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CB-839 With Radiation Therapy and Temozolomide in Treating Participants With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma

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ClinicalTrials.gov Identifier: NCT03528642
Recruitment Status : Not yet recruiting
First Posted : May 18, 2018
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase 1b trial studies the side effects and best dose of glutaminase inhibitor CB-839 hydrochloride (CB-839) in combination with radiation therapy and temozolomide in treating participants with IDH-mutated diffuse or anaplastic astrocytoma. CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or stopping them from spreading. Giving CB-839 with radiation therapy and temozolomide may work better in treating participants with IDH-mutated diffuse astrocytoma or anaplastic astrocytoma.

Condition or disease Intervention/treatment Phase
Anaplastic Astrocytoma, IDH-Mutant Diffuse Astrocytoma, IDH-Mutant IDH1 Gene Mutation IDH2 Gene Mutation Drug: Glutaminase Inhibitor CB-839 Hydrochloride Other: Questionnaire Administration Radiation: Radiation Therapy Drug: Temozolomide Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Trial of CB-839 in Combination With Radiation Therapy and Temozolomide in Patients With IDH-Mutated Diffuse Astrocytoma and Anaplastic Astrocytoma
Estimated Study Start Date : February 8, 2019
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020


Arm Intervention/treatment
Experimental: Treatment (CB-839, temozolomide, RT)
Participants receive CB-839 PO BID 7 days a week, temozolomide PO QD 7 days a week, and undergo RT 5 days a week for up to 5.5 weeks (diffuse astrocytoma) or 6.5 weeks (anaplastic astrocytoma) in the absence of disease progression or unacceptable toxicity.
Drug: Glutaminase Inhibitor CB-839 Hydrochloride
Given PO
Other Name: CB-839 HCl

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

Drug: Temozolomide
Given PO
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) [ Time Frame: Up to 6.5 weeks ]
    MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity (DLT) in at least 2 patients (out of 6). A total of 6 patients must be treated at the MTD. It is possible that the MTD will be unknown after this study (e.g., if the highest tested dose has fewer than 2 patients with DLT, out of 6). In this case, the highest dose is defined as the RP2D. A 3 + 3 cohort expansion design to determine toxicity-based dose escalation of glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) and external beam fractionated radiation therapy (RT) with concurrent temozolomide (TMZ) among patients with IDH-mutated diffuse astrocytoma (DA) or anaplastic astrocytoma (AA).


Secondary Outcome Measures :
  1. Objective response rate (ORR) as defined by Response Assessment in Neuro-Oncology (RANO) criteria [ Time Frame: Up to 6 months from the start of study treatment ]
    ORR is defined as the rate of either complete response (CR), partial response (PR), or minor response (MR) by RANO criteria for low-grade gliomas at 6 months after initiation of RT/TMZ/CB-839 HCl therapy. The ORR will be estimated using properties of the binomial distribution. 95% exact confidence intervals will also be calculated.

  2. Clinical benefit rate (CBR) as defined by RANO criteria [ Time Frame: Up to 6 months from the start of study treatment ]
    CBR is defined as the rate of either CR, PR, MR, or stable disease (SD) by RANO criteria for low-grade gliomas at 6 months after initiation of RT/TMZ/CB-839 HCl therapy. The CBR will be estimated using properties of the binomial distribution. 95% exact confidence intervals will also be calculated.

  3. Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Up to 2 years ]
    The safety and tolerability of RT/TMZ/CB-839 HCl in patients is based on physician reported adverse event (AE) data.

  4. Progression-free survival (PFS2) as defined by response assessment in neuro-oncology (RANO) criteria [ Time Frame: Up to 2 years ]
    PFS2 rate will be estimated using properties of the binomial distribution. 95% exact confidence intervals will also be calculated.

  5. Overall survival (OS2) as defined by RANO criteria [ Time Frame: Up to 2 years ]
    OS2 rate will be estimated using properties of the binomial distribution. 95% exact confidence intervals will also be calculated.

  6. Assessment of pharmacokinetic (PK) parameters [ Time Frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose on days -7, 1, and 15 ]
    The PK of CB-839 HCl will also be summarized using descriptive statistics and will be compared to historical data. Measurement of plasma concentrations of CB-839 HCl and its metabolites (if authentic standards are available) will be performed using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assays. The plasma concentration-time data will be analyzed by standard noncompartmental analysis using the program Phoenix WinNonlin 6.4 to determine apparent total clearance of the drug from plasma after oral administration (Cl/F), area under the plasma concentration-time curve from time zero to time t (AUCt), area under the plasma concentration-time curve from time zero to infinity, Cmax, time to reach maximum plasma concentration following drug administration (Tmax), t1/2, and accumulation.

