PRIMARY OBJECTIVE:
I. To determine the response rate of the combination of pembrolizumab and pemetrexed in
patients with recurrent or metastatic salivary gland cancer (R/M SGC).
SECONDARY OBJECTIVES:
I. To determine the progression-free survival (PFS), overall survival (OS), and adverse
events of the combination of pembrolizumab and pemetrexed in patients with recurrent or
metastatic salivary gland cancer (R/M SGC).
II. To assess safety and tolerability of the combination of pembrolizumab and pemetrexed in
patients with recurrent or metastatic salivary gland cancer (R/M SGC).
CORRELATIVE RESEARCH OBJECTIVES:
I. To investigate the frequency of MTAP loss by immunohistochemistry in R/M SGC and whether
it correlates with enhanced response to pemetrexed.
II. To measure the degree of PDL1 expression using formalin-fixed tumor samples, and
determine the extent of PDL1 expression correlates with response to study treatment.
III. To investigate expression of thymidylate synthase by immunohistochemistry in R/M SGC and
whether it correlates with enhanced response to pemetrexed.
IV. To investigate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and correlation with
response to study treatment.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes and pemetrexed disodium IV
over 10 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35
cycles (2 years) in the absence of disease progression or unacceptable toxicity. Cycles of
pemetrexed disodium repeat every 21 days in the absence of disease progression or
unacceptable toxicity. Patients who had stable disease, partial response, or complete
response after completion of 35 cycles of pembrolizumab, may continue pembrolizumab for an
additional 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity.
After completion of study intervention, patients are followed up at 30 days, and then every 3
months for up to 3 years.
Inclusion Criteria:
- REGISTRATION - INCLUSION CRITERIA
- Age >= 18 years
- Histologically confirmed diagnosis of recurrent or metastatic salivary gland cancer
not amenable to curative-intent therapy
- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
version (v)1.1 criteria
- NOTE: Tumor lesions in a previously irradiated area are considered measurable
disease if progression has been demonstrated in such lesions. Disease that is
measurable by physical examination only is not eligible
- Prior treatment:
- Prior treatment with checkpoint inhibitor(s) allowed
- Any number of lines of prior therapy in the recurrent/metastatic setting is
permitted at the investigator's discretion
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- NOTE: PS must be assessed again within 7 days prior to first dose of study drug
- Hemoglobin >= 9.0 g/dL (obtained =< 8 days prior to registration)
- NOTE: Must be met without growth factor support and no transfusions <14 days
prior to testing
- Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 8 days prior to
registration)
- Platelet count >= 100,000/mm^3 (obtained =< 8 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 8 days prior to
registration)
- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x
ULN for patients with liver involvement) (obtained =< 8 days prior to registration)
- Prothrombin time (PT)/international normalized ratio (INR)/activated partial
thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant
therapy and INR or aPTT is within target range of therapy (obtained =< 8 days prior to
registration)
- Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 45 ml/min using the
Cockcroft-Gault formula (obtained =< 8 days prior to registration)
- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only
- Note: If testing done for eligibility is > 72 hours prior to first dose, then
pregnancy testing must be repeated and result must be negative for patient to
receive treatment
- Persons able to become pregnant OR able to father a child must be willing to use an
adequate method of contraception while on treatment and for 180 days after last
treatment
- Life expectancy >= 12 weeks
- Provide written informed consent
- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)
- Willingness to provide mandatory blood specimens for correlative research
- Willingness to provide mandatory tissue specimens for correlative research
- RE-REGISTRATION (SECOND COURSE) ELIGIBILITY
- Either
- Stopped initial treatment with study treatment after attaining an
investigator-determined confirmed complete response (CR) based on RECIST 1.1, and
- Was treated with at least 8 cycles of study treatment before discontinuing
treatment, and
- Received at least 2 treatments with pembrolizumab beyond the date when the
initial CR was declared OR
- Had stable disease (SD), partial response (PR), or CR and stopped study treatment
after completion of 35 administrations (approximately 2 years) of study treatment
for reasons other than disease progression or intolerability
- Experienced an investigator-determined radiographic disease progression by RECIST 1.1
after stopping initial treatment, and
- No new anticancer treatment was administered after the last dose of study
treatment, and
