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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)

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ClinicalTrials.gov Identifier: NCT04113616
Recruitment Status : Recruiting
First Posted : October 3, 2019
Last Update Posted : September 1, 2021
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia (AML), Secondary to Myeloproliferative Neoplasms (MPN) Drug: KRT-232 Drug: Cytarabine Drug: Decitabine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : September 25, 2019
Estimated Primary Completion Date : December 15, 2023
Estimated Study Completion Date : July 15, 2024


Arm Intervention/treatment
Experimental: Part A - Arm 1

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

Drug: Cytarabine
Cytarabine is an anti-cancer chemotherapy drug taken via injection.
Other Names:
  • cytosine arabinoside
  • Cytosar-U
  • Depocyt
  • Arabinosylcytosine
  • Ara-C

Experimental: Part A - Arm 2

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

Drug: Decitabine
Decitabine is an anti-cancer chemotherapy drug taken via injection.
Other Name: Dacogen

Experimental: Part A - Arm 3

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

Drug: Decitabine
Decitabine is an anti-cancer chemotherapy drug taken via injection.
Other Name: Dacogen

Experimental: Part B - Arm 1
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
KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.

Experimental: Part B - Arm 2
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
KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.

Experimental: Part B - Arm 3
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
KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.




Primary Outcome Measures :
  1. Part A: To determine KRT-232 recommended phase 2 dose (RP2D) [ Time Frame: 28 Days ]
    Number of dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine or decitabine

  2. Part B: To determine the RP2D of KRT-232 [ Time Frame: 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 :
  1. Part A: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) [ Time Frame: 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

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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • 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 Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04113616


Contacts
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Contact: John Mei 650-542-0136 jmei@kartosthera.com
Contact: Timothy Sbardellati tsbardellati@kartosthera.com

Locations
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Sponsors and Collaborators
Kartos Therapeutics, Inc.
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Responsible Party: Kartos Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04113616    
Other Study ID Numbers: KRT-232-104
First Posted: October 3, 2019    Key Record Dates
Last Update Posted: September 1, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kartos Therapeutics, Inc.:
navtemadlin
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Cytarabine
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors