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)
- Conditions
- Relapsed or Refractory Acute Myeloid Leukemia (AML)Acute Myeloid Leukemia (AML), Secondary to Myeloproliferative Neoplasms (MPN)
- Interventions
- Registration Number
- NCT04113616
- Lead Sponsor
- Kartos Therapeutics, Inc.
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 70
- 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
Key
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A - Arm 2 KRT-232 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. Part A - Arm 3 KRT-232 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. Part B - Arm 2 KRT-232 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. Part B - Arm 1 KRT-232 KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle Part A - Arm 1 KRT-232 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. Part B - Arm 3 KRT-232 KRT-232 administered at 180 mg orally, once daily (QD) on Days 1-7 with 14 days off on a 21-day treatment cycle. Part A - Arm 2 Decitabine 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. Part A - Arm 1 Cytarabine 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. Part A - Arm 3 Decitabine 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.
- Primary Outcome Measures
Name Time Method Part A: To determine KRT-232 recommended phase 2 dose (RP2D) 28 Days Number of dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine or decitabine
Part B: To determine the RP2D of KRT-232 2 years after last patient enrolled The safety review committee (SRC) will determine the RP2D based on safety and tolerability data obtained from each arm
- Secondary Outcome Measures
Name Time Method Part A: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) 12 weeks Proportion of patients achieving complete remission (CR) or complete remission with partial hematological improvement (CRh) as determined by Modified 2017 European LeukemiaNet (ELN) response criteria
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 Proportion of patients achieving complete remission (CR), complete remission with partial hematological improvement (CRh), and CR with incomplete hematologic recovery (CRi) as determined by Modified 2017 European LeukemiaNet (ELN) response criteria
Trial Locations
- Locations (58)
University Hospital Jena
🇩🇪Jena, Germany
Cliniques universitaires Saint-Luc
🇧🇪Brussels, Belgium
UZ Gent
🇧🇪Ghent, Belgium
Hôpital Saint-Louis
🇫🇷Paris, France
Institut Jules Bordet
🇧🇪Anderlecht, Belgium
AOUS Le Scotte
🇮🇹Siena, Italy
University of Chicago
🇺🇸Chicago, Illinois, United States
St. George Hospital
🇦🇺Kogarah, Australia
Universitaetsklinikum Schleswig-Holstein
🇩🇪Lübeck, Germany
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdańsk, Poland
Universitätsklinikum Leipzig
🇩🇪Leipzig, Germany
Hadassah Medical Center Ein Kerem
🇮🇱Jerusalem, Israel
Calvary Mater Newcastle Hospital
🇦🇺Waratah, Australia
Mount Sinai
🇺🇸New York, New York, United States
Weill Cornell
🇺🇸New York, New York, United States
Royal Perth Hospital
🇦🇺Perth, Australia
Centre Hospitalier Universitaire (CHU) de Bordeaux
🇫🇷Bordeaux, France
Institut Paoli Calmettes
🇫🇷Marseille, France
Universitätsklinikum Halle
🇩🇪Halle, Germany
Centre Hospitalier (CH) Jolimont
🇧🇪Haine-Saint-Paul, Belgium
Oxford University Hospitals NHS Trust, Churchill Hospital
🇬🇧Oxford, United Kingdom
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Perth Blood Institute
🇦🇺West Perth, Australia
Del-Pesti Centrumkorhaz Orszagos Hematologiai es Infektologi
🇭🇺Budapest, Hungary
The Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Universitaria Maggiore della Carità Novara
🇮🇹Novara, Piemonte, Italy
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario de Gran Canaria Doctor Negrin
🇪🇸Las Palmas, Spain
Somogy Megyei KAposi Mor Oktato Korhaz
🇭🇺Kaposvár, Hungary
Rambam Health Care Campus
🇮🇱Haifa, Israel
szabolcs-szatmár-bereg megyei kórházak és egyetemi oktatókórház Jósa András Oktatókórház
🇭🇺Debrecen, Hungary
Monash Health
🇦🇺Clayton, Australia
Tel-Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Assaf Harofeh Medical Center AHMC
🇮🇱Tel Aviv, Israel
Hospital Universitario Virgen de la Victoria de Málaga
🇪🇸Málaga, Spain
A.O.O.R. Villa Sofia Cervello
🇮🇹Palermo, Sicilia, Italy
AORMN Hospital Hematology and BMT Center
🇮🇹Pesaro, Italy
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
University Hospital of Wales
🇬🇧Cardiff, United Kingdom
The Royal Marsden Hospital
🇬🇧London, United Kingdom
MD Anderson Cancer Center
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Semmelweis Egyetem
🇭🇺Budapest, Hungary
University of Maryland Medical Center
🇺🇸Baltimore, Maryland, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Centre Hospitalier Universitaire (CHU) de Nice
🇫🇷Nice, France
AOU Policlinico S.Orsola-Malpighi
🇮🇹Bologna, Italy
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Inje University Busan Paik Hospital
🇰🇷Busan, Korea, Republic of
The Catholic University of Korea-Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
The Ohio State University
🇺🇸Columbus, Ohio, United States
AZ Turnhout
🇧🇪Turnhout, Belgium
Oregon Health and Science University
🇺🇸Portland, Oregon, United States