Inclusion Criteria:
1. Participants must have locally advanced or unresectable histologically or
cytologically confirmed WD G3 NET.
- - other primary sites: gastrointestinal site, unknown primary site, lung
neuroendocrine carcinoma with carcinoid morphology, or other non-pancreatic
primary sites with well-differentiated (WD) morphology and Ki67 > 20%.
- - WD G3 NET occurring de novo or in the setting of grade progression allowed
(provided WD G3 NET is thought to be the dominant histology at the time of
enrollment).
- - Tumors with ambiguous histology and/or Ki67 >/=55% must be reviewed at the
participating site to confirm that they are not poorly differentiated.
Tumors
with confirmed ambiguous histology will be considered eligible.
2. At least 1 measurable target lesion according to RECIST 1.1, including the following
criteria.
- - non-nodal lesion that measures >=1.0 cm in the longest diameter.
- - lymph node (LN) lesion that measures as >=1.5 cm in the short axis.
- - the lesion is suitable for repeat measurement using computed tomography (CT) /
magnetic resonance imaging (MRI) (CT/MRI).
- - the lesion is not <1.5 cm and the only measurable site available for
pre-treatment biopsy.
- - lesions previously treated with radiation or other locoregional therapy are
considered measurable if progression has been demonstrated in such lesions.
- - in the setting of grade progression, every attempt should be made to select
measurable target lesions that are thought to represent G3 disease (based on
biopsy results, tumor growth rate, or other features).
3. University of California, San Francisco (UCSF) participants only-eligibility for
Hyperpolarized 13C (C13 HP) MRI.
- - At least two measurable lesions that are >=1.0 cm in diameter, at least one
accessible to percutaneous core needle biopsy, and one (ideally separate from
biopsy site) amenable to metabolic MRI.
- - No contraindications to MRI.
- - No prior local therapy to the target lesions (s) -unless clear progression in the
lesions(s).
4. Radiographic evidence of progressive disease within 6 months (Required unless >50%
liver involvement and/or Ki67 > 30%).
5. Progression on at least one prior line of therapy if Ki67 < 30%.
6. Age >=18 years (No dosing or adverse event data are currently available on the use of
lenvatinib plus pembrolizumab in patients <18 years of age, children are excluded from
this study but will be eligible for future pediatric trials).
7. Eastern Cooperative Oncology Group (ECOG) performance status <= 1.
8. Have adequate organ function as defined below (Specimens must be collected within 14
days prior to the start of study treatment):
- - Adequate bone marrow function:
- Absolute neutrophil count >=1,500/microliter (mcL)
- Platelets >=100,000/mcL.
- - Hemoglobin >=1,500/mcL.
- - Hemoglobin >=9.0 g/dL or >=5.6 mmol/L.
- - Adequate hepatic function,
- Total bilirubin <=1.5 X institutional upper limit of normal, unless elevated due
to Gilbert's syndrome and direct bilirubin is within normal limits.
- - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)
<=2.5 X institutional upper limit of normal (ULN) (<=5 × ULN for participants
with liver metastases).
- - Adequate renal function,
- Creatinine <= 1.5 x institutional upper limit of normal OR.
- - Creatinine clearance >=30 mL/min for participant with creatinine levels >1.5 ×
institutional ULN,
- Urine protein-to-creatinine ratio (UPCR) <1 (unless urine protein <1 g/24 hour)
OR.
- - Urine protein dipstick <= 1+(unless urine protein <1 g/24 hour).
- - Coagulation: International normalized ratio (INR) OR prothrombin time (PT)
Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT)
<=1.5 × ULN unless participant is receiving anticoagulant therapy (and PT or aPTT
is within therapeutic range of intended use of anticoagulants).
9. Participant (or legally acceptable representative) must have the ability to understand
a written informed consent document, and the willingness to sign it.
10. Adequately controlled blood pressure (BP) with or without anti-hypertensive
medications, defined as BP <140/90 (NOTE: BP should be controlled without a change in
medications within one week of day 1 cycle 1).
11. Individuals with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.
12. Must have a life expectancy of greater than 3 months, as determined by the
investigator.
13. Stage 1 (if undergoing C13 HP MRI) and Stage 2: Patients must agree to have a biopsy
of the primary tumor or metastatic tissue at baseline, and there must be a lesion that
can be biopsied with acceptable clinical risk (as judged by the investigator).
- - Patients with unsuccessful baseline biopsies may undergo an additional biopsy
attempt (at the same or a different site, determined by the investigator).
