Clinical Trials /

C-Met Inhibitor AMG 337, Oxaliplatin, Leucovorin Calcium, and Fluorouracil in Treating Patients With Advanced Stomach or Esophageal Cancer

NCT02344810

Description:

This partially randomized phase I/II trial studies the side effects and best dose of c-Met inhibitor AMG 337 when given together with oxaliplatin, leucovorin calcium, and fluorouracil and to see how well they work in treating patients with stomach or esophageal cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. C-Met inhibitor AMG 337 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as, oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving c-Met inhibitor AMG 337 with oxaliplatin, leucovorin calcium, and fluorouracil may kill more tumor cells.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Colorectal Adenocarcinoma
  • Esophageal Carcinoma
  • Gastric Adenocarcinoma
  • Small Intestinal Adenocarcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: C-Met Inhibitor AMG 337, Oxaliplatin, Leucovorin Calcium, and Fluorouracil in Treating Patients With Advanced Stomach or Esophageal Cancer
  • Official Title: A Phase I and Randomized Phase II Double Blinded Placebo Controlled Study of mFOLFOX6 +/- AMG 337 in the First Line Treatment of Patients With Her2/Neu Negative and High MET Expressing Advanced Gastric and Esophageal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: EA2132
  • SECONDARY ID: NCI-2014-01315
  • SECONDARY ID: EA2132
  • SECONDARY ID: EA2132
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT02344810

Conditions

  • Adenocarcinoma of the Esophagus
  • Adenocarcinoma of the Gastroesophageal Junction
  • Diffuse Adenocarcinoma of the Stomach
  • Gastrointestinal Cancer
  • Intestinal Adenocarcinoma of the Stomach
  • Mixed Adenocarcinoma of the Stomach
  • Stage IIIA Esophageal Cancer
  • Stage IIIA Gastric Cancer
  • Stage IIIB Esophageal Cancer
  • Stage IIIB Gastric Cancer
  • Stage IIIC Esophageal Cancer
  • Stage IIIC Gastric Cancer
  • Stage IV Esophageal Cancer
  • Stage IV Gastric Cancer

Interventions

DrugSynonymsArms
c-Met inhibitor AMG 337AMG 337, AMG337Arm A (AMG 337, mFOLFOX6)
oxaliplatin1-OHP, Dacotin, Dacplat, Eloxatin, L-OHPArm A (AMG 337, mFOLFOX6)
leucovorin calciumCF, CFR, LVArm A (AMG 337, mFOLFOX6)
fluorouracil5-fluorouracil, 5-Fluracil, 5-FUArm A (AMG 337, mFOLFOX6)

Purpose

This partially randomized phase I/II trial studies the side effects and best dose of c-Met inhibitor AMG 337 when given together with oxaliplatin, leucovorin calcium, and fluorouracil and to see how well they work in treating patients with stomach or esophageal cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. C-Met inhibitor AMG 337 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as, oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving c-Met inhibitor AMG 337 with oxaliplatin, leucovorin calcium, and fluorouracil may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the toxicity of combination therapy with AMG 337 (c-Met inhibitor AMG 337) and
      mFOLFOX6 (oxaliplatin, leucovorin calcium, and fluorouracil) chemotherapy in patients with
      advanced or metastatic gastrointestinal (GI) cancers. (Phase I) II. To determine the dose of
      AMG 337 to be used in combination with mFOLFOX6 chemotherapy in the phase II portion of the
      trial. (Phase I) III. To determine the pharmacokinetics of AMG 337 in combination with
      mFOLFOX6. (Phase I) IV. To determine if the addition of AMG 337 to mFOLFOX6 chemotherapy
      improves median progression-free survival (PFS) in the first line treatment of patients with
      human epidermal growth factor receptor 2 (Her2Neu) negative and high c-met proto-oncogene
      (MET) expressing advanced esophagogastric and gastroesophageal junction (GEJ) adenocarcinoma.
      (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the
      placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with
      Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma,
      with regards to overall survival (OS). (Phase II) II. To evaluate the addition of AMG 337 to
      mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in
      the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced
      esophagogastric and GEJ adenocarcinoma, with regards to response rate and disease control
      rate. (Phase II) III. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also
      to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of
      patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ
      adenocarcinoma, with regards to toxicity rates. (Phase II) IV. To evaluate the addition of
      AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy
      combination in the first line treatment of patients with Her2Neu negative and high c-MET
      expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to time to
      development of new metastasis. (Phase II) V. To evaluate the addition of AMG 337 to mFOLFOX6
      chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first
      line treatment of patients with Her2Neu negative and high c-MET expressing advanced
      esophagogastric and GEJ adenocarcinoma, with regards to evaluation of MET amplification.
      (Phase II) VI. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to
      evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of
      patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ
      adenocarcinoma, with regards to evaluation of MET amplification and MET expression as
      determined by DAKO immunohistochemistry (IHC) for comparison to Ventana IHC. (Phase II) VII.
      To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the
      placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with
      Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma,
      with regards to a retrospective re-evaluation of the cutpoint used by the computer algorithm
      for c-MET IHC to assess its ability to distinguish responding versus non-responding patients
      will be undertaken in this population, so that a potentially more optimal cutpoint to define
      high c-MET tumors in patients can be identified. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of c-Met inhibitor AMG 337 followed by a
      phase II study.

