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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 : Recruiting
First Posted : May 18, 2018
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE May 17, 2018
First Posted Date  ICMJE May 18, 2018
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE December 6, 2018
Estimated Primary Completion Date December 5, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03528642 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CB-839 With Radiation Therapy and Temozolomide in Treating Participants With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma
Official Title  ICMJE A Phase Ib Trial of CB-839 in Combination With Radiation Therapy and Temozolomide in Patients With IDH-Mutated Diffuse Astrocytoma and Anaplastic Astrocytoma
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.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of CB-839 hydrochloride (HCl) when combined with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed IDH-mutated diffuse astrocytoma (DA) and anaplastic astrocytoma (AA).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Determine the safety and tolerability of RT/TMZ/CB-839 HCl in patients based on physician reported adverse event (AE) data.

III. Estimate the 2-year progression-free survival (PFS2) of RT/TMZ/CB-839 HCl in patients with IDH-mutated glioma based on the Response Assessment in Neuro-Oncology (RANO) criteria.

IV. Estimate the 2-year overall survival (OS2) of RT/TMZ/CB-839 HCl in patients with IDH-mutated glioma based on RANO criteria.

CORRELATIVE OBJECTIVES:

I. Determine the patient-reported tolerability of RT/TMZ/CB-839 HCl using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) instrument to measure self-reported symptom severity and interference with daily activities.

II. Determine the neurocognitive impact of CB-839 HCl when used in combination with RT/TMZ.

III. Determine the effect of CB-839 HCl/RT/TMZ on plasma oncometabolite levels of glutamine, glutamate, aspartate, asparagine, and 2-hydroxyglutarate (2-HG) in patients with IDH-mutated glioma and associate the changes with disease response.

IV. Determine the effect of CB-839 HCl/RT/TMZ on tumor 2-HG, glutamine, and glutamate MRS signals in patients with IDH-mutated glioma and associate the signal with disease response.

V. Determine the pharmacokinetics (PK) of CB-839 HCl when used alone and in combination with TMZ.

VI. To perform molecular profiling assays on archived tumor tissue and peripheral blood, including, but not limited to, low-pass whole genome sequencing (WGS), whole exome sequencing (WES), and messenger RNA sequencing (RNA-Seq) in order to identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned, and identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and ribonucleic acid (RNA)-based assessment platforms.

VII. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

VIII. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

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

Participants receive CB-839 PO twice daily (BID) 7 days a week, temozolomide PO once daily (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.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anaplastic Astrocytoma, IDH-Mutant
  • Diffuse Astrocytoma, IDH-Mutant
Intervention  ICMJE
  • 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
    • TMZ
Study Arms  ICMJE 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.
Interventions:
  • Drug: Glutaminase Inhibitor CB-839 Hydrochloride
  • Other: Questionnaire Administration
  • Radiation: Radiation Therapy
  • Drug: Temozolomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 17, 2018)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 5, 2022
Estimated Primary Completion Date December 5, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03528642
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sani H Kizilbash Mayo Clinic Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP