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

Sponsor

Cardiff Oncology (Industry)

Overall Status

Completed

CT.gov ID

NCT03303339

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Onvansertib Drug: Cytarabine Drug: Decitabine	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

72 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Nov 17, 2017

Actual Primary Completion Date :

Nov 17, 2021

Actual Study Completion Date :

Nov 17, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: Onvansertib + low-dose cytarabine 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 Onvansertib orally Drug: Cytarabine subcutaneously
Experimental: Phase 1b: Onvansertib + decitabine 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 Onvansertib orally Drug: Decitabine intravenously
Experimental: Phase 2: Onvansertib + decitabine 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 Onvansertib orally Drug: Decitabine intravenously

Arm

Intervention/Treatment

Experimental: Phase 1b: Onvansertib + low-dose cytarabine

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

Onvansertib orally

Drug: Cytarabine

subcutaneously

Experimental: Phase 1b: Onvansertib + decitabine

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

Onvansertib orally

Drug: Decitabine

intravenously

Experimental: Phase 2: Onvansertib + decitabine

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

Onvansertib orally

Drug: Decitabine

intravenously

Outcome Measures

Primary Outcome Measures

Number of Participants With Dose Limiting Toxicity (DLT) [Baseline up to 30 days after last dose of study drug (up to 27 months)]
DLT is defined as an adverse reaction or suspected adverse reaction, during the 28 days according to the Common Terminology Criteria for Adverse Events (CTCAE).
Number of Participants With Adverse Events (AEs) [Baseline up to 30 days after last dose of study drug (up to 27 months)]
The severity of each AE will be graded using the Common Terminology Criteria for Adverse Events (CTCAE).
Number of Participants With Clinically Significant Change from Baseline in Electrocardiograms (ECG) [Baseline up to 30 days after last dose of study drug (up to 27 months)]
Number of Participants with Clinically Significant Physical Examination Findings [Baseline up to 30 days after last dose of study drug (up to 27 months)]
Number of Participants With Clinically Significant Change From Baseline in Body Weight [Baseline up to 30 days after last dose of study drug (up to 27 months)]
Number of Participants With Clinically Significant Change From Baseline in vital signs [Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months)]
Number of Participants With Clinically Significant Change From Baseline in laboratory parameters [Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months)]]
Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status [Baseline and end of trial (approximately up to up to 27 months)]
ECOG performance measured on-therapy.
Phase 2: Rate of Complete Response (CR) + Complete Response with Incomplete Blood Count Recovery (CRi) [Baseline and end of trial (up to up to 27 months)]
Defined as a morphologic leukemia-free state.

Secondary Outcome Measures

Phase 2: Rate of achievement of a morphologic Leukemia-free (MLF) State [Baseline and end of trial (up to 27 months)]
Defined as bone marrow (BM) <5% blasts in an aspirate with spicules (a BM biopsy should be performed if spicules are absent) and no blasts with Auer rods or persistence of extramedullary disease.
Phase 2: Rate of partial response (PR) [Baseline up to 30 days after last dose of study drug (up to 27 months)]
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
Phase 2: Duration of response (DOR) [Baseline and end of trial (up to 27 months)]
Time from documentation of response until documentation of recurrence of or progression of disease.
Phase 2: Event-free survival (EFS) [Baseline and end of trial (up to 27 months)]
Time from enrollment until disease progression or death from any cause.
Phase 2: Overall survival (OS) [Baseline up to 30 days after last dose of study drug (up to 27 months)]
Time from enrollment until death from any cause
Pharmacokinetic parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib [Up to 24 months]
Pharmacokinetic parameter: Minimum Observed Plasma Trough Concentration (Cmin) for Onvansertib [Up to 24 months]
Pharmacokinetic parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib [Up to 24 months]
Pharmacokinetic parameter: Area under the curve over the first 24 hours AUC(0-24) for Onvansertib [Up to 24 months]
Pharmacokinetic parameter: Plasma terminal elimination half-life (t1/2) for Onvansertib [Up to 24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles	Los Angeles	California	United States	90095
2	Yale University	New Haven	Connecticut	United States	06510
3	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
4	Allina Health Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
5	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
6	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
7	MD Anderson Cancer Center	Houston	Texas	United States	77030
8	Virginia Cancer Specialists - Fairfax Office	Fairfax	Virginia	United States	22031
9	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109