Clinical trial NCT03303339: Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: PLK1
PLK Inhibitor
Onvansertib
Lead sponsor: Cardiff Oncology
Sponsor class: INDUSTRY
First posted: 2017-10-06
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Disease Status and Prior Therapy:

   1. Histologically confirmed AML with \>20% blasts
   2. 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.
   3. 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
2. Age ≥18 years
3. ECOG performance status ≤2
4. Participants must be willing and able to review, understand, and provide written consent before starting any study-specific procedures or therapy.
5. 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

   1. 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
   2. 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:

1. Treatment-related AML or acute promyelocytic leukemia (APL)
2. Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death
3. Clinical evidence of active central nervous system leukemia at the time of screening
4. Alanine aminotransferase and/or aspartate aminotransferase ≥2.5 x upper limit of normal (ULN)
5. Total bilirubin \> 2.0 mg/dL (or \> 3.0 mg/dL in participants with documented Gilbert syndrome)
6. Serum creatinine ≥2.0 mg/dL
7. New York Heart Association Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition
8. Myocardial infarction in the previous 12 weeks (from the start of treatment)
9. Resting left ventricular ejection fraction \<50% at the time of screening
10. 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.
11. Active and uncontrolled disease (other than AML) or infection as judged by the treating physician
12. 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)
13. 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.
14. 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.

Primary outcomes:
measure: Number of Participants Who Experienced Dose Limiting Toxicities (DLT)
timeFrame: Up to Day 28 of Cycle 1
measure: Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status
timeFrame: Baseline and end of study (approximately up to up to 27 months)
measure: Phase 2: Number of Participants Who Achieved a Complete Response (CR)
timeFrame: Up to 27 months
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Baseline up to 30 days after last dose of study drug (up to 27 months)
Secondary outcomes:
measure: Phase 2: Number of Participants Who Achieved a Morphologic Leukemia-free (MLF) State
timeFrame: Up to 27 months
measure: Phase 2: Number of Participants With Partial Response (PR)
timeFrame: Up to 27 months
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to 27 months
measure: Phase 2: Event-free Survival (EFS)
timeFrame: 12 Months
measure: Phase 2: Overall Survival (OS)
timeFrame: 12 Months
measure: Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib
timeFrame: Cycle 1: Days 1 and 5
measure: Pharmacokinetic Parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib
timeFrame: Cycle 1: Days 1 and 5
measure: Pharmacokinetic Parameter: Area Under the Curve Over the First 24 Hours AUC(0-24) for Onvansertib
timeFrame: Cycle 1: Days 1 and 5
measure: Pharmacokinetic Parameter: Plasma Terminal Elimination Half-life (t1/2) for Onvansertib
timeFrame: Cycle 1: Days 1 and 5
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Minneapolis
country: United States
facility: Allina Health Virginia Piper Cancer Institute
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists - Fairfax Office
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
References:
citation: Hagege A, Ambrosetti D, Boyer J, Bozec A, Doyen J, Chamorey E, He X, Bourget I, Rousset J, Saada E, Rastoin O, Parola J, Luciano F, Cao Y, Pages G, Dufies M. The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy. Theranostics. 2021 Sep 21;11(19):9571-9586. doi: 10.7150/thno.61711. eCollection 2021.