Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
RP7214, Dihydro-orotate Dehydrogenase (DHODH)
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.
Interventions
DRUGRP7214
RP7214 will be administered daily twice a day orally; Azacitidine will be administered from Days 1 to 7 of each 28-day cycle
Sponsors
Rhizen Pharmaceuticals SA
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label, non-randomized, two-part Phase I/Ib study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of RP7214 in combination with azacitidine | 28 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 2 years | 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) | 2 years | Defined as the percentage of patients achieving a CR, CRi, PR and Stable Disease (SD) lasting for at least 8 weeks. |
| Duration of Remission | 2 years | Defined as the number of days from the date of first remission (CR, CRi, or PR) to the recurrence or Progressive Disease (PD) |
| Tmax | 35 days | Pharmacokinetics: Time to Reach Maximum Concentration (Tmax) of RP7214 |
| Cmax | 35 days | Pharmacokinetics: Maximum Concentration (Cmax) of RP7214 |
| AUC | 35 days | Pharmacokinetics: Area Under the Concentration Curve (AUC) of RP7214 |
| Percentage of patients requiring blood and/or platelet transfusions | 2 years | Defined as number of patients requiring blood and/or platelet transfusions |
Outcome results
None listed