An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML)

NCT04113616 | Terminated Phase 1 FDA Drug

• 1 other identifier: KRT-232-104
• Study Type: interventional
• Target: 70
• Locations: 12 countries
• Sites: 59

Brief Summary

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, when administered alone and in combination with low-dose cytarabine (LDAC) or Decitabine for the treatment of adults with Acute Myeloid Leukemia (AML) and AML secondary to myeloproliferative neoplasms (MPN). Participants must be relapsed/refractory (having failed prior therapy) and will be assigned to receive monotherapy (KRT-232 alone) or combination therapy (KRT-232 with LDAC or KRT-232 with Decitabine).

Conditions

Relapsed or Refractory Acute Myeloid Leukemia (AML); Acute Myeloid Leukemia (AML), Secondary to Myeloproliferative Neoplasms (MPN)

Keywords

navtemadlin

Outcome Measures

Primary Outcomes (2)

• Part A: To determine KRT-232 recommended phase 2 dose (RP2D)

  Number of dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine or decitabine

  28 Days

• Part B: To determine the RP2D of KRT-232

  The safety review committee (SRC) will determine the RP2D based on safety and tolerability data obtained from each arm

  2 years after last patient enrolled

Secondary Outcomes (2)

• Part A: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh)

  12 weeks

• Part B: To determine the rates of complete remission (CR), CR with partial hematological improvement (CRh) and CR with incomplete hematologic recovery (CRi)

  12 weeks

Study Arms (6)

Part A - Arm 1

EXPERIMENTAL

KRT-232+LDAC: KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with LDAC administered at 20 mg/m2/day subcutaneously on Days 1-10 in a 28-day cycle.

Drug: KRT-232; Drug: Cytarabine

Part A - Arm 2

EXPERIMENTAL

KRT-232(7-Day)+Decitabine: KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.

Drug: KRT-232; Drug: Decitabine

Part A - Arm 3

EXPERIMENTAL

KRT-232(14-Day)+Decitabine: KRT-232 will be administered orally, once daily (QD), on Days 1-7 and Days 15-21 (7 days on/7 days off/7 days on/7 days off) in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.

Drug: KRT-232; Drug: Decitabine

Part B - Arm 1

EXPERIMENTAL

KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle

Drug: KRT-232

Part B - Arm 2

EXPERIMENTAL

KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle in Cycle 1, followed by 240 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day cycle, in the subsequent cycles.

Drug: KRT-232

Part B - Arm 3

EXPERIMENTAL

KRT-232 administered at 180 mg orally, once daily (QD) on Days 1-7 with 14 days off on a 21-day treatment cycle.

Drug: KRT-232

Interventions

KRT-232 DRUG

KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.

Part A - Arm 1; Part A - Arm 2; Part A - Arm 3; Part B - Arm 1; Part B - Arm 2; Part B - Arm 3

Cytarabine DRUG

Cytarabine is an anti-cancer chemotherapy drug taken via injection.

Also known as: cytosine arabinoside, Cytosar-U, Depocyt, Arabinosylcytosine, Ara-C

Part A - Arm 1

Decitabine DRUG

Decitabine is an anti-cancer chemotherapy drug taken via injection.

Also known as: Dacogen

Part A - Arm 2; Part A - Arm 3

Eligibility Criteria

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

You may qualify if:

• Part A: Patients with relapsed or refractory AML, or newly-diagnosed AML secondary to MPN
• Part B:Patients with relapsed or refractory AML secondary to MPN (myelofibrosis \[MF\], polycythemia vera \[PV\], or essential thrombocythemia \[ET\]); patients may have been treated with ≥1 prior lines of therapy for their AML secondary to MPN.
• Adequate hepatic and renal function
• Appropriate prior treatment with an FLT3 or IDH1/2 inhibitor where applicable

You may not qualify if:

• Patients who are TP53 mutation positive
• Prior treatment with an MDM2 antagonist therapy
• Patients treated with ≥ 18 g/m2 of cytarabine within the prior 90 days are not eligible to be treated with cytarabine on this study but may be treated with decitabine (for Part A) .
• Patients previously treated with decitabine are not eligible to receive decitabine on this study but may be treated with cytarabine (for Part A) .
• Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy (for Part A)
• Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment (for Part B)
• Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
• Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
• Patients with known CNS involvement with AML, acute promyelocytic leukemia (APL), or a history of bleeding diathesis
• Patients who have had major surgery within 28 days prior to the first treatment with KRT-232
• Women who are pregnant or breastfeeding