  7. Assessment of self-reported symptoms as measured by MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) instrument [ Time Frame: Up to 2 years ]
    MDASI-BT instrument is used to measure self-reported symptom severity and interference with daily activities. The study will use descriptive statistics to describe how patients rate symptom severity and interference with function at each time point. Compliance rates will be calculated as the number of received valid forms over the number of expected forms. Differences between groups in compliance will be tested by use of Fisher's exact test at every time point.

  8. Assessment of neurocognitive impact [ Time Frame: Baseline up to 2 years ]
    For each test in the battery, a standard error of measurement will be used to derive the Reliable Change Index (RCI) which will be used to represent the 90% confidence interval for the difference in raw scores from baseline to follow-up assessment will be coded as 1 (deterioration), 2 (no change), and 3 (improved) according to the RCI. Percentage of patients in each dose cohort who show meaningful losses or gains in the various tests or test domains over the course of the study will be provided by frequency tables. Dose cohort differences will be compared using chi-squared analysis. Time-to-progressions will be estimated by Kaplan-Meier method and analyzed by Cox regression model adjusting all stratification factors.

  9. Assessment of plasma oncometabolites [ Time Frame: Baseline up to day 71 ]
    Plasma oncometabolites (asparagine, aspartate, glutamine, glutamate, and 2-HG) will be compared using changes in values after treatment with the patient's individual baseline values using either the paired t-test or the Mann-Whitney nonparametric U-test as needed. A significant change is defined as a 10% change from baseline.

  10. Assessment of tumor oncometabolites as measured by magnetic resonance spectroscopy (MRS) [ Time Frame: Baseline up to day 45 ]
    Tumor oncometabolites (2-HG, glutamine, and glutamate, as measured by MRS) will be compared using changes in values after treatment with the patient's individual baseline values using either the paired t-test or the Mann-Whitney nonparametric U-test as needed. A significant change is defined as a 10% change from baseline.



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histopathologic or molecular confirmation of either IDH-mutant DA or IDH-mutant AA. Acceptable IDH mutations for study eligibility include any IDH1 mutation at codon 132 or any IDH2 mutation at codon 172.
  • Age ≥16 years. The intended neurocognitive tests have not been validated in children below the age of 16.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%).
  • Hemoglobin > 9.0 g/dL
  • Leukocytes >= 3.0 x 10^9/L
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN)
  • Partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) =< 1.5 x ULN
  • Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the investigator's discretion.
  • Total bilirubin =< 1.5 x institutional ULN and < 3 mg/dL for patients with Gilbert's disease
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) & alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 60 mL/minute
  • If there is history of human immunodeficiency virus (HIV) infection, patients must be on effective antiretroviral therapy and HIV viral load must be undetectable within 6 months of study enrollment.
  • If there is history of chronic hepatitis B virus (HBV) infection, patients must have either been treated or are on suppressive therapy (as indicated), and HBV viral load must be undetectable.
  • If there is history of hepatitis C virus (HCV) infection, patients must have been treated and HCV viral load must be undetectable.
  • Patient must have measurable disease by RANO criteria (dose expansion cohort only).
  • Patient must be at least 7 days beyond stereotactic biopsy and/or at least 14 days beyond open craniotomy.
  • Patients must have been on a stable or decreasing dose of corticosteroids over the last 7 days.
  • Patients must have been on a stable or decreasing dose of antiepileptic therapy over the last 14 days.
  • Females of childbearing potential must have a negative pregnancy test (=<14 days) prior to start of trial treatment. The effects of CB-839 HCl on the developing human fetus are unknown. For this reason and because alkylating agents as well as TMZ are known to be teratogenic, 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 and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CB-839 HCl administration.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients must not have received prior chemotherapy to treat the glioma.
  • Patients who are receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to CB-839 HCl or TMZ.
  • Patient must not have received prior radiation therapy to the brain. Prior radiation therapy to the head and neck is also excluded if radiation fields overlap.
  • No prior use of Gliadel wafers.
  • Patient must have no evidence of either infratentorial or spinal involvement with tumor.
  • Patients who are unable to swallow tablets.
  • Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than 3 years.
  • Pregnant women are excluded from this study because CB-839 HCl is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with CB-839 HCl, breastfeeding should be discontinued if the mother is treated with CB-839 HCl. These potential risks may also apply to TMZ.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03528642


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Sani Kizilbash Mayo Clinic Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03528642     History of Changes
Other Study ID Numbers: NCI-2018-00876
NCI-2018-00876 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10218 ( Other Identifier: Mayo Clinic Cancer Center LAO )
10218 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
First Posted: May 18, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents