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
|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)|
|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|
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
Other Name: CB-839 HCl
Other: Questionnaire Administration
Radiation: Radiation Therapy
- 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).
- 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.
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
|Principal Investigator:||Sani Kizilbash||Mayo Clinic Cancer Center LAO|