      PHASE I: Patients receive c-Met inhibitor AMG 337 orally (PO) once daily (QD) on days 1-28;
      and oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and
      fluorouracil IV over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 treatment arms.

      ARM A: Patients receive c-Met inhibitor AMG 337 PO QD on days 1-28; and oxaliplatin IV over 2
      hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and
      15.

      ARM B: Patients receive placebo PO QD on days 1-28; and oxaliplatin IV over 2 hours,
      leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15.

      In both arms, courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (AMG 337, mFOLFOX6)ExperimentalPatients receive c-Met inhibitor AMG 337 PO QD on days 1-28; and oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15.
  • c-Met inhibitor AMG 337
  • oxaliplatin
  • leucovorin calcium
  • fluorouracil
Arm B (placebo, mFOLFOX6)Active ComparatorPatients receive placebo PO QD on days 1-28; and oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15.
  • oxaliplatin
  • leucovorin calcium
  • fluorouracil

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a life expectancy >= 12 weeks

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Women must not be pregnant or breast-feeding; all females of childbearing potential
             must have a blood test or urine study within 48 hours prior to randomization to rule
             out pregnancy; a female of childbearing potential is any woman, regardless of sexual
             orientation or whether they have undergone tubal ligation, who meets the following
             criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
             been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
             at any time in the preceding 24 consecutive months)

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) for the duration of study
             therapy and for 3 months after the last dose of AMG 337 plus mFOLFOX6 chemotherapy;
             should a woman become pregnant or suspect she is pregnant while participating in this
             study, she should inform her treating physician immediately; should a man impregnate
             or suspect that he has impregnated a woman while participating in this study, he
             should inform his treating physician immediately

          -  Patients must NOT have a known immediate or delayed hypersensitivity reaction to drugs
             chemically related to fluorouracil, platins or their excipients nor have a known
             history of dihydropyrimidine dehydrogenase (DPD) deficiency

          -  Patients must be able to swallow tablets whole

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Hemoglobin >= 9 g/dL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 X institutional upper limit of normal (ULN) or =< 5 X ULN if the patient has
             liver metastases

          -  Creatinine =< 1.5 X institutional ULN or creatinine clearance >= 50 mL/min for
             patients with creatinine levels above institutional normal

          -  Patients must NOT be taking current medications or substances that are inhibitors or
             inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)

          -  Patients with known human immunodeficiency virus (HIV) are not eligible if cluster of
             differentiation (CD)4 count is =< 200 cell/mm^3 or if receiving antiretroviral therapy

          -  Patients must not have a pre-existing > grade 1 (Common Terminology Criteria for
             Adverse Events version 4 [CTCAEv4]) motor or sensory neuropathy

          -  Patients must not have an uncontrolled infection, active hepatic, biliary disease or
             other uncontrolled intercurrent illnesses including, but not limited to: uncontrolled
             ascites, uncontrolled hypertension, symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia or psychiatric illness/addictive disorders that
             would limit compliance with study requirements

          -  PHASE I:

          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1 criteria within 4 weeks prior to registration; patients must not have
             clinical or radiographic evidence of brain metastasis

          -  Patients must have histologically or cytologically confirmed adenocarcinoma
             originating from anywhere in the gastrointestinal tract

