Clinical Trials /

Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

NCT03263429

Description:

This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, 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 glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer
  • Official Title: Phase I/II Study to Evaluate the Safety, Efficacy, and Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC GI 1703
  • SECONDARY ID: NCI-2017-01461
  • NCT ID: NCT03263429

Conditions

  • Colorectal Cancer
  • Metastatic Colorectal Cancer
  • RAS Wild Type Colorectal Cancer
  • Refractory Colorectal Cancer

Interventions

DrugSynonymsArms
Glutaminase Inhibitor CB-839Panitumumab/Irinotecan/CB-839
PanitumumabPanitumumab/Irinotecan/CB-839
Irinotecan HydrochloridePanitumumab/Irinotecan/CB-839

Purpose

This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, 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 glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.

Detailed Description

      Objectives:

      Primary Objective of Phase I:

      • Determine the safety and tolerability of CB-839 in combination with panitumumab and
      irinotecan.

      Primary Objective of Phase II:

      • Determine the efficacy of CB-839 in combination with panitumumab and irinotecan as measured
      by the response rate (RR) in patients with previously EGFR treated RAS wildtype colorectal
      adenocarcinoma.

      Secondary Objectives of Phase II:

      OUTLINE: This is a dose-escalation study of glutaminase inhibitor CB-839.

      Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28,
      panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15, and irinotecan
      hydrochloride IV over 90 minutes on day 1 and 15. Courses repeat every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days and then every 3
      months for up to 1 year.

        -  Determine the disease control rate (DCR), progression-free survival (PFS), and overall
           survival (OS).

        -  Perform the following correlative studies (in the Phase II component):

             -  Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with
                clinical outcome and biological correlates (plasma glutamate levels, exosomes)

             -  Quantify exosomal content in the plasma.
    

Trial Arms

NameTypeDescriptionInterventions
Panitumumab/Irinotecan/CB-839ExperimentalCB-839 in a pill form taken by mouth two times a day Panitumumab given through a vein over 60 or 90 minutes on day 1 and 15 of each 28-day cycle Irinotecan given through a vein over 90 minutes on Day 1 and 15 of each 28-day cycle 18F-FSPG PET/CT scans (during phase II) at baseline and day 28 of cycle 1
  • Glutaminase Inhibitor CB-839
  • Irinotecan Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Signed and dated written informed consent.

          -  Histologically or cytologically-confirmed diagnosis of metastatic KRAS wildtype
             colorectal cancer (CRC).

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

          -  In Dose Escalation, patients must have had at least one prior line of chemotherapy for
             advanced disease or progressed within 6 months of adjuvant therapy (prior chemotherapy
             and/or anti-EGFR therapy is permitted).

        In Dose Expansion, patients must have received prior anti-EGFR therapy.

          -  At least one measureable lesion as defined by RECIST 1.1 which can be followed by CT
             or MRI.

          -  Adequate organ function including:

               -  Absolute neutrophil count (ANC) ≥ 1,500/μL

               -  Platelets ≥ 100,000/μL

               -  Serum albumin ≥ 3.0 g/dL

               -  Serum creatinine ≤ 2 mg/dL, or calculated creatinine clearance > 50 mL/min (per
                  the Cockcroft-Gault formula)

               -  Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

               -  Aspartate transaminase (AST) and Alanine Aminotransferase (ALT) ≤ 5.0 x ULN.

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to receiving first dose of protocol-indicated treatment; and additionally
             agree to use at least 2 methods of acceptable contraception or abstain from
             heterosexual intercourse from the time of signing consent, and until 2 months after
             patient's last dose of protocol-indicated treatment.

        Women of childbearing potential are defined as those not surgically sterile or not
        post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a
        bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12
        months in the absence of an alternative medical cause, then patient will be considered a
        female of childbearing potential). Postmenopausal status in females under 55 years of age
        should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory
        reference range for postmenopausal women.

        Men able to father children who are sexually active with WOCBP must agree to use at least 2
        methods of acceptable contraception (Appendix 4) from the time of signing consent and until
        2 months after patient's last dose of protocol-indicated treatment.