- - For patients with an intact primary and no metastatic site that can be safely
biopsied, a biopsy of the primary is acceptable, but must be approved by the
principal investigator.
- - Baseline tumor biopsy may be omitted if the tumor is inaccessible and/or a biopsy
is thought to post high procedural risk due to location or other factors:
••If participants have only 1 measurable lesion per RECIST 1.1, the biopsy
specimen should be obtained from a non-target lesion (or archival tissue should
be used).
- - If fresh tumor tissue cannot be collected, the overall study (lead-site)
principal investigator may approve the use of archival tissue.
The use of
archival tissue in lieu of a fresh tumor biopsy will be evaluated on a
case-by-case basis and must be approved by the overall study (lead-site) PI.
••Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides.
Newly obtained biopsies are preferred to archived tissue.
- - Stage 1 patients who are not undergoing C13 HP MRI can omit baseline biopsy.
••Use of archived tissue is encouraged if accessible.
14. Male participants are eligible to participate if they agree to the following starting
with the first dose of study therapy through 7 days after the last dose of lenvatinib
(and refrain from donating sperm during this period). (Note that 30 days after
lenvatinib is stopped, if the participant is on pembrolizumab only, no male
contraception measures are needed.)
- - 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 (see appendix 5) 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 7 days after lenvatinib is stopped, if the participant is on
pembrolizumab only, no male contraception measures are needed.
15. Female participants are eligible if not pregnant or breastfeeding, and at least 1 of
the following conditions applies during the intervention period and for at least 120
days post pembrolizumab or 30 days post lenvatinib, whichever occurs last:
- - Not be a woman of childbearing potential (WOCBP), e.g., postmenopausal (no menses
for > 1 year) or permanently sterilized.
- - Is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <1% per year), with low user dependency.
- - Abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long-term and persistent basis) NOTE: The investigator should
evaluate the potential for contraceptive method failure (i.e., noncompliance,
recently initiated) in relationship to the first dose of study intervention.
Exclusion Criteria:
1. Has poorly differentiated neuroendocrine carcinoma (e.g., small cell NEC, large cell
NEC, Merkel cell carcinoma, prostate neuroendocrine carcinoma) or WD Grades 1 or 2 NET
(without evidence of G3 NET).
2. Uncontrolled blood pressure (BP) (Systolic BP >=140 mmHg or diastolic BP >=90 mmHg)
despite an optimized regimen of antihypertensive medication.
3. Significant gastrointestinal malabsorption or any other condition that might affect
the absorption of lenvatinib.
4. Has pre-existing >= grade 3 (G3) gastrointestinal or non-gastrointestinal fistula.
5. Has clinically significant cardiovascular disease within 12 months from the first dose
of study intervention, including New York Heart Association (NYHA) 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 would be permitted. 6. Radiographic evidence of major blood vessel encasement/invasion/infiltration (e.g.,
carotid artery) or intratumoral cavitation. 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.
*Portal vein or inferior vena cava involvement by tumor is allowed at the discretion
of the investigator (and is distinguished from invasion through the wall of a vessel).
7. Active hemoptysis or tumor bleeding (bright red blood of at least 0.5 teaspoons)
within 3 weeks prior to the first dose of study drug.
8. Hypersensitivity (>=G3) or known intolerance to lenvatinib or pembrolizumab or any of
its excipients.
9. Serious non-healing wound, ulcer, or bone fracture.
10. Bleeding or thrombotic disorders or participants at risk for severe hemorrhage.
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing 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. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- - Individuals with new or progressive asymptomatic small (<1 cm) brain metastases
are eligible if the treating physician determines that immediate CNS-specific
treatment is not required and is unlikely to be required during the first cycle
of therapy.
- - Participants with previously treated brain metastases (e.g., whole brain
radiation therapy, surgery, or radiosurgery) may participate provided they are
radiologically stable (i.e., without evidence of progression by imaging) for at
least 4 weeks by repeat imaging (note that the repeat imaging should be performed
during study screening), clinically stable and without requirement of steroid
treatment for at least 14 days prior to the first dose of study intervention.
13. Has an 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, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed.
14. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
15. Has an active infection requiring systemic therapy.
16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is
required unless mandated by a local health authority.
17. Has a known history of hepatitis B (defined as hepatitis B surface antigen (HBsAg)
reactive) or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is
detected) infection. Note: No testing for hepatitis B (HBV) and hepatitis C is
required unless mandated by a local health authority.
- - Participants with controlled hepatitis C are eligible (no detectable HCV RNA
qualitative) provided anti-viral therapy completed at least 4 weeks prior to
enrollment.