- The participant meets all of the safety parameters listed in the inclusion
criteria and none of the safety parameters listed in the exclusion criteria, and
- The study is ongoing
Exclusion Criteria:
- REGISTRATION - EXCLUSION CRITERIA
- Any of the following because this study involves an agent that has known genotoxic,
mutagenic and teratogenic effects:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential and persons able to father a child who are
unwilling to employ adequate contraception
- Persons expecting to conceive or father children during study treatment or within
180 days (6 months) after the last treatment
- Any of the following prior therapies:
- Surgery < 3 weeks prior to registration
- Systemic anti-cancer therapy < 3weeks prior to registration
- Radiotherapy < 2 weeks prior to registration OR Palliative radiation < 1 week
prior to registration
- NOTES: Must have recovered from all radiation related adverse effects (=<
grade 1) Must not currently require corticosteroids Must not have had
radiation pneumonitis
- Live vaccine < 4 weeks prior to registration
- NOTES: Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette-Guerin (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
- Received an investigational agent or used an investigational device or
participated in a study of an investigational agent < 4 weeks prior to
registration
- Known active human immunodeficiency virus (HIV) infection (defined as patients who are
not on anti-retroviral treatment and have detectable viral load and CD4+ < 500/ml)
- NOTE: HIV-positive patients who are well controlled on anti-retroviral therapy
are allowed to enroll
- Active autoimmune disease requiring systemic treatment < 2 years prior to
registration, documented history of severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents with use of disease modifying
agents, corticosteroids or immunosuppressive drugs
- NOTE: Exceptions are allowed for:
- Vitiligo
- Resolved childhood asthma/atopy
- Intermittent use of bronchodilators or inhaled steroids
- Daily steroids at dose of =< 10 mg of prednisone (or equivalent)
- Local steroid injections
- Stable hypothyroidism on replacement therapy
- Stable diabetes mellitus on therapy (with or without insulin)
- Sjogren's syndrome
- 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 and is allowed
- Current or prior use of immunosuppressive medication < 14 days prior to registration
- NOTE: The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intraarticular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g.,
premedication for computed tomography [CT] scans)
- Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection requiring systemic therapy
- Interstitial lung disease or clinically significant pleural effusion
- Clinically significant ascites
- Serious, chronic gastrointestinal conditions associated with diarrhea (e.g.,
Crohn's disease or others)
- Known history of hepatitis B (i.e., known positive hepatitis B virus [HBV]
surface antigen [HBsAg] reactive)
- Known active hepatitis C (i.e., positive for hepatitis C virus [HCV] ribonucleic
acid [RNA] detected by polymerase chain reaction [PCR])
- Known active tuberculosis (TB)
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Unstable cardiac arrhythmia or
- Psychiatric illness/social situations that would limit compliance with study
requirements (e.g., substance abuse)
- Co-morbid systemic illnesses or other severe concurrent disease or current evidence of
any condition, therapy, or laboratory abnormality which, in the judgment of the
investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- Failure to recover to =< grade 1 (or baseline) from adverse events due to previously
administered therapies or prior surgery
- Exceptions: Neuropathy, fatigue, and/or alopecia may be grade 1
- Known active central nervous system (CNS) metastases
- NOTE: Patients with previously treated brain metastases may participate provided
all of the following are true:
- They are stable (without evidence of progression by imaging =< 4 weeks prior
to registration and any neurologic symptoms have returned to baseline)
- Have no evidence of new or enlarging brain metastases, and
- Are not using steroids =< 14 days prior to registration
- Known leptomeningeal disease
- Hypersensitivity (>= grade 3) to pembrolizumab or any of its excipients
- Previous serious adverse event (>= grade 3) attributed to prior checkpoint inhibitor
therapy
- History of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- History of grade >= 3 immune-related adverse event or any grade of immune-related
neurologic or ocular adverse event while receiving immunotherapy
- Note: Patients who had endocrine adverse events =< grade 2 are allowed to enroll
if they are stable on appropriate replacement therapy and asymptomatic
- Other active malignancy < 2 years prior to registration
- EXCEPTIONS: Non-melanotic skin cancer, superficial bladder cancer, papillary
thyroid cancer, or carcinoma-in-situ of the cervix or others curatively treated
and now considered to be at less than 30% risk of relapse
- History of allogenic tissue/solid organ transplant
