase 2, Simon's 2-stage designed study with 2 cohorts of anti-PD-1/PD-L1 experienced patients with untreated brain metastases: 1) melanoma and 2) renal cell carcinoma (RCC).

Related Conditions:
  • Melanoma
  • Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting


Phase 2

Trial Eligibility



  • Brief Title: Pembrolizumab and Lenvatinib in Patients With Brain Metastases From Melanoma or Renal Cell Carcinoma
  • Official Title: A Multicenter Phase 2 Trial to Evaluate Intracranial Response to Pembrolizumab and Lenvatinib in Patients With Brain Metastases From Melanoma or Renal Cell Carcinoma Who Are Anti-PD1/PD-L1 Experienced

Clinical Trial IDs

  • ORG STUDY ID: 2000030391
  • NCT ID: NCT04955743


  • Melanoma
  • Renal Cell Carcinoma
  • Brain Metastases
  • PD1/PD-L1 Experienced
  • Pembrolizumab
  • Lenvatinib
  • Metastatic Melanoma


PembrolizumabCohort 1: Melanoma
LenvatinibCohort 1: Melanoma


This is a phase 2, Simon's 2-stage designed study with 2 cohorts of anti-PD-1/PD-L1 experienced patients with untreated brain metastases: 1) melanoma and 2) renal cell carcinoma (RCC).

Detailed Description

      This is a phase 2, Simon's 2-stage designed study with 2 cohorts of anti-PD-1/PD-L1
      experienced patients with untreated brain metastases: 1) melanoma and 2) renal cell carcinoma
      (RCC). The primary endpoint of this study is to determine the best intracranial response of
      combined pembrolizumab and lenvatinib in patients with untreated brain metastases from
      melanoma or RCC who are anti-PD-1/PD-L1--experienced. Secondary endpoints include best
      overall objective response (combined intracranial and extracranial response),
      progression-free survival (PFS), overall survival (OS), duration of intracranial response,
      and rate of adverse events. Exploratory/correlative endpoints will include evaluation of
      pre-treatment tumor tissue (either intracranial or extracranial) for immunohistochemical
      markers (PDL-1, tumor infiltrating lymphocytes, and angiogenic factors) and genetic analysis
      of tumor mutations or mutational burden. Pre-treatment and on-treatment blood samples will be
      collected and evaluated for biomarkers of response by cytokine profiling and transcriptomic

      Patients must have at least one evaluable asymptomatic intracranial lesion, no smaller than
      5mm and no larger than 3 cm. Patients may have prior radiation to or surgical resection of a
      symptomatic brain metastasis as long as at least one untreated lesion or unequivocally
      growing lesion is present for response assessment. Pembrolizumab 200mg IV every 3 weeks will
      be administered in combination with lenvatinib 20 mg PO daily for up to 2 years.

      Patients must have received at least 2 doses of an anti-PD-1/PD-L1 mAb at some point in their
      treatment course and must have unequivocal intracranial progression. Intracranial progression
      in patients who are anti-PD-1/PD-L1 experienced is defined as either development of a new
      brain lesion(s) or unequivocal progression in a previously irradiated or resected brain
      lesion(s) site. Patients can be deemed to have progression after discussion and group
      consensus of the case at tumor board. Secondary imaging assessments to confirm intracranial
      progression are not required.

      Patients who are enrolled from sites outside of the Sponsor (Yale) must have patient
      eligibility approved by the Sponsor.

      Archival tissue from extracranial and/or CNS metastases will be obtained, if available, for
      correlative studies. A baseline pre-treatment fresh biopsy will also be required from an
      accessible metastasis unless there is not an easily accessible site to biopsy or if a biopsy
      is determined to be unfeasible by the treating physician after discussion with the study PI.
      The tumor tissue will be studied retrospectively for PD-L1 expression, TIL characteristics,
      and other immune and angiogenic markers that may predict sensitivity to this drug

      First response assessment will be performed at 6 weeks and will include MRI of the brain and
      CT body scans (or other clinically indicated body imaging such as MRI or PET CT) to assess
      systemic disease. Brain metastasis response will be determined using modified RECIST
      (mRECIST) 1.1 criteria, and extracranial disease response will be determined using RECIST
      1.1. Responses will be confirmed with repeat imaging done at 12 weeks. Subsequent imaging
      will be performed at 12-week intervals thereafter and include an MRI of the brain along with
      body imaging, which may include CT, MRI, or PET/CT, as clinically indicated. Patients will
      discontinue treatment for disease progression, unacceptable toxicity, patient withdrawal from
      the study, termination of study, or death. Patients may be treated beyond progression of
      intracranial metastases after consultation with the study PI, provided symptomatic lesions
      are treated with stereotactic radiosurgery (SRS) or surgery. Dose reduction of pembrolizumab
      for immune-related toxicities is not permitted. Dose-reduction of lenvatinib for related
      toxicities is permitted.

