Last updated on May 2020

Testing the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer


Brief description of study

This phase I trial studies the side effects and best dose of MDM2 inhibitor KRT-232 in treating patients with glioblastoma (brain cancer) that is newly diagnosed or has come back (recurrent). MDM2 inhibitor KRT-232 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Study Description

PRIMARY OBJECTIVES:

I. Determine the concentration and variability in concentration of MDM2 inhibitor KRT-232 (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 MDM2 inhibitor KRT-232 followed by a phase I dose-escalation study.

PART I: Patients with recurrent glioblastoma receive MDM2 inhibitor AMG 232 (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 MDM2 inhibitor AMG 232 (KRT-232) PO QD on days 1-7. Cycles repeat every 21 days in absence of disease progression or unacceptable toxicity.

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 MDM2 inhibitor AMG 232 (KRT-232) PO once weekly for 6 weeks or 3 times weekly on days 2, 3, and 5 for 6 weeks or 2 times weekly on days 2 and 4 for 6 weeks during radiation therapy.

PART II (EXPANSION COHORT): Patients receive MDM2 inhibitor AMG 232 (KRT-232) PO QD on days 1-7. Cycles repeat every 21 days in absence of disease progression or unacceptable toxicity.

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 death.

Clinical Study Identifier: NCT03107780

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