A Study of CFI-400945 With or Without Azacitidine in Patients With AML, MDS or CMML

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of an investigational drug called CFI-400945 alone and in combination with azacitidine.

Detailed Description
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This study will be evaluating the safety and tolerability of CFI-400945 in subjects with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia. The study is designed to build on encouraging data from another study and to obtain further safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) data of CFI-400945.

Official Title
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Phase 1b/2 Clinical Study of the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of CFI-400945 as a Single Agent or in Combination With Azacitidine in Patients With AML, MDS or CMML

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, AML, MDS, CMML

Intervention / Treatment
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* Drug: CFI-400945
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be >18 years of age For Parts 1A and 1B, the following malignancy types will be included: Relapsed or refractory AML. MDS, after prior hypomethylating agents. CMML, with progressive disease/lack of response after hypomethylating agents For Parts 1A and 1B, Patients may have relapsed or refractory disease. For Parts 2A and 2B, the following malignancy types will be included: Relapsed or Refractory AML. MDS patients should be limited to high risk disease MDS or CMML should be previously untreated and patients with AML may have relapsed or refractory disease; Have clinically acceptable laboratory screening results (i.e., clinical chemistry, hematology, and urinalysis) within certain limits per protocol. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: Patients who have received investigational therapy, radiotherapy, immunotherapy, monoclonal antibodies, or chemotherapy within 14 days or 5 half-lives (whichever is shorter) Allogeneic or autologous transplant for AML with infusion of stem cells within 90 days before Cycle 1 Day 1, or on active immunosuppressive therapy for graft-versus-host disease (GVHD) or GVHD prophylaxis within 2 weeks of Cycle 1 Day 1. Any Grade ≥ 2 persistent non-hematological toxicity related to allogeneic transplant, such as those requiring systemic immunosuppressive therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation and expansion for monotherapy and combination arms with azacitidine
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1A: Monotherapy escalation and expansion<br>Dose escalation and expansion arm with CFI-400945 | Drug: CFI-400945<br>* The starting dose is 32 mg/day for escalation arms and the recommended starting dose for the expansion arms.<br>* Other names: 400945;|
| Experimental: 2A: Combination escalation and expansion<br>Dose escalation and expansion arm with CFI-400945 and azacitidine | Drug: CFI-400945<br>* The starting dose is 32 mg/day for escalation arms and the recommended starting dose for the expansion arms.<br>* Other names: 400945;Drug: Azacitidine<br>* Azacitidine will be given at its labeled dose and schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent AEs | The number of subjects who experience an adverse event that was possibly related to study drug | 36 months | 
| Treatment emergent changes in vital signs | The number of subjects who experience changes in blood pressure, heart rate, respiratory rate, body temperature that was possibly related to study drug. | 36 months | 
| Treatment emergent changes in clinical laboratory tests | The number of subjects who experience a change in laboratory parameters that was possibly related to study drug. | 36 months | 
| Treatment emergent changes in physical examinations, ECOG performance status, electrocardiograms (ECGs), echocardiograms and cardiac troponins | The number of subjects who experience changes in physical examinations, performance status, ECG, troponins that were possibly related to study drug. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Complete Remission Rate, CRc (complete remission + complete remission with incomplete blood count recovery + complete remission with incomplete platelet count recovery [CR + CRi + CRp]) | Response rate will be summarized by dose cohort and overall using the percent of patients in patient with AML | 36 months | 
| Overall response rate (ORR, defined as Complete remission + Marrow CR + Partial remission + Hematologic Improvement (CR + mCR+ PR + HI) | Response rate will be summarized by dose cohort and overall using the percent of patients in patients with MDS, CMML | 36 months | 
| The pharmacokinetics of CFI-400945 will be assessed through AUC. | Area under the plasma concentration (AUC) versus time curve from time 0 to time of least measurable concentration tabulated by dose group. | 36 months | 
| To assess the pharmacokinetic profile of CFI-400945 through Cmax. | Cmax will be assessed through the maximum measured plasma concentration occurring at Tmax tabulated by dose group. | 36 months | 
| To assess the pharmacokinetic profile of CFI-400945 through T1/2. | Elimination half life will be calculated and tabulated by dose group. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polo-like kinase 4, PLK4, serine/threonine kinase Polo-like kinase 4, CFI-400945, 945, Polo-Like Kinase 4 inhibitors/antagonists, hematologic malignancies, PLK-4, UHN, University Health Network, Treadwell, Treadwell Therapeutics, Treadwell Tx