- ACC Cohort (Cohort 1) only: Patients must have pathologically or cytologically
confirmed adenoid cystic carcinoma. Cancers arising from non-salivary gland primary
sites are allowed.
- Non-ACC Cohort (Cohort 2) only: Patients must have pathologically or cytologically
confirmed salivary gland cancer of any histology (except for adenoid cystic carcinoma
that is enrolled into cohort 1).
- Patients must have recurrent and/or metastatic disease not amenable to other curative
- At least 4 weeks must have elapsed since the end of prior systemic treatment and/or
since completion of radiotherapy with resolution of all treatment related toxicity to
NCI CTCAE Version 5.0 grade ≤1 (or tolerable grade 2) or back to baseline (except for
alopecia, lymphopenia, or hypothyroidism) prior to starting study drug treatment.
- Patients must have RECIST V1.1 measurable disease defined as at least one non-nodal
lesion measuring ≥ 20 mm with conventional techniques or as ≥10mm with CT scan, MRI,
or calipers by clinical exam in the longest dimension AND/OR a nodal lesion measuring
> 15 mm in the shortest dimension. Tumors in previously irradiated fields may be
considered measurable if there is evidence of tumor progression after radiation
- Cohort 1 and acinic cell carcinoma patients in Cohort 2 only: Patients must have
documentation of a new or progressive lesion on radiologic imaging study performed
within 6 months prior to study enrollment (progression of disease over any interval is
allowed) and/or new/worsening disease related symptoms within 6 months prior to study
enrollment. Note: This assessment will be performed by the treating investigator and
evidence of progression by RECIST criteria is not required.
- Age ≥ 18 years of age on the day of signing informed consent.
- ECOG performance status 0 or 1 (or Karnofsky ≥ 70%).
- Patients must have tissue from the primary tumor or metastases available for
correlative studies. Either a paraffin block or at least 20 unstained slides are
acceptable (paraffin block or at 30 unstained slides would be ideal). Patients without
available tissue for submission may still be eligible if approved by the Principal
- Screening laboratory values must meet the following criteria:
- Neutrophils ≥1500/μL
- Platelets ≥ 100x10^3/μL
- Hemoglobin ≥ 9.0 g/dL (without packed red blood cell (pRBC) transfusion within
the last 2 weeks)
- AST and ALT ≤ 2.5 x ULN (if liver metastases are present, AST and ALT ≤ 5x ULN)
- Total Bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 x ULN (except participants with Gilbert Syndrome, who can
have a total bilirubin < 3.0 mg/dL)
- Serum creatinine ≤ 1.5 x ULN OR creatinine clearance (CrCl) ≥ 40 mL/min per the
Cockcroft-Gault formula if creatinine is >1.5 x ULN
- Female CrCl = (140 - age in years) x weight in kg x 0.85 72 serum creatinine in
- Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
- INR </= 1.5, unless participant is receiving anticoagulant therapy as long as PT
or aPTT is within therapeutic range of intended use of anticoagulants
- Participants must be willing to sign the written informed consent form. A signed
informed consent form must be appropriately obtained prior to the conduct of any trial
- Male participants must agree to use adequate contraception as detailed in Appendix 2
of this protocol not be planning/expecting to father children, and refrain from
donating sperm from the time of the screening visit through 120 days after the last
dose of trial treatment.
- A female participant is eligible to participate if she is not pregnant (for women of
child-bearing potential, a pregnancy test must be negative within 72 hours prior to
initiation; if a urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required), not breast feeding, not planning/expecting to
conceive children from the time of the screening visit through 120 days after the last
dose of trial treatment, and at least one of the following conditions applies:
- Not a woman of child bearing potential including:
- pre-menopausal with one of the following: documented hysterectomy, documented
bilateral salpingectomy, documented bilateral oophorectomy
- Postmenopausal females defined as no menses for 12 months without an alternative
medical cause (a high follicle stimulating hormone level in the postmenopausal
range may be used to confirm a post-menopausal state in women not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the absence of
12 months of amenorrhea, confirmation with two FSH measurements in the
postmenopausal range is required.
