This phase I trial studies the side effects and best dose of navtemadlin in treating patients with glioblastoma (brain cancer) that is newly diagnosed or has come back (recurrent). Navtemadlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. Determine the concentration and variability in concentration of navtemadlin (AMG 232 \[KRT 232\]) in brain and brain-associated tissue in patients with recurrent glioblastoma (GBM). (Part 1) II. Determine the maximum tolerated dose (MTD) of AMG 232 (KRT 232) given in combination with standard radiation following surgery for patients with newly diagnosed GBM harboring unmethylated MGMT promoters and wild-type TP53. (Part 2) SECONDARY OBJECTIVES: I. Determine the safety and toxicity of AMG 232 (KRT 232) in patients with recurrent GBM. (Part 1) II. Assess the variability of AMG 232 (KRT 232) concentration in tumor enhancing versus (vs.) infiltrative tissue. (Part 1) III. Assess the pharmacodynamic effect of AMG 232 (KRT 232) on p21 elevation. (Part 1) IV. Determine the safety of AMG 232 (KRT 232) given concurrently with radiation therapy (RT) and adjuvantly as monotherapy for patients with newly diagnosed GBM harboring unmethylated MGMT promoters and wild-type TP53. (Part 2) V. Assess AMG 232 (KRT 232) exposure and correlations with pharmacodynamic (PD) effect on p21 elevation. (Part 2) VI. Assess PD effect on MIC-1 elevation in serum. (Part 2) OUTLINE: This is a phase 0, intratumoral pharmacokinetic (PK)/PD study of navtemadlin followed by a phase I dose-escalation study. PART I: Patients with recurrent glioblastoma receive navtemadlin (KRT-232) orally (PO) once daily (QD) for 2 days. Within 3-6 hours of the last dose, patients undergo standard-of-care surgery. Upon recovery (within 45 days), patients with TP53 wild-type tumors continue to receive navtemadlin (KRT-232) PO QD on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) at baseline as well as on study and/or end of treatment and collection of blood and tissue samples at baseline and on study. PART II: Within 6 weeks of standard-of-care surgery, patients with newly diagnosed glioblastoma undergo radiation therapy daily during weeks 1-6. Patients also receive navtemadlin (KRT-232) PO 1 time weekly (day 2), 2 times weekly (days 2, 4), 3 times weekly (days 2, 3, 5), 4 times weekly (days 2, 3, 4, 5), or 5 times weekly (days 1-5) for 6 weeks during radiation therapy. Patients also undergo MRI at baseline and end of treatment and collection of blood samples at baseline and on study. PART II (EXPANSION COHORT): Patients receive navtemadlin (KRT-232) PO QD on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at baseline, on study, and end of treatment. After completion of study treatment, patients are followed every 2 months for the first two years from the off-treatment date, and then every 6 months until 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
32
Undergo collection of blood and tissue samples
Undergo MRI
Given PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Pharmacokinetics (PK) parameters with target inter-tumor drug concentration at >= 25 nm (Part 1)
Part 2 of the trial will proceed only if at least one of the doses yielded a 50% PK response rate. If both doses reached 50% PK response rate, both doses will be studied in Part 2 of the trial.
Time frame: Up to 5 years
Maximum tolerated dose (MTD) of MDM2 inhibitor AMG 232 (KRT-232) when combined with concomitant radiation therapy (Part 2)
MTD will be determined according to dose-limiting toxicities graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Beginning April 1, 2018 version 5.0 will be utilized for adverse event reporting). The target dose-limiting toxicity (DLT) rate is 33%. If the MTD is not reached among the pre-specified doses, the dose for the expanded cohort will be the highest dose studied for which the DLT rate is less than 33%.
Time frame: Up to 16 weeks
Incidence of adverse events (Part 1)
Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Beginning April 1, 2018 version 5.0 will be utilized for adverse event reporting). Will be used for scoring toxicity and adverse events. The severity and frequency of toxicity will be tabulated by the tested dose or doses, or combination regimens using descriptive statistics. The proportion of patients who experienced grade 3 or above toxicities will be estimated along with 95% confidence intervals by each type of toxicity.
Time frame: Up to 30 days following the last dose of study drug
Variability of MDM2 inhibitor AMG 232 (KRT-232) concentration in tumor enhancing versus infiltrative tissue (Part 1)
Will be summarized using descriptive statistics.
Time frame: Up to 5 years
p21 elevation in tissue (Part 1)
Will be coded as binary outcome either elevated or not elevated compared to a reference value from archived tumor tissues in matched patient population. A proportion of patients with elevated p21 will be estimated using a binomial distribution along with 95% confidence interval.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Undergo radiation therapy
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Henry Ford Hospital
Detroit, Michigan, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
...and 1 more locations
Time frame: Up to 5 years
Incidence of adverse events (Part 2)
Assessed by CTCAE version 4.0 (Beginning April 1, 2018 version 5.0 will be utilized for adverse event reporting). Will be used for scoring toxicity and adverse events. The severity and frequency of toxicity will be tabulated by the tested dose or doses, or combination regimens using descriptive statistics. The proportion of patients who experienced grade 3 or above toxicities will be estimated along with 95% confidence intervals by each type of toxicity.
Time frame: Up to 10 weeks
MIC-1 elevation in serum (Part 2)
The PK variables and changes in MIC-1 will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters and MIC-1 changes will be compared across dose level using non-parametric statistical testing techniques.
Time frame: Up to 5 years
MDM2 inhibitor AMG 232 (KRT-232) exposure (Part 2)
Assessed by liquid chromatography/tandem mass spectrometry. A full pharmacokinetic profile of AMG 232 (KRT 232) will be proposed in this study to assess exposure-response relationships with various pharmacodynamic (PD) endpoints (i.e., MIC-1 changes, toxicity, and efficacy). Correlation with PD effect on p21 elevation will be determined.
Time frame: Up to 5 years