Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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The purpose of the phase 1b/2 study is to determine whether Onvansertib given orally daily for 5 consecutive days every 28 days is safe and tolerable in adult patients who have relapsed/refractory Acute Myeloid Leukemia (AML), or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose and recommended phase 2 dose of Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, Onvansertib in combination with decitabine will be studied to provide further data on the safety profile of the combination and to preliminarily assess the activity of the chosen combination in patients with untreated AML who are not candidates for aggressive induction therapy, or who have received one prior treatment for their AML.

Official Title
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A Phase 1b/2 Study of PCM-075 (Onvansertib) in Combination With Either Low-Dose Cytarabine or Decitabine in Subjects With Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Onvansertib
* Drug: Cytarabine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Status and Prior Therapy: Histologically confirmed AML with >20% blasts Phase 1b: Participants with AML who are refractory to or have relapsed after initial treatment for their disease, with no more than three prior lines of therapy. Participants who have received prior treatment with cytarabine or decitabine are not excluded. Phase 2: i. Participants with AML who are refractory to, or have relapsed after, initial treatment for their disease, with no more than one prior line of therapy, and are judged not to be candidates for re-induction therapy that includes hematopoietic cell transplantation. Participants who have received prior cytarabine or decitabine are not excluded. OR ii. Participants with newly diagnosed, untreated AML ineligible for, or who have refused, standard intensive induction therapy Age ≥18 years ECOG performance status ≤2 Participants must be willing and able to review, understand, and provide written consent before starting any study-specific procedures or therapy. All men and women must agree to practice effective contraception during the entire study period and after discontinuing study drug, unless documentation of infertility exists Sexually active, fertile women must use two effective forms of contraception (abstinence, intrauterine device, oral contraceptive, or double barrier device) from the time of informed consent and until at least 6 months after discontinuing study drug Sexually active men and their sexual partners must use effective contraceptive methods from the time of participant informed consent and until at least 3 months after discontinuing study drug Exclusion Criteria: Treatment-related AML or acute promyelocytic leukemia (APL) Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death Clinical evidence of active central nervous system leukemia at the time of screening Alanine aminotransferase and/or aspartate aminotransferase ≥2.5 x upper limit of normal (ULN) Total bilirubin > 2.0 mg/dL (or > 3.0 mg/dL in participants with documented Gilbert syndrome) Serum creatinine ≥2.0 mg/dL New York Heart Association Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition Myocardial infarction in the previous 12 weeks (from the start of treatment) Resting left ventricular ejection fraction <50% at the time of screening QT (Interval from the beginning of the QRS complex to the end of the T wave on an electrocardiogram) interval with Fridericia's correction [QTcF] >450 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during screening and that result may be used to determine eligibility. Active and uncontrolled disease (other than AML) or infection as judged by the treating physician Treatment with systemic therapy for the primary disease within 14 days (except for hydroxyurea or isolated doses of cytarabine or decitabine for white blood cell control) Grade 2 or greater toxicities from prior therapy, except for Grade 2 toxicities that are not expected to resolve and that in the judgment of the Investigator do not pose a significant safety risk to subject participation. Participants with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the participant's ability to sign the informed consent form or his/her ability to cooperate and participate in the study, or to interfere with the interpretation of the results.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Onvansertib + low-dose cytarabine<br>Onvansertib, administered in escalating doses orally Day 1 through Day 5 every 28 days (1 cycle) in combination with cytarabine, which will be administered in all cohorts as 20 mg/m^2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle). Onvansertib administration, in combination with cytarabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved. | Drug: Onvansertib<br>* Onvansertib orally<br>Drug: Cytarabine<br>* subcutaneously<br>|
| Experimental: Phase 1b: Onvansertib + decitabine<br>Onvansertib will be administered in escalating doses orally, Day 1 through Day 5 every 28 days (1 cycle) in combination with decitabine, administered consistently in all cohorts as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle). Onvansertib administration, in combination with decitabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved. | Drug: Onvansertib<br>* Onvansertib orally<br>Drug: Decitabine<br>* intravenously<br>|
| Experimental: Phase 2: Onvansertib + decitabine<br>Onvansertib recommended phase 2 dose, orally Day 1 through Day 5 every 28 days (1 cycle) and decitabine, administered consistently as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle), with treatment modifications or delays based on return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject management. | Drug: Onvansertib<br>* Onvansertib orally<br>Drug: Decitabine<br>* intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose Limiting Toxicities (DLT) | Dose-limiting toxicities were defined as events related to onvansertib that were considered an adverse reaction or suspected adverse reaction during the first cycle of therapy and that fulfilled one of the following: Hematologic (persistent pancytopenia resistant to current standards of care that continues for ≥42 days and is not related to leukemic infiltration or another cause unrelated to study therapy) or Non-Hematologic (any Grade 3 abnormalities that persist >7 days without decreasing in severity despite standards of care, are clinically significant, or that are Grade 4 and symptomatic). | Up to Day 28 of Cycle 1 | 
| Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status | ECOG performance status was determined using 6-point scale from 0-5, with 0 meaning a participant was fully active/able to carry on all pre-disease activities without restriction and 5 meaning the participant was deceased. | Baseline and end of study (approximately up to up to 27 months) | 
| Phase 2: Number of Participants Who Achieved a Complete Response (CR) | Complete Response also includes Complete Response with Incomplete Blood Count Recovery (CRi). Complete response is defined by the following criteria: Morphologic leukemia-free state plus: Subject is independent of transfusions Absolute neutrophil count of >1000/mm3 Platelets of ≥100,000/mm3 Complete response with incomplete blood count recovery meets all criteria for CR except for either neutropenia (ANC <1000/mm3) or thrombocytopenia (<100,000/mm3) but must include transfusion independence. | Up to 27 months | 
| Number of Participants With Adverse Events (AEs) | Any clinically significant change in electrocardiogram (ECG), physical examination findings, body weight, vital signs, and laboratory parameters were recorded as Adverse Events. | Baseline up to 30 days after last dose of study drug (up to 27 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Number of Participants Who Achieved a Morphologic Leukemia-free (MLF) State | Defined as bone marrow (BM) <5% blasts in an aspirate with spicules and no blasts with Auer rods or persistence of extramedullary disease. | Up to 27 months | 
| Phase 2: Number of Participants With Partial Response (PR) | PR criteria includes all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate and a normalization of blood counts. | Up to 27 months | 
| Phase 2: Duration of Response (DOR) | Duration of Response (DOR) is the time (in months) from the first response of CR, CRi or PR until recurrence of or progression of disease (or death). MLF State is also included as a response when calculating DOR. Responding subjects without death or progression will be censored at the date of their last evaluable disease assessment. | Up to 27 months | 
| Phase 2: Event-free Survival (EFS) | EFS is defined as the time from enrollment until disease progression or death from any cause and reported as the proportion of participants event free at 12 months. | 12 Months | 
| Phase 2: Overall Survival (OS) | OS is defined as the time from enrollment until death from any cause and reported as the proportion of participants alive at 12 months. | 12 Months | 
| Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib |  | Cycle 1: Days 1 and 5 | 
| Pharmacokinetic Parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib |  | Cycle 1: Days 1 and 5 | 
| Pharmacokinetic Parameter: Area Under the Curve Over the First 24 Hours AUC(0-24) for Onvansertib |  | Cycle 1: Days 1 and 5 | 
| Pharmacokinetic Parameter: Plasma Terminal Elimination Half-life (t1/2) for Onvansertib |  | Cycle 1: Days 1 and 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PLK1, PLK Inhibitor, Onvansertib