        Men able to father children are defined as those who are not surgically sterile (i.e.
        patient has not had a vasectomy).

        Exclusion Criteria:

        , Within 28 days before first dose of protocol-indicated treatment:

          -  Anti-cancer treatment including chemotherapy, radiation, hormonal therapy, targeted
             therapy, immunotherapy, or biological therapy.

          -  Major surgery requiring general anesthesia. (Note: within this time frame, placement
             of a central line or portacath is acceptable and does not exclude.)

          -  Receipt of an investigational agent.

             . Within 14 days before first dose of protocol-indicated treatment:

          -  Active uncontrolled infection. Patients with infection under active treatment and
             controlled with antibiotics initiated at least 14 days prior to initiation of
             protocol-indicated treatment are not excluded (e.g. urinary tract infection controlled
             with antibiotics).

               -  Known Grade 4 toxicity probably or definitely attributed to past irinotecan
                  treatment.

               -  Active inflammatory bowel disease, other bowel disease causing chronic diarrhea
                  (defined as > 4 loose stools per day), or bowel obstruction.

               -  History of interstitial pneumonitis or pulmonary fibrosis, or evidence of
                  interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan.

               -  Unable to receive oral medication.

               -  Central nervous system metastasis, unless asymptomatic or previously treated and
                  stable; and no evidence of CNS progression for at least 30 days prior to
                  initiating protocol-indicated treatment. Anticonvulsant and/or corticosteroid
                  therapy will be allowed if patient is on a stable or decreasing dose of such
                  treatment for at least 30 days prior to initiating protocol-indicated treatment.

               -  Patients with known Gilbert's disease.

               -  Patient is pregnant or breastfeeding.

               -  Current or previous malignant disease (other than colorectal cancer) within the
                  last 5 years; with the exception of the following if considered curatively
                  treated: non-melanoma skin cancer(s), carcinoma in situ of the cervix, and ductal
                  carcinoma in situ. Subjects with another active malignancy requiring concurrent
                  anti-cancer intervention are excluded. (Note the following does not exclude:
                  effectively treated malignancy that has been in remission for more than 5 years
                  and is considered to be cured AND no additional anti-cancer therapy is ongoing
                  and required during the study period.)

               -  Known positive test for Human Immunodeficiency Virus (HIV), Acquired
                  Immunodeficiency Syndrome (AIDS), Hepatitis A, Hepatitis B, Hepatitis C, or
                  Cytomegalovirus (CMV).

               -  Known psychiatric condition, social circumstance, or other medical condition
                  reasonably judged by the patient's study physician to unacceptably increase the
                  risk of study participation; or to prohibit the understanding or rendering of
                  informed consent or anticipated compliance with scheduled visits, treatment
                  schedule, laboratory tests and other study requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (Phase I) B-839 in combination with panitumumab and irinotecan hydrochloride
Time Frame:Up to 12 months
Safety Issue:
Description:The maximum tolerated dose will be determined

Secondary Outcome Measures

Measure:Disease control rate
Time Frame:Up to 12 months
Safety Issue:
Description:The disease control rate will be evaluated.
Measure:Maximum Standardized Uptake Value (SUVmax) of fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) uptake (Phase II)
Time Frame:Up to 8 weeks
Safety Issue:
Description:evaluate the relationship between 18F-FSPG uptake at baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The slope will describe the shape of the relationship between SUVmax and change in tumor size, while the coefficient of determination (R2) describes the strength of the relationship between the two measures. A similar linear regression analysis will be conducted to quantify the relationship between the change in SUVmax as measured from baseline to after one cycle of therapy and change in tumor size.
Measure:Plasma exosomal content (phase II)
Time Frame:Up to 12 months
Safety Issue:
Description:Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.
Measure:Progression free survival (phase II)
Time Frame:Up to 12 months
Safety Issue:
Description:will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.
Measure:Overall Survival
Time Frame:Up to 12 months
Safety Issue:
Description:will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Last Updated

September 13, 2017