- - Participants with controlled HBV are eligible if they meet the following
criteria:
- Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral
load must be less than 500 IU/mL before the first dose of study drug.
Participants on active HBV therapy with viral loads under 100 IU/mL should
stay on the same therapy throughout study treatment.
- - Participants who are positive for anti-Hepatitis B Core (HBc), negative for
HbsAg, and negative or positive for anti-HBs, and who have an HBV viral load
under 100 IU/mL, do not require HBV antiviral prophylaxis.
18. Is known to have active tuberculosis (TB, Bacillus tuberculosis).
19. Diagnostic assessments:
- - Participants with urine protein creatinine ratio (UPCR) >1 or proteinuria >-2+
(>=100 mg/dL) on urinalysis/urine dipstick testing will undergo 24-hour urine
collection for quantitative assessment of proteinuria.
Participants with urine
protein >=1 g/24 hour will be ineligible.
- - Prolongation of QTc interval to > 480 milliseconds (ms).
Investigator may use the
average of 3 triplicates if screening QTc > 450 ms. Rescreening is allowed after
discontinuation of any drugs known to prolong QTc. NOTE: If the QTcF is prolonged
to >480 ms in the presence of a pacemaker, the participant will not be excluded
if the participant is considered at low risk for ventricular arrhythmias by the
investigator.
- - Left ventricular ejection fraction (LVEF) below the institutional (or local
laboratory) normal range as determined by multigated acquisition scan (MUGA) or
echocardiogram (ECHO).
20. Pregnant women are excluded from this study because lenvatinib plus pembrolizumab are
products with the potential for teratogenic or abortifacient effects.
- - A woman of child bearing potential (WOCBP) must have a negative highly sensitive
pregnancy test (urine or serum) within 14 days of the first dose of the study
intervention.
- - If a urine test cannot be confirmed as negative (e.g., a positive or 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.
21. Women who are breastfeeding are excluded from the study because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with lenvatinib plus pembrolizumab (breastfeeding should be discontinued if the
mother is treated with lenvatinib plus pembrolizumab).
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality
(including electrolyte abnormalities that have not been corrected, e.g., potassium,
calcium, magnesium) that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the best
interest of the participant to participate, in the opinion of the treating
investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
Listed below are specific concomitant therapies or vaccinations that are prohibited
during the study (exceptions noted):
24. Currently participating in or has participated in a trial of an investigational device
within 4 weeks prior to the first dose of trial treatment.
25. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks or 5 times the half-life time, whichever is shorter prior to study
treatment start.
Participants must have recovered from all adverse events (AE) due to previous
therapies to <=Grade 1 (except for alopecia) or baseline, and <=Grade 2 for
neuropathy.
- - Concomitant administration of hormone therapy for breast cancer, and luteinizing
hormone-releasing hormone (LHRH) analogs for prostate cancer allowed.
- - Concomitant somatostatin analogs for functional neuroendocrine tumors are allowed
as per standard of care assuming a stable dose for at least two months and
progressive disease has been documented on that dose.
- - Note: Participants who have entered the follow-up phase of an investigational
study may participate if it has been 4 weeks after the last dose of the previous
investigational agent.
26. Has received prior treatment with lenvatinib, or any anti-programmed cell death
protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX 40, CD137). Treatment with
another Vascular Endothelial Growth Factor Inhibitor (VEGF inhibitor_ (besides
lenvatinib) is allowed if at least 6 months have elapsed since discontinued therapy.
27. Has received prior radiotherapy within 2 weeks of the start of study treatment.
Participants must have recovered from all radiation-related toxicities (to Grade <=1),
not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout
is permitted for palliative radiation (<=2 weeks of radiotherapy) for non-CNS disease.
28. Has had major surgery within 3 weeks prior to the first dose of study interventions.
Note: Adequate wound healing after major surgery must be assessed clinically,
independent of time elapsed for eligibility.
29. Has had an allogeneic tissue/solid organ transplant.
30. Patients who are currently receiving medication with a known risk of prolonging the QT
interval inducing Torsade's de Pointes (TdP) and the treatment cannot either be
discontinued or switched to a different medication prior to starting study drug
treatment. A list of prohibited drugs with a known risk of TdP is provided in Appendix
6.
31. 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 drug.
32. Received a live or attenuated vaccine within 30 days of the planned start of study
treatment (C1D1). 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 (e.g., FluMist®) are live attenuated vaccines and are
not allowed. Coronavirus disease of 2019 (COVID-19) vaccinations are also allowed.
