SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03831932

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Phase I/II Study of AZD9291(Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of glutaminase inhibitor CB-839 hydrochloride, and to see how well it works when given together with osimertinib in treating patients with stage IV non-small cell lung cancer and a mutation in the EGFR gene. Glutaminase inhibitor CB-839 hydrochloride and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03831932 Advanced Lung Carcinoma EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR T790M Mutation Negative Lung Non-Small Cell Carcinoma Metastatic Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

3 Interventions

Name: Glutaminase Inhibitor CB-839

Description: Given PO

Type: Drug

Treatment (CB-839 HCl, osimertinib)

Name: Glutaminase Inhibitor CB-839 Hydrochloride

Description: Given PO

Type: Drug

Treatment (CB-839 HCl, osimertinib)

Name: Osimertinib

Description: Given PO

Type: Drug

Treatment (CB-839 HCl, osimertinib)


Primary Outcomes

Measure: Recommended phase II dose (RP2D) (Phase I)

Time: Up to 28 days

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 30 days after completion of therapy

Secondary Outcomes

Description: Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Measure: Dose limiting toxicities (DLT) (Phase I)

Time: Up to 28 days

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Progression-free survival (PFS) (Phase II)

Time: From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Overall survival (OS) (Phase II)

Time: From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy

Other Outcomes

Description: Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl) (Phase I)

Time: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle

Description: Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-AZD9291 PK (Phase I)

Time: Day 2 of cycle 2 and day 1 of each subsequent cycle

Description: Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in EGFR mutational status (Phase II)

Time: Baseline up to disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in circulating levels of glutamine, glutamate, aspartate, and asparagine (Phase II)

Time: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.

Measure: Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging (Phase II)

Time: Baseline up to 2 cycles of treatment

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 L858R

The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.. Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy specimen. --- L858R ---

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy specimen. --- L858R ---


2 T790M

Liquid biopsies cannot be used for eligibility determination - Must be T790M mutation negative as determined by local Clinical Laboratory Improvement Amendments (CLIA)-certified assessment of a tissue biopsy obtained after progression on front-line therapy - Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib, erlotinib, afatinib). --- T790M ---

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted Advanced Lung Carcinoma EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR T790M Mutation Negative Lung Non-Small Cell Carcinoma Metastatic Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess the safety and tolerability of osimertinib (AZD9291) and glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) (telaglenastat) and determine the recommended phase II dose (RP2D) in patients with metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC). --- T790M ---

To determine the efficacy of AZD9291 and CB-839 HCl (telaglenastat) in patients with metastatic, EGFR activating mutation-positive, T790M mutation-negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy, as defined by response rate (RR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. --- T790M ---

To determine the progression free survival (PFS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy. --- T790M ---

To determine the overall survival (OS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed PD on front-line EGFR inhibitor therapy. --- T790M ---

(Phase II) EXPLORATORY/CORRELATIVE OBJECTIVES: I. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with response to treatment as well as disease progression (EGFR sensitizing mutations, T790M resistance mutation, recognized bypass mechanisms). --- T790M ---



HPO Nodes


HPO:
Carcinoma
Genes 11
PTEN CDKN1B APC MLH1 MSH2 FGFR3 KIT DKC1 RSPO1 STK11 NLRP1
Neoplasm of the lung
Genes 43
WT1 KRAS SLC22A18 STK11 IRF1 AKT1 C11ORF95 PRKN PPP2R1B ERBB2 TRPV3 TSC1 POU6F2 TSC2 EWSR1 RELA KEAP1 REST DIS3L2 SFTPA2 GPC3 MBTPS2 LMNA PTEN BRAF BRCA2 EGFR RB1 TRIP13 PDGFRB TERT SFTPC PIK3CA TRIM28 DICER1 MAP3K8 HPGD SLCO2A1 H19 TP53 NOTCH3 BAP1 WRN
Non-small cell lung carcinoma
Genes 2
TP53 BAP1