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Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RP7214 in Combination With Azacitidine in Patients With Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

Primary Purpose

Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
RP7214
Sponsored by
Rhizen Pharmaceuticals SA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring RP7214, Dihydro-orotate Dehydrogenase (DHODH)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patient must sign informed consent.
  2. Patient should be ≥ 18 years of age.
  3. Patients who are candidates for treatment with azacitidine and present with one of the following:

    a. Part I: Dose Escalation study i. Patient with histologically or cytologically confirmed relapsed/refractory AML as per World Health Organization (WHO) classification, 2016 'OR' ii. Newly diagnosed AML patients who are ineligible for intensive induction chemotherapy due to co-morbidity or other factors 'OR' iii. Intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS) 'OR' iv. Chronic Myelomonocytic Leukemia (CMML) b. Part II: Dose Expansion study i. Newly diagnosed AML patients who are ineligible for intensive induction chemotherapy due to co-morbidity or other factors.

  4. Patient should have an Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2.
  5. Patients must be amenable to serial bone marrow biopsies/aspirates and peripheral blood sampling as required by the protocol.

Exclusion Criteria:

  1. Any cancer-directed therapy taken (e.g., chemotherapy, immunotherapy, biologic therapy or an investigational drug) within 14 days or 5 half-lives, whichever is shorter, prior to C1D1. For radiation therapy, at least 60 days should elapse from prior Total Body Irradiation (TBI) and at least 14 days from local palliative radiation therapy.
  2. Patients with rapidly increasing peripheral blast counts (WBC count > 25,000/μL) while on hydroxyurea prior to C1D1.
  3. Patients with Acute Promyelocytic Leukemia (French American-British Class M3 AML).
  4. Patients on immunosuppressive therapy post autologous or allogeneic stem cell transplantation (ASCT or Allo-SCT) at the time of screening, or with clinically significant Graft-Versus-Host Disease (GVHD) in the opinion of the Investigator or has not recovered from transplant-associated toxicities prior to C1D1.
  5. Patient who discontinued prior therapy with DHODH inhibitors or azacitidine due to drug-related toxicity.
  6. Evidence of uncontrolled/progressing infection.
  7. Patients with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or Disseminated Intravascular Coagulation (DIC).
  8. Presence of isolated extramedullary relapse.
  9. Pregnant or lactating women

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    Part I (dose escalation) RP7214 + Azacitidine

    Part II (dose expansion) RP7214 + Azacitidine

    Arm Description

    Participants will receive RP7214 orally in combination with Azacitidine in a 28-day cycle. The dose levels will be escalated until MTD/a recommended Phase 2 dose (RP2D) has been identified.

    Participants will receive RP7214 orally at the MTD/RP2D in combination with Azacitidine in a 28-day cycle.

    Outcomes

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of RP7214 in combination with azacitidine
    The maximum tolerated dose will be defined as the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels.

    Secondary Outcome Measures

    Tmax
    Pharmacokinetics: Time to Reach Maximum Concentration (Tmax) of RP7214
    Objective Response Rate (ORR)
    Defined as the percentage of patients who achieve Complete Remission (CR), Complete Remission with incomplete bone marrow recovery (CRi) and Partial Remission (PR)
    Clinical Benefit Rate (CBR)
    Defined as the percentage of patients achieving a CR, CRi, PR and Stable Disease (SD) lasting for at least 8 weeks.
    Duration of Remission
    Defined as the number of days from the date of first remission (CR, CRi, or PR) to the recurrence or Progressive Disease (PD)
    Percentage of patients requiring blood and/or platelet transfusions
    Defined as number of patients requiring blood and/or platelet transfusions
    Cmax
    Pharmacokinetics: Maximum Concentration (Cmax) of RP7214
    AUC
    Pharmacokinetics: Area Under the Concentration Curve (AUC) of RP7214

    Full Information

    First Posted
    January 29, 2022
    Last Updated
    October 27, 2022
    Sponsor
    Rhizen Pharmaceuticals SA
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05246384
    Brief Title
    Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RP7214 in Combination With Azacitidine in Patients With Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia
    Official Title
    A Phase I/Ib, Open-label Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RP7214, a Dihydro-orotate Dehydrogenase (DHODH) Inhibitor, Administered Orally in Combination With Azacitidine in Patients With Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2022
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Change in development plan
    Study Start Date
    January 2023 (Anticipated)
    Primary Completion Date
    December 2024 (Anticipated)
    Study Completion Date
    November 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Rhizen Pharmaceuticals SA

