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).
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
analysis.
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
combination.
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
followed.
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
treatment.
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
anti-PD1/PD-L1).
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
treatment.
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
corticosteroids.
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
treatment.
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
proteinuria.
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.