      Number of Patients:

      A total of up to 62 eligible patients will be enrolled (27 patients with melanoma with
      allowance for 3 additional patients if any are unevaluable and 29 patients with RCC with
      allowance for 3 additional patients if any are unevaluable). Either cohort can be stopped for
      futility according to Simon's two-stage design. The study will accrue for approximately 36
      months and will be open for approximately 24 additional months as patients on study are

Trial Arms

Cohort 1: MelanomaExperimentalParticipants who are melanoma (PD-1/PD-L1-experienced)
  • Pembrolizumab
  • Lenvatinib
Cohort 2: Renal Cell CarcinomaExperimentalParticipants who are Renal Cell Carcinoma (PD-1/PD-L1 experienced).
  • Pembrolizumab
  • Lenvatinib

Eligibility Criteria

        Inclusion Criteria:

          1. Male/female participants who are at least 18 years of age on the day of signing
             informed consent with histologically confirmed diagnosis of melanoma or RCC and
             untreated metastatic brain disease will be enrolled in this study.

             Male participants: A male participant must agree to use a contraception as detailed in
             the 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.

             Female participants: A female participant 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) OR

               2. A WOCBP who agrees to follow the contraceptive guidance per protocol during the
                  treatment period and for at least 120 days after the last dose of study

          2. The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

          3. Have histologic or cytologic confirmation from any body site of metastatic melanoma
             irrespective of BRAF mutation status or renal cell carcinoma irrespective of
             histologic subtype.

          4. Patients who have had prior resection or biopsy of a CNS and/or extracranial
             metastasis will be required to provide a formalin-fixed, paraffin embedded (FFPE)
             specimen from tumor taken at the time of surgery, if available. Fresh biopsies of a
             metastatic lesion should be performed if clinically able.

             Note: Participants are not required to have new or repeat brain metastasis biopsies
             for enrollment on the trial.

             Note: For those who have never had CNS brain metastasis biopsies, tissue of an
             accessible extracranial lesion will be obtained pre-treatment, unless deemed not
             possible by the treating physician and upon discussion with PI. In this case, archival
             extracranial metastatic tissue will be suitable.

          5. Have at least one brain metastasis that is at least 5 mm AND twice the MRI slice
             thickness, but less than or equal to 3 cm, which is asymptomatic, has not been
             previously radiated, and is not requiring immediate local therapy or steroids. Lesions
             situated in a previously irradiated area are considered allowed if measurable per the
             aforementioned criteria and if progression has been demonstrated. Patients with any
             lesion(s) >3 cm can be enrolled provided the following: (1) the lesion must receive
             local treatment prior to initiation of study drugs (either by stereotactic
             radiosurgery or resection), (2) the patient is not symptomatic from the lesion(s) once
             local therapy has been administered, and (3) at least one additional, non-treated
             lesion between 5 mm and 3 cm is still present.

          6. Prior treatment for either the Melanoma or RCC cohorts may include: Patients must have
             received at least 2 doses of an anti-PD-1/PD-L1 drug at some point in their treatment
             course. Any number of prior treatments including PD-1/PD-L1 inhibitors are allowed.
             Anti-PD-1/PD-L1 does not have to be the most recent therapy. Patients with melanoma
             who developed brain metastasis within 6 months of the last dose of adjuvant anti-PD-1
             can be enrolled.

          7. Life expectancy of at least 3 months.

          8. A history of radiotherapy for brain metastases is allowed up to 1 week before study
             treatment provided that neurologic sequelae are resolved, and that measurable
             untreated target lesion(s) remain.

          9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the date of allocation.

         10. Adequately controlled blood pressure (BP) with or without antihypertensive
             medications, defined as a systolic BP ≤150 or a diastolic BP ≤90 mmHg at screening and
             on Cycle 1 Day 1.

             Note: Eligibility of a participant that is receiving ≥3 antihypertensive medications
             prior to study entry will require PI approval.

         11. Have adequate organ function as defined in the protocol. Specimens must be collected
             within 10 days prior to the start of study treatment.

        Exclusion Criteria:

          1. Symptomatic melanoma or RCC brain metastases at the time of therapy initiation.

          2. Active use of corticosteroids to control CNS symptoms, unless steroid requirement has
             been decreasing and currently on ≤10 mg of prednisone or its equivalent without CNS
             symptoms for 7 days or more.

