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

• ClinicalTrials.gov Identifier: NCT03303339
• Recruitment Status: Active, not recruiting
• First Posted: October 6, 2017
• Last Update Posted: February 21, 2021
• Sponsor: Cardiff Oncology
• Information provided by (Responsible Party): Cardiff Oncology

Tracking Information

• First Submitted Date: September 6, 2017
• First Posted Date: October 6, 2017
• Last Update Posted Date: February 21, 2021
• Actual Study Start Date: November 17, 2017
• Estimated Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2017)

• Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
• Number of Participants with Clinically Significant Physical Examination Findings [ 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 Body Weight [ 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 vital signs [ Time Frame: 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: 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 [ Time Frame: 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) [ Time Frame: Baseline and end of trial (up to up to 27 months) ]
  Defined as a morphologic leukemia-free state.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 27, 2018)

• Phase 2: Rate of achievement of a morphologic Leukemia-free (MLF) State [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Minimum Observed Plasma Trough Concentration (Cmin) for Onvansertib [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Area under the curve over the first 24 hours AUC(0-24) for Onvansertib [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Plasma terminal elimination half-life (t1/2) for Onvansertib [ Time Frame: Up to 24 months ]

Original Secondary Outcome Measures (submitted: October 2, 2017)

• Phase 2: Rate of achievement of a morphologic Leukemia-free (MLF) State [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 PCM-075 [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Minimum Observed Plasma Trough Concentration (Cmin) for PCM-075 [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for PCM-075 [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Area under the curve over the first 24 hours AUC(0-24) for PCM-075 [ Time Frame: Up to 24 months ]
• Pharmacokinetic parameter: Plasma terminal elimination half-life (t1/2) for PCM-075 [ Time Frame: Up to 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia

Intervention

• Drug: Onvansertib
  Onvansertib orally
• Drug: Cytarabine
  subcutaneously
• Drug: Decitabine
  intravenously

Study Arms

• 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.
  Interventions:

  • Drug: Onvansertib
  • Drug: Cytarabine
• 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.
  Interventions:

  • Drug: Onvansertib
  • Drug: Decitabine
• 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.
  Interventions:

  • Drug: Onvansertib
  • Drug: Decitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 18, 2020): 72
• Original Estimated Enrollment (submitted: October 2, 2017): 116
• Estimated Study Completion Date: December 15, 2021
• Estimated Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03303339
• Other Study ID Numbers: TROV-052; U1111-1201-6416 ( Other Identifier: WHO )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Cardiff Oncology
• Study Sponsor: Cardiff Oncology
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Cardiff Oncology
• Verification Date: February 2021