Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma

NCT03031730 | Terminated Phase 1 Results FDA Drug

• 4 other identifiers: NCI-2017-00099NCI1007610076UM1CA186688
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 7

Brief Summary

This phase I trial studies the side effects and best dose of MDM2 Inhibitor KRT-232 when given together with carfilzomib, lenalidomide, and dexamethasone in treating patient with multiple myeloma that has come back (relapsed) or has not responded to previous treatment (refractory). KRT-232 (AMG 232) may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Lenalidomide help shrink or slow the growth of multiple myeloma. Drugs used in chemotherapy, such as carfilzomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving MDM2 Inhibitor KRT-232, lenalidomide, carfilzomib, and dexamethasone together may work better in treating patients with multiple myeloma.

Conditions

Plasmacytoma; Recurrent Multiple Myeloma; Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (2)

• Evaluate Safety and Tolerability of KRT-232 (AMG 232) in Combination With Carfilzomib, Lenalidomdie, and Dexamethasone (KRd)

  at least 6 months of treatment, an average of 1 year

• Determine Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of KRT-232 (AMG 232) in Combination With Carfilzomib, Lenalidomdie, and Dexamethasone (KRd)

  at least 6 months of treatment, an average of 1 year

Secondary Outcomes (2)

• Evaluate PD Effects of KRT-232 (AMG 232) Through Serum MIC-1 Levels.

  30 days after last dose

• Assess KRT-232 (AMG 232) Exposure-response Relationships (PD, Toxicity, and Efficacy).

  30 days after last dose

Study Arms (1)

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

EXPERIMENTAL

Patients receive MDM2 Inhibitor KRT-232 PO QD on days 1-7, carfilzomib IV over 10-30 minutes on days 1-2, 8-9, and 15-16 of cycles 1-12 and on days 1-2 and 15-16 of cycles 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or dexamethasone sodium phosphate IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients undergo echocardiography during screening and bone marrow biopsy and aspiration, and blood sample collection throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration and Biopsy; Drug: Carfilzomib; Drug: Dexamethasone; Drug: Dexamethasone Sodium Phosphate; Procedure: Echocardiography; Drug: Lenalidomide; Drug: Navtemadlin

Interventions

Dexamethasone Sodium Phosphate DRUG

Given IV

Also known as: Cebedex, Corson, Dalalone, Decaject, Dekasol LA, Dexacen, Dexamethasone Sodium Phosphates, Dexasone, Dezone, ReadySharp Dexamethasone, Soludecadron, Solurex, Topidex

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Echocardiography PROCEDURE

Undergo echocardiography

Also known as: EC

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Lenalidomide DRUG

Given PO

Also known as: CC 5013, CC-5013, CC5013, CDC 501, Revlimid

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

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 (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

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

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Bone Marrow Aspiration and Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Carfilzomib DRUG

Given IV

Also known as: Carfilnat, CFZ, Kyprolis, PR 171, PR-171, PR171

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Dexamethasone DRUG

Given PO

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, LenaDex, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex

Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Eligibility Criteria

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

You may qualify if:

• Subjects must have histologically confirmed diagnosis of multiple myeloma
• Subjects must have measurable disease, as defined by at least one of the following:
• Serum monoclonal protein M-protein level \>= 0.5 g/dL
• Urinary M-protein excretion of \>= 200 mg over a 24-hour period
• Involved free light chain level \>= 10 mg/dL, along with an abnormal free light chain ratio
• Subjects must have disease that has relapsed and/or refractory after their most recent therapy, with progressive disease (PD) being defined as an increase of 25% from the lowest response value in any one or more of the following:
• Serum M-component protein (the absolute increase must be \>= 0.5 g/dL) and/or
• Urine M-component protein (the absolute increase must be \>= 200 mg/24 hours) and/or
• Only in subjects without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be \> 10 mg/dL
• Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
• Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder
• Subjects with one to three lines of therapy for their disease with a line of therapy defined as one or more cycles of a planned treatment program; using this definition, treatment with induction therapy, followed by high dose chemotherapy and autologous stem cell transplantation, and finally by maintenance therapy, would constitute one line, provided that multiple myeloma did not meet criteria for progression at any time during this period
• Subjects must have completed their most recent drug therapy directed at multiple myeloma in the following timeframes:
• Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy, or investigational agent) at least 21 days prior to cycle 1 day 1 (C1D1) KRT-232 (AMG 232) + KRd
• Corticosteroids at least 3 weeks prior to starting KRT-232 (AMG 232) + KRd, except for a dose equivalent to dexamethasone of =\< 4 mg/day

You may not qualify if:

• Subjects with myeloma that is relapsed and/or refractory to KRd when used in combination defined as progression of disease while on therapy or within 60 days of completing therapy
• Subjects must show evidence of wild-type (WT) p53 status on somatic tissue specimens as assessed by deoxyribonucleic acid (DNA) sequencing; note that since patients with relapsed myeloma have a rapidly proliferating disease, patient can be enrolled and begin treatment prior to obtaining the results of this test; patients who are discovered to have a TP53 mutation will be removed from study after cycle one and can continue on carfilzomib, lenalidomide, and dexamethasone (KRd); all enrolled patients will be followed for toxicity
• Subjects who are receiving any other investigational agents
• Subjects who have undergone major surgery within 28 days of study day 1; vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week prior to starting KRT-232 (AMG 232) + KRd
• Subjects with known central nervous system involvement of myeloma should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Subjects with history of allergic reactions attributed to compounds of similar chemical or biologic composition to KRT-232 (AMG 232) or carfilzomib, lenalidomide, or dexamethasone
• Subjects' medication list such as herbal medicines (e.g., St. John's wort), vitamins, and supplements will be reviewed before starting first dose of KRT-232 (AMG 232) and at each clinic visit; any potential drug interactions will be brought and discussed with the principal investigator; use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide) within the 14 days prior to receiving the first dose of KRT-232 (AMG 232) is not permitted; other medications (such as fentanyl and oxycodone) may be allowed per investigator's assessment/evaluation
• Treatment with medications known to cause 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
• 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
• Subjects 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
• Subjects 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)
• Subjects with history of bleeding diathesis
• Subjects with active infection requiring IV antibiotics within 2 weeks of study enrollment (day 1) are excluded
• Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus RNA by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody \[HepCAb\], followed by hepatitis C virus RNA by PCR if HepCAb is positive); subjects with hepatitis B virus suppressed on therapy, and previously treated/eradicated hepatitis C virus are eligible for study
• Human immunodeficiency virus (HIV)-positive subjects positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive subjects must have:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (7)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

NYP/Weill Cornell Medical Center

New York, New York, 10065, United States

Location

University of Texas at Austin

Austin, Texas, 78712, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Plasmacytoma; Multiple Myeloma

Interventions

Specimen Handling; Biopsy; carfilzomib; Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; Lenalidomide; 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

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Hans C Lee
• Organization: MD Anderson Cancer Center

askmdanderson@mdanderson.org

877-632-6789

Study Officials

• Hans C Lee

  University of Texas MD Anderson Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: January 25, 2017
• First Posted: January 26, 2017
• Study Start: June 14, 2018
• Primary Completion: July 24, 2024
• Study Completion: July 24, 2024
• Last Updated: February 10, 2026
• Results First Posted: February 10, 2026

Record last verified: 2026-01

Locations

US (7)