          -  Patients must have progression on standard therapies, for which effective therapy is
             not available (or patients are not a candidate for or are intolerant of such
             therapies)

          -  Patients must NOT have previous or concurrent malignancy; exceptions are made for
             patients who meet any of the following conditions:

               -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
                  superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)

               -  Prior malignancy completely excised or removed and patient has been continuously
                  disease free for > 5 years from registration

          -  Patients may have received prior surgery or radiotherapy if > 4 weeks prior to
             registration and patient does not have any unresolved or unstable serious toxicity

          -  Patients must not be receiving an investigational agent concurrently and must not have
             received any other investigational agents within 4 weeks prior to randomization

          -  PHASE II:

          -  Patients must have measurable disease by RECIST 1.1 criteria within 4 weeks prior to
             registration to Step 0; patients must not have clinical or radiographic evidence of
             brain metastasis because of their poor prognosis

          -  Patient disease status must be as follows:

               -  Adenocarcinoma or poorly differentiated carcinoma of the stomach, esophagus or
                  gastroesophageal (GE) junction

               -  Histologically or cytologically confirmed Her2/neu negative cancer prior to
                  pre-registration; Her2/neu status must be determined by a Clinical Laboratory
                  Improvement Amendments (CLIA) certified laboratory

               -  Locally advanced or metastatic disease that is inoperable and not amenable to
                  curative therapy; linitis plastica is permitted

               -  Patient must NOT have gastric carcinoid, sarcomas or squamous cell carcinoma

          -  Patients may have received prior surgery or radiotherapy if > 4 weeks prior to
             registration to Step 0 and patient does not have any unresolved or unstable serious
             toxicity

          -  Patients must NOT have previous or concurrent malignancy; exceptions are made for
             patients who meet any of the following conditions:

               -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or
                  superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)

               -  Prior malignancy completely excised or removed and patient has been continuously
                  disease free for > 5 years from registration to Step 0

          -  Patients must not be receiving an investigational agent concurrently and must not have
             received any other investigational agents within 4 weeks prior to registration to Step
             0

          -  Patient may not have received prior chemotherapy for advanced disease or prior
             oxaliplatin or anti-MET therapy

          -  Previous neo-adjuvant or adjuvant treatment is allowed provided that it was
             discontinued >= 6 months prior to registration to Step 0

          -  Patients must have paraffin-embedded tumor specimen available for submission for
             central determination of MET expression status

               -  NOTE: it is recommended that patients not be pre-registered until the required
                  tumor specimens are on hand and ready for submission; if submission of tissue
                  will be submitted more than 5 working days after pre-registration, immediately
                  notify the receiving laboratory

          -  Patients must have had MET expression status determined by the Immunohistochemistry
             Laboratory and Image Analysis Laboratory in the Department of Pathology of The
             University of Texas MD Anderson Cancer Center in Houston: the report from the central
             laboratory indicates tumor tissue has MET

               -  NOTE: for this protocol, 'MET High' will be defined as: >= 50% tumor cells with a
                  staining intensity of 2+ or 3+ in IHC utilizing the CONFIRM anti-total MET, SP44,
                  rabbit monoclonal primary antibody
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of c-Met inhibitor AMG 337, defined as the highest dose level at which < 33% of 6 patients experience a dose limiting toxicity graded according to CTCAE v.4 (Phase I)
Time Frame:28 days
Safety Issue:
Description:The study will have 90% power to detect the above improvement in PFS using a one-sided 0.10 level log rank test.

Secondary Outcome Measures

Measure:Overall survival (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Response rate (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Disease control rate (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of toxicity graded according to CTCAE v.4 (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:The study will have at least 83% power to detect an absolute differences of 26% or more (e.g. 64% versus 38% true toxicity rates) between the two arms for any given adverse event, using a one-sided 5% level Fisher's exact test.
Measure:Time to development of new metastasis (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Evaluation of MET amplification via fluorescence in situ hybridization (FISH) (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Evaluation of MET amplification and MET expression as determined by DAKO IHC (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:Comparison of DAKO IHC to Ventana IHC and comparison of amplification by FISH to overexpression by Ventana IHC amongst all pre-registered patients.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Eastern Cooperative Oncology Group

Last Updated

October 19, 2017