Sponsors & Collaborators

• Kartos Therapeutics, Inc.: lead

Study Sites (59)

University of Chicago

Chicago, Illinois, 60637, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Mount Sinai

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Weill Cornell

New York, New York, 10065, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Monash Health

Clayton, Australia

Location

St. George Hospital

Kogarah, Australia

Location

Royal Perth Hospital

Perth, 6000, Australia

Location

Calvary Mater Newcastle Hospital

Waratah, 2298, Australia

Location

Perth Blood Institute

West Perth, 6005, Australia

Location

Institut Jules Bordet

Anderlecht, 1070, Belgium

Location

Cliniques universitaires Saint-Luc

Brussels, Belgium

Location

UZ Gent

Ghent, Belgium

Location

Centre Hospitalier (CH) Jolimont

Haine-Saint-Paul, 7100, Belgium

Location

AZ Turnhout

Turnhout, Belgium

Location

Centre Hospitalier Universitaire (CHU) de Bordeaux

Bordeaux, 33000, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

Centre Hospitalier Universitaire (CHU) de Nice

Nice, 06000, France

Location

Hôpital Saint-Louis

Paris, France

Location

Universitätsklinikum Halle

Halle, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, Germany

Location

University Hospital Jena

Jena, 07747, Germany

Location

Universitätsklinikum Leipzig

Leipzig, Germany

Location

Universitaetsklinikum Schleswig-Holstein

Lübeck, Germany

Location

Semmelweis Egyetem

Budapest, 1085, Hungary

Location

Del-Pesti Centrumkorhaz Orszagos Hematologiai es Infektologi

Budapest, Hungary

Location

szabolcs-szatmár-bereg megyei kórházak és egyetemi oktatókórház Jósa András Oktatókórház

Debrecen, Hungary

Location

Somogy Megyei KAposi Mor Oktato Korhaz

Kaposvár, 7400, Hungary

Location

Rambam Health Care Campus

Haifa, 3109601, Israel

Location

Hadassah Medical Center Ein Kerem

Jerusalem, Israel

Location

The Chaim Sheba Medical Center

Ramat Gan, 5265601, Israel

Location

Tel-Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Assaf Harofeh Medical Center AHMC

Tel Aviv, Israel

Location

Universitaria Maggiore della Carità Novara

Novara, Piedmont, 28100, Italy

Location

A.O.O.R. Villa Sofia Cervello

Palermo, Sicily, 90146, Italy

Location

AOU Policlinico S.Orsola-Malpighi

Bologna, Italy

Location

AORMN Hospital Hematology and BMT Center

Pesaro, Italy

Location

AOUS Le Scotte

Siena, 53100, Italy

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland

Location

Inje University Busan Paik Hospital

Busan, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

The Catholic University of Korea-Seoul St. Mary's Hospital

Seoul, South Korea

Location

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario de Gran Canaria Doctor Negrin

Las Palmas, 35010, Spain

Location

MD Anderson Cancer Center

Madrid, 28033, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Virgen de la Victoria de Málaga

Málaga, 29010, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Birmingham Heartlands Hospital

Birmingham, United Kingdom

Location

University Hospital of Wales

Cardiff, United Kingdom

Location

The Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Oxford University Hospitals NHS Trust, Churchill Hospital

Oxford, United Kingdom

Location

MeSH Terms

Conditions

Recurrence; Leukemia, Myeloid, Acute

Interventions

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; Cytarabine; Decitabine

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Azacitidine; Aza Compounds; Organic Chemicals; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2019
• First Posted: October 3, 2019
• Study Start: September 25, 2019
• Primary Completion: September 27, 2023
• Study Completion: September 27, 2023
• Last Updated: March 22, 2024

Record last verified: 2024-03

Locations

DE (5); KR (4); GB (4); IL (5); FR (4); HU (4); US (8); BE (5); ES (9); PL (1); AU (5); IT (5)