          3. Overt hemorrhage from CNS metastases.

          4. Presence of leptomeningeal disease.

          5. Unable to undergo MRI imaging (either due to such conditions as inability to lie flat
             for the scan duration, incompatible medical devices at risk for malfunction, and
             foreign metal objects that pose a safety risk for imaging).

          6. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required.

          7. Has received anti-cancer therapy including investigational agents within 14 days prior
             to allocation or less than 4 weeks from prior immunomodulating antibody (excluding

             Note: Participants must have recovered from all AEs due to previous therapies to
             ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy, rash, and/or alopecia may
             be eligible.

             Note: If participant received major surgery, they must have recovered adequately from
             the toxicity and/or complications from the intervention prior to starting study

          8. Has received prior CNS radiotherapy within 1 week of start of study treatment.
             Participants must have recovered from all radiation-related toxicities and not require

          9. Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

         10. Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

             Note: Participants who have entered the follow-up phase of an investigational study
             may participate as long as it has been 4 weeks after the last dose of the previous
             investigational agent.

         11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

         12. Has a known additional malignancy that is progressing or is requiring active

         13. Has active autoimmune disease that has required systemic treatment in the past 3
             months or a documented history of clinical severe autoimmune disease, or a syndrome
             that requires chronic systemic steroids or immunosuppressive agents. Replacement
             therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
             for adrenal or pituitary insufficiency with prednisone < 10 mg or the equivalent,
             etc.) is not considered a form of systemic treatment. Subjects with thyroid disease or
             vitiligo will not be excluded from the study.

         14. Has presence of gastrointestinal condition including malabsorption, gastrointestinal
             anastomosis, or any other condition that might affect the absorption of lenvatinib.

         15. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.

         16. Serious non-healing or dehiscing wound.

         17. 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.

         18. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the
             first dose of study drug.

         19. Has clinically significant cardiovascular disease within 6 months of the first dose of
             study intervention including New York Heart Association Class III or IV congestive
             heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or
             cardiac arrhythmia associated with hemodynamic instability.

             Note: Medically controlled arrhythmia is permitted.

         20. Has prolongation of QTc interval (calculated using Fridericia's formula) to >480 msec.

         21. 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.

         22. Has urine protein ≥2 g/24-hour. Note: Participants with >1+ proteinuria on urine
             dipstick will undergo 24-hour urine collection for quantitative assessment of

         23. Evidence of a bleeding diathesis, risk for severe hemorrhage, or clinically
             significant coagulopathy.

         24. Uncontrolled hypertension (systolic BP >150 mmHg or diastolic BP >90 mmHg) in spite of
             an optimized regimen of antihypertensive medication.

         25. Has a history of (non-infectious, non-radiation-induced) pneumonitis not responsive to
             steroids or has current pneumonitis. Patients will also be excluded if there are
             respiratory issues including active infection or require supplemental oxygen for
             activities of daily living.

         26. Has an active infection requiring systemic therapy.

         27. Has a known history of Human Immunodeficiency Virus (HIV).

         28. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as a detectable qualitative HCV
             RNA level) infection.

             Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local
             health authority.

         29. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         30. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         31. 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 trial treatment.

         32. Women of child-bearing potential who are unwilling to or unable to use an acceptable
             method of contraception to avoid pregnancy for the entire study and for at least 5
             months after cessation of study drug or have a positive pregnancy test at screening or
             baseline, or who are pregnant or breast feeding.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best brain metastasis response rate (BMRR)
Time Frame:up to 2 years from the start of treatment
Safety Issue:
Description:Best brain metastasis response rate (BMRR), defined as PR and CR per modified RECIST 1.1.

Secondary Outcome Measures

Measure:Best overall objective response rate
Time Frame:up to 2 years from the start of treatment
Safety Issue:
Description:Best overall objective response rate, defined as Partial Response (PR) and Complete Response (CR) per RECIST 1.1.
Measure:Progression Free Survival (PFS)
Time Frame:up to 2 years from the start of treatment or to time of disease progression
Safety Issue:
Description:PFS, defined as the time from start of study drug administration to the date of the first documentation of disease progression or death from any cause, whichever occurs first.
Measure:Overall Survival (OS)
Time Frame:up to 2 years from the start of treatment or to time of death
Safety Issue:
Description:OS, defined as the time from start of study drug administration to date of death from any cause.
Measure:Duration of brain metastasis response
Time Frame:up to 2 years from the start of treatment
Safety Issue:
Description:Duration of brain metastasis response, defined as the time from response to the time of the first documentation of intracranial disease progression.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Yale University

Last Updated

July 23, 2021