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

NCT03107780 | Terminated Phase 1 FDA Drug

• 5 other identifiers: NCI-2017-00568ALLIANCE-ABTC-1604ABTC-1604U10CA180821UM1CA137443
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Glioblastoma; Gliosarcoma; MGMT-Unmethylated Glioblastoma; Recurrent Glioblastoma

Outcome Measures

Primary Outcomes (2)

• 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.

  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%.

  Up to 16 weeks

Secondary Outcomes (6)

• Incidence of adverse events (Part 1)

  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)

  Up to 5 years

• p21 elevation in tissue (Part 1)

  Up to 5 years

• Incidence of adverse events (Part 2)

  Up to 10 weeks

• MIC-1 elevation in serum (Part 2)

  Up to 5 years

Study Arms (1)

Treatment (MDM2 inhibitor AMG 232 [KRT-232])

EXPERIMENTAL

See Detailed Description

Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Drug: Navtemadlin; Radiation: Radiation Therapy

Interventions

Biospecimen Collection PROCEDURE

Undergo collection of blood and tissue samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (MDM2 inhibitor AMG 232 [KRT-232])

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (MDM2 inhibitor AMG 232 [KRT-232])

Navtemadlin DRUG

Given PO

Also known as: (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-2-methyl-1-(((1-methylethyl)sulfonyl)methyl)propyl)-2-oxo-3-piperidineacetic Acid, AMG 232, AMG-232, KRT 232, KRT-232, KRT232, MDM2 Inhibitor KRT-232

Treatment (MDM2 inhibitor AMG 232 [KRT-232])

Radiation Therapy RADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Treatment (MDM2 inhibitor AMG 232 [KRT-232])

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be 18 years of age or older
• Patients must have a Karnofsky performance status \>= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
• Absolute neutrophil count \>= 1,500/ul
• Platelets \>= 100,000/ul
• Hemoglobin \>= 10 g/dL (transfuse as necessary to raise levels, no transfusions within 7 days of start)
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN
• Alkaline phosphatase \< 2.0 x ULN
• Creatinine =\< institutional ULN
• Creatinine clearance \>= 60 ml/min/1.73 m\^2 for patients with creatinine levels above institutional normal
• Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =\< 1.5 x institutional ULN
• Patients must be able to provide written informed consent
• Patients must have MRI within 21 days before starting treatment; patients must be able to tolerate MRI with gadolinium
• Patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the baseline MRI
• Women of childbearing potential must have a negative serum pregnancy test prior to study entry; women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation through 5 weeks (women) after receiving the last dose of AMG 232 (KRT 232); 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 3 months after completion of AMG 232 (KRT 232) administration; adequate methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or intrauterine device (IUD) (women); bilateral tubal ligation (women)

You may not qualify if:

• Patients receiving any other investigational agents are ineligible
• Part 1 patients who have not recovered to \< Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible
• Patients with a history of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to AMG 232 (KRT 232) are ineligible; the AMG 232 (KRT 232) investigator brochure can be referenced for more information
• Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of AMG 232 (KRT 232)
• Patients may not use herbal or non-traditional medications while receiving AMG 232 (KRT 232) therapy; all herbal medicines (e.g., St. John's wort), and supplements consumed by the subject within the 30 days prior to receiving the first dose of AMG 232 (KRT 232) should be reviewed by the principal investigator
• Drugs known to be sensitive CYP3A4 substrates with narrow therapeutic windows (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfenadine) are not allowed; patients must be switched to alternative drugs at least 14 days prior to receiving the first dose of AMG 232 (KRT 232); those patients who cannot switch to alternative drugs will be excluded from the study; please note that the list of drugs above is not an exhaustive list; refer to reliable sources such as the FDA website (Drug development and drug interactions), or Micromedex when evaluating potential drug-interactions
• Treatment with medications known to cause corrected QT (QTc) interval prolongation within 7 days of study day 1 is not permitted unless approved by the sponsor; use of ondansetron is permitted for treatment of nausea and vomiting
• Patients with 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, are ineligible; patients with active infection requiring intravenous (IV) antibiotics within 2 weeks of study day 1 are excluded; patients with myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association \[NYHA\] class III and higher), unstable angina, or cardiac arrhythmia requiring medication are excluded
• Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis), are ineligible
• Patients with history of bleeding diathesis are ineligible
• Patients with positive hepatitis B surface antigen (HepBsAg), positive hepatitis total core antibody with negative HBsAG, or detectable hepatitis C virus ribonucleic acid (RNA) by a polymerase-chain reaction (PCR) assay are ineligible (screening is generally done by hepatitis C antibody \[HepCAb\], followed by hepatitis C virus RNA by PCR if HepCAb is positive)
• Pregnant women are excluded from this study as no studies evaluating the reproductive toxicity of AMG 232 (KRT 232) have been conducted to date; the teratogenic potential of AMG 232 (KRT 232) in laboratory animals, if any, is unknown; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AMG 232 (KRT 232), breastfeeding should be discontinued if the mother is treated with AMG 232 (KRT 232) through 1 week after receiving the last dose of study drug
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AMG 232 (KRT 232); in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Patients with a planned use of Novo-TTF (Optune) are ineligible

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (11)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233, United States

Location

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

UPMC-Shadyside Hospital

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; navtemadlin; 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; 2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Therapeutics; Physical Phenomena

Study Officials

• Eudocia Lee

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2017
• First Posted: April 11, 2017
• Study Start: July 9, 2018
• Primary Completion: August 15, 2025
• Study Completion: August 15, 2025
• Last Updated: November 13, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

US (11)