- A woman of child bearing potential who agrees to highly effective contraception
from the start of therapy through 120 days after the last dose of study
- Participants must be able to swallow and retain oral medication or have a
functioning G-tube in place.
- Untreated metastatic brain (subjects with treated brain metastases will be eligible,
provided that they are radiographically stable, i.e. without evidence of progression
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 treatment).
- Concurrent anti-cancer therapy (chemotherapy, definitive radiation therapy, surgery,
immunotherapy, biologic therapy or tumor embolization) other than study treatment.
Concurrent therapy with bisphosphonates or denosumab for bone metastases is allowed,
provided they are started prior to study entry. Palliative radiation to non-target
lesions is also allowed.
- Prior malignancy if diagnosed and treated within 2 years of trial drug initiation
(with the exception of non-melanomatous skin cancers). Patients may be included if
they have completed therapy for a prior malignancy >2 years prior to drug initiation
and are currently NED. Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, or carcinoma in situ (breast DCIS, or cervical CIS) that
have undergone potentially curative at any time therapy are not excluded from trial
- History of allergy or intolerance to study drug components (or any of their
excipients), or severe (> Grade 3) hypersensitivity reaction to any excipients of
pembrolizumab or any monoclonal antibody.
- Prior use of lenvatinib or any PD-1/PD-L1 or anti-PD-L2 targeted therapies or with an
agent directed at another stimulatory or co-inhibitory T-cell receptor (CTLA-4, OX-40,
- Uncontrolled hypertension (systolic pressure >140mm Hg or diastolic pressure >90mm
Hg), despite optimal medical management.
- Prior systemic anti-cancer therapy including use of another investigational drug or
device (i.e., outside study treatment) during, or within 4 weeks of trial entry (time
of initiation of experimental drug).
- Clinically significant proteinuria:
°Subjects having >1+ proteinuria on urinalysis will undergo 24-hour urine collection
for quantitative assessment of proteinuria. Subjects with proteinuria ≥1gm/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
(baseline echocardiogram is not required unless clinically indicated).
- Subjects with thrombotic, embolic, venous or arterial events, such as cerebrovascular
accidents (including transient ischemic attacks), deep venous thrombosis or pulmonary
embolism within 6 months of study treatment start.
- Prolongation of QTc interval to >480 msec
- Any hemorrhage or bleeding event ≥ NCI CTCAE v5.0 Grade ≥3 within 4 weeks prior to
start of study medication.
- Active infection (any infection requiring systemic treatment)
- Subject is known to be positive for Human Immunodeficiency Virus (HIV) or active
Hepatitis C Virus (HCV) or active hepatitis B (HBV) infection (positive viral load).
Testing for HIV, HCV, or HBV prior to initiation of the study drug is not required. If
patient's have a known history of treated HCV, then a viral load is required to
confirm clearance of infection.
- Serious non-healing wound, ulcer or bone fracture, that is not tumor related.
- History of organ allograft (including corneal transplant).
- 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 first dose of study treatment.
- Has a history or current evidence of any medical or other condition, therapy or
laboratory abnormality which, in the opinion of the investigator, might confound the
results of the study, or preclude participation in a clinical study.
- 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 10 mg/d of
prednisone or equivalent) may be approved after consultation with the Primary
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with the use of disease modifying agents, corticosteroids or immunosuppressive
drugs), with the exception of autoimmune thyroid disease, vitiligo, type 1 diabetes
mellitus, or psoriasis. Replacement therapy (e.g., thyroxine, 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
- Renal failure requiring active hemo- or peritoneal dialysis.
- Has received a live-virus vaccination within 30 days of planned treatment start.
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.
- Has known psychiatric or substance abuse disorders that would interfere with the
cooperation with the requirements of the trial.