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    This is a multi-center, open-label, non-randomized, two-part Phase I/Ib study of RP7214 in combination with azacitidine in patients with AML, MDS and CMML. Part I is a 3+3 dose-escalation study to identify the MTD/RP2D of RP7214 and azacitidine combination in patients with AML, MDS, and CMML. Part II is a dose-expansion study to evaluate the clinical activity and safety of RP7214 and azacitidine combination in AML.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia
    Keywords
    RP7214, Dihydro-orotate Dehydrogenase (DHODH)

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Sequential Assignment
    Model Description
    open-label, non-randomized, two-part Phase I/Ib study
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Part I (dose escalation) RP7214 + Azacitidine
    Arm Type
    Experimental
    Arm Description
    Participants will receive RP7214 orally in combination with Azacitidine in a 28-day cycle. The dose levels will be escalated until MTD/a recommended Phase 2 dose (RP2D) has been identified.
    Arm Title
    Part II (dose expansion) RP7214 + Azacitidine
    Arm Type
    Experimental
    Arm Description
    Participants will receive RP7214 orally at the MTD/RP2D in combination with Azacitidine in a 28-day cycle.
    Intervention Type
    Drug
    Intervention Name(s)
    RP7214
    Intervention Description
    RP7214 will be administered daily twice a day orally; Azacitidine will be administered from Days 1 to 7 of each 28-day cycle
    Primary Outcome Measure Information:
    Title
    Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of RP7214 in combination with azacitidine
    Description
    The maximum tolerated dose will be defined as the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels.
    Time Frame
    28 days
    Secondary Outcome Measure Information:
    Title
    Tmax
    Description
    Pharmacokinetics: Time to Reach Maximum Concentration (Tmax) of RP7214
    Time Frame
    35 days
    Title
    Objective Response Rate (ORR)
    Description
    Defined as the percentage of patients who achieve Complete Remission (CR), Complete Remission with incomplete bone marrow recovery (CRi) and Partial Remission (PR)
    Time Frame
    2 years
    Title
    Clinical Benefit Rate (CBR)
    Description
    Defined as the percentage of patients achieving a CR, CRi, PR and Stable Disease (SD) lasting for at least 8 weeks.
    Time Frame
    2 years
    Title
    Duration of Remission
    Description
    Defined as the number of days from the date of first remission (CR, CRi, or PR) to the recurrence or Progressive Disease (PD)
    Time Frame
    2 years
    Title
    Percentage of patients requiring blood and/or platelet transfusions
    Description
    Defined as number of patients requiring blood and/or platelet transfusions
    Time Frame
    2 years
    Title
    Cmax
    Description
    Pharmacokinetics: Maximum Concentration (Cmax) of RP7214
    Time Frame
    35 days
    Title
    AUC
    Description
    Pharmacokinetics: Area Under the Concentration Curve (AUC) of RP7214
    Time Frame
    35 days

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patient must sign informed consent. Patient should be ≥ 18 years of age. Patients who are candidates for treatment with azacitidine and present with one of the following: a. Part I: Dose Escalation study i. Patient with histologically or cytologically confirmed relapsed/refractory AML as per World Health Organization (WHO) classification, 2016 'OR' ii. Newly diagnosed AML patients who are ineligible for intensive induction chemotherapy due to co-morbidity or other factors 'OR' iii. Intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS) 'OR' iv. Chronic Myelomonocytic Leukemia (CMML) b. Part II: Dose Expansion study i. Newly diagnosed AML patients who are ineligible for intensive induction chemotherapy due to co-morbidity or other factors. Patient should have an Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2. Patients must be amenable to serial bone marrow biopsies/aspirates and peripheral blood sampling as required by the protocol. Exclusion Criteria: Any cancer-directed therapy taken (e.g., chemotherapy, immunotherapy, biologic therapy or an investigational drug) within 14 days or 5 half-lives, whichever is shorter, prior to C1D1. For radiation therapy, at least 60 days should elapse from prior Total Body Irradiation (TBI) and at least 14 days from local palliative radiation therapy. Patients with rapidly increasing peripheral blast counts (WBC count > 25,000/μL) while on hydroxyurea prior to C1D1. Patients with Acute Promyelocytic Leukemia (French American-British Class M3 AML). Patients on immunosuppressive therapy post autologous or allogeneic stem cell transplantation (ASCT or Allo-SCT) at the time of screening, or with clinically significant Graft-Versus-Host Disease (GVHD) in the opinion of the Investigator or has not recovered from transplant-associated toxicities prior to C1D1. Patient who discontinued prior therapy with DHODH inhibitors or azacitidine due to drug-related toxicity. Evidence of uncontrolled/progressing infection. Patients with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or Disseminated Intravascular Coagulation (DIC). Presence of isolated extramedullary relapse. Pregnant or lactating women

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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