This is a phase 2 single-arm, open-label clinical trial determining efficacy of cabozantinib
in combination with pembrolizumab in subjects with advanced gastric and gastroesophageal
adenocarcinoma. These are subjects who have progressed, or not tolerated, at least one prior
line of chemotherapy with a fluoropyrimidine and platinum agent.
- Patients must have histologically or cytologically confirmed gastric or
- Must have locally advanced, recurrent, or metastatic disease not amenable to curative
- Must have progressed, or not tolerated, at least one line of treatment with a platinum
and fluoropyrimidine containing regimen. At least one cycle of combination
chemotherapy including a platinum (oxaliplatin, cisplatin, carboplatin) and
fluoropyrimidine (capecitabine or 5-Fluorouracil) for advanced disease. Combination
regimens with platinum/fluoropyrimidine containing a taxane and or a checkpoint
inhibitor are allowed. Patients progressing within six months of perioperative
chemotherapy or definitive chemoradiation for localized disease are eligible.
- Must have received and progressed on one previous line of treatment containing a
checkpoint inhibitor (if PD-L1 Combined Positive Score (CPS) score unknown or ≥ 1%).
Patients with PD-L1 CPS score < 1% are eligible independent of whether they have
received previous checkpoint inhibitors.
- Age ≥ 18 years
- Performance status: Eastern Cooperative Oncology Group (ECOG) performance status ≤2
- Life expectancy of greater than 3 months
- Adequate organ and marrow function as defined below:
1. Leukocytes: ≥ 2,000/mcL
2. absolute neutrophil count: ≥ 1000/mcL
3. platelets: ≥ 60,000/mcl
4. total bilirubin: within normal institutional limits
5. AST(SGOT)/ALT(SPGT): ≤ 3 X institutional upper limit of normal or ≤ 5 X if liver
metastases are present
6. creatinine: within normal institutional limits
7. hemoglobin: ≥ 9 g/dL
8. Serum albumin: ≥ 2.8 g/dL
9. Urine protein/creatinine ration (UPCR): ≤ 1 mg/mg
- The effects of cabozantinib on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation,
and for 4 months following completion of therapy. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
- A female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
1. Has not undergone a hysterectomy or bilateral oophorectomy; or
2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
- Ability to swallow tablets
- Ability to understand and the willingness to sign a written informed consent.
- Patients who have had chemotherapy within 2 weeks prior to entering the study
- All toxicities attributed to prior anti-cancer therapy other than alopecia must have
resolved to grade 1 or baseline
- Patients may not be receiving any other investigational agents.
- Patients with known brain metastases or cranial epidural disease unless accurately
treated with radiotherapy and/or surgery (including radiosurgery) and stable for at
least 4 weeks before first dose of study treatment. These individuals should be
excluded from this clinical trial because of their poor prognosis and because they
often develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the first dose of
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab, cabozantinib or other agents used in study.
- Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed
anticoagulants are the following:
1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is
2. Low-dose low molecular weight heparins (LMWH) are permitted.
3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
known brain metastases who are on a stable dose of LMWH for at least 6 weeks
before first dose of study treatment, and who have had no clinically significant
hemorrhagic complications from the anticoagulation regimen or the tumor.
- The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
1.3 x the laboratory ULN within 7 days before the first dose of study treatment.
- Uncontrolled intercurrent illness including, but not limited to, the following
1. ongoing or active infection
2. symptomatic congestive heart failure
3. uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
4. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
or other ischemic event, or thromboembolic event (eg, deep venous thrombosis,
pulmonary embolism) within 6 months before first dose
5. unstable angina pectoris
6. cardiac arrhythmia
7. evidence of tumor invading GI tract, active peptic ulcer disease, inflammatory
inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis,
symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of
the pancreatic duct or common bile duct, or gastric outlet obstruction.
8. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose.
9. Note: Complete healing of an intra-abdominal abscess must be confirmed before
10. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
(2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary
hemorrhage) within 12 weeks before first dose.
11. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
12. Lesions invading or encasing any major blood vessels.
13. Other clinically significant disorders that would preclude safe study
1. Serious non-healing wound/ulcer/bone fracture
2. Uncompensated/symptomatic hypothyroidism
3. Moderate to severe hepatic impairment (Child-Pugh B or C)
14. psychiatric illness/social situations that would limit compliance with study
- Major surgery within 8 weeks before first dose of study treatment. Complete wound
healing from major surgery must have occurred 1 month before first dose and from minor
surgery (eg, simple excision, tooth extraction) at least 10 days before first dose.
Subjects with clinically relevant ongoing complications from prior surgery are not
- Prior treatment with cabozantinib
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 28 days before first dose of study treatment.
1. Corrected QT (QTc) = QT / ∛RR
1. QT: duration of QT interval
2. RR: duration of RR interval
2. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two
additional ECGs at intervals of approximately 3 min must be performed within 30
min after the initial ECG, and the average of these three consecutive results for
QTcF will be used to determine eligibility.
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
- History of another primary cancer within the last 3 years with the exception of
non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical
carcinoma in-situ and not treated with systemic therapy.
- Inability to comply with study and follow-up procedures as judged by the Investigator
- Patients must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
- Has squamous cell or undifferentiated gastric cancer.
- Has received prior cytotoxic, biologic or other systemic anticancer therapy including
investigational agents within 2 weeks prior to randomization.
- Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before the first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
- Has received a live vaccine within 30 days prior to the first dose of study
intervention. 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
- 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 intervention.
- Has severe hypersensitivity (Grade ≥ 3) to pembrolizumab or cabozantinib and/or any of
- Has an active autoimmune disease that has required systemic treatment in 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.
- Has a history of (non‐infectious) pneumonitis that required steroids or has current
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection.
1. Note: No HIV testing is required unless mandated by local health authority.
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
- Has a history or current evidence of any condition (eg, known deficiency of the enzyme
dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality 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.