Clinical Trials /

Ph II Study of Cabozantinib With Pembrolizumab in Metastatic Gastric and Gastroesophageal Adenocarcinoma

NCT04164979

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ph II Study of Cabozantinib With Pembrolizumab in Metastatic Gastric and Gastroesophageal Adenocarcinoma
  • Official Title: Phase 2 Study of Cabozantinib Combined With Pembrolizumab in Metastatic or Recurrent Gastric and Gastroesophageal Adenocarcinoma (mGC)

Clinical Trial IDs

  • ORG STUDY ID: UCI 18-124
  • SECONDARY ID: 2019-5426
  • NCT ID: NCT04164979

Conditions

  • Gastric Adenocarcinoma
  • GastroEsophageal Cancer

Interventions

DrugSynonymsArms
CabozantinibCABOMETYX, COMETRIQCabozantinib and Pembrolizumab
PembrolizumabKEYTRUDACabozantinib and Pembrolizumab

Purpose

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.

Detailed Description

      Treatment on study will be administered in 21 day cycles.
    

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib and PembrolizumabExperimentalSubjects receive Cabozantinib 40mg PO daily on days 1-21 and Pembrolizumab 200mg IV on day 1 every 21 days.
  • Cabozantinib
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed gastric or
             gastroesophageal adenocarcinoma

          -  Must have locally advanced, recurrent, or metastatic disease not amenable to curative
             intent surgery.

          -  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
             following criteria:

               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.

        Exclusion Criteria:

          -  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
             study treatment.

          -  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
                  permitted.

               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
             conditions:

               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
                  first dose.

              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
                  manifestation.

              12. Lesions invading or encasing any major blood vessels.

              13. Other clinically significant disorders that would preclude safe study
                  participation:

                    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
                  requirements.

          -  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
             eligible.

          -  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
             eligible.

          -  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
             allowed.

          -  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
             their excipients.

          -  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
             pneumonitis.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Progression-free Survival at 6 Months
Time Frame:6 Months
Safety Issue:
Description:This is defined as the percentage of subjects who are free of progression 6 months after study treatment start. Progression is defined death, radiographic progression or clinical deterioration attributed disease progression as judged by an investigator. Radiographic progression is defined using the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm and/or appearance of new lesions.

Secondary Outcome Measures

Measure:Percentage of Grade 3-5 Adverse Events
Time Frame:From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.
Safety Issue:
Description:To evaluate the tolerability of administering cabozantinib in combination with pembrolizumab in patients with advanced gastric and gastroesophageal adenocarcinoma from the start of treatment, duration of treatment and up to 4 weeks after completion of study treatment. Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0.
Measure:Overall Response Rate as Assessed by RECIST v1.1
Time Frame:From date of registration until first date of disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.]
Safety Issue:
Description:To assess the overall response rate to the combination of cabozantinib and pembrolizumab. Overall response rate (ORR) is defined as confirmed complete response (CR) and partial response (PR). Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1): Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as a 30% decrease in the sum of diameters of target lesions. ORR = CR + PR
Measure:Overall Survival of Patients Who Received Cabozantinib and Irinotecan
Time Frame:From date of registration for up to 18 months after last patient is enrolled or until death from any cause, whichever came first.
Safety Issue:
Description:To evaluate overall survival in patients with advanced gastric and gastroesophageal adenocarcinoma treated with this combination of cabozantinib and irinotecan.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, Irvine

Trial Keywords

  • Gastric Adenocarcinoma
  • Gastroesophageal Adenocarcinoma
  • Cabozantinib
  • Pembrolizumab

Last Updated

November 13, 2019