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

NCT03303339

Description:

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, or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose or recommended phase 2 dose of Onvansertib in combination with decitabine or and Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, one regimen (either Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine) 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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: TROV-052
  • SECONDARY ID: U1111-1201-6416
  • NCT ID: NCT03303339

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
OnvansertibPhase 1b: Onvansertib + low-dose cytarabine
CytarabinePhase 1b: Onvansertib + low-dose cytarabine
DecitabinePhase 1b: Onvansertib + decitabine

Purpose

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, or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose or recommended phase 2 dose of Onvansertib in combination with decitabine or and Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, one regimen (either Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine) 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.

Trial Arms

NameTypeDescriptionInterventions
Phase 1b: Onvansertib + low-dose cytarabineExperimentalOnvansertib, 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/m2 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/m2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until Maximum Tolerated Dose/Recommended Phase 2 Dose is achieved.
  • Onvansertib
  • Cytarabine
Phase 1b: Onvansertib + decitabineExperimentalOnvansertib 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/m2 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/m2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until Maximum Tolerated Dose/Recommended Phase 2 Dose is achieved.
  • Onvansertib
  • Decitabine
Phase 2: Onvansertib + cytarabine or decitabineExperimentalOnvansertib Recommended Phase 2 Dose, orally Day 1 through Day 5 every 28 days (1 cycle) and either cytarabine, 20 mg/m2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle), or decitabine, administered consistently as 20 mg/m2 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.
  • Onvansertib
  • Cytarabine
  • Decitabine

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. Planned concomitant use of medications known to prolong the QT/QTc interval

         12. Presence of risk factors for torsade de pointes, including family history of Long QT
             Syndrome or uncorrected hypokalemia

         13. Active and uncontrolled disease (other than AML) or infection as judged by the
             treating physician

         14. 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)

         15. 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.

         16. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Phase 2: Rate of achievement of a morphologic Leukemia-free (MLF) State
Time Frame:Baseline and end of trial (up to 27 months)
Safety Issue:
Description: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.
Measure:Phase 2: Rate of partial response (PR)
Time Frame:Baseline up to 30 days after last dose of study drug (up to 27 months)
Safety Issue:
Description: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
Measure:Phase 2: Duration of response (DOR)
Time Frame:Baseline and end of trial (up to 27 months)
Safety Issue:
Description:Time from documentation of response until documentation of recurrence of or progression of disease.
Measure:Phase 2: Event-free survival (EFS)
Time Frame:Baseline and end of trial (up to 27 months)
Safety Issue:
Description:Time from enrollment until disease progression or death from any cause.
Measure:Phase 2: Overall survival (OS)
Time Frame:Baseline up to 30 days after last dose of study drug (up to 27 months)
Safety Issue:
Description:Time from enrollment until death from any cause
Measure:Pharmacokinetic parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Minimum Observed Plasma Trough Concentration (Cmin) for Onvansertib
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Area under the curve over the first 24 hours AUC(0-24) for Onvansertib
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Plasma terminal elimination half-life (t1/2) for Onvansertib
Time Frame:Up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Trovagene, Inc.

Trial Keywords

  • PLK1
  • PLK Inhibitor
  • Onvansertib

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