Clinical Trials /

Safety and Efficacy Study of PD-616 Plus Cytarabine to Treat Acute Myelogenous Leukemia or Myelodysplastic Syndrome

NCT01795924

Description:

The purpose of this study is to determine whether PD-616 in combination with low-dose Cytarabine is safe and effective in the treatment of untreated or relapsed/refractory acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy Study of PD-616 Plus Cytarabine to Treat Acute Myelogenous Leukemia or Myelodysplastic Syndrome
  • Official Title: An Open-Label, Phase 1/2 Study of PD-616 and Low-dose Cytarabine in Patients With Untreated or Relapsed/Refractory Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: RT12-US-AML-a
  • NCT ID: NCT01795924

Conditions

  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
PD-616TPA, 12-O-Tetra-Decanoyl-Phorbol-13-AcetatePD-616 plus low-dose Cytarabine

Purpose

The purpose of this study is to determine whether PD-616 in combination with low-dose Cytarabine is safe and effective in the treatment of untreated or relapsed/refractory acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

Detailed Description

      Protocol RT12-US-AML-a is a 2-part, Phase 1/2, multi-center, open-label, dose-escalation
      study of PD-616 in combination with low-dose cytarabine in patients with AML or high-risk MDS
      not eligible for standard therapy.

      Part 1 of this study (Phase 1 portion) employs a sequential group-dose escalation design to
      determine the DLT and MTD of PD-616 in combination with low-dose cytarabine (primary
      objective). The safety and PK profiles as well as the preliminary efficacy of PD-616 in
      combination with cytarabine also will be examined (secondary objectives). Approximately 21
      patients are planned to be enrolled in Part 1.

      After provision of written informed consent, patients are to be evaluated for study
      eligibility during the Screening period which should be within 14 days before the first day
      of study drug administration (Cycle 1, Day 1 [C1D1]; Baseline). Patients who are determined
      to be eligible, based on Screening assessments, will be enrolled in the study on C1D1, which
      is the first day of study drug administration.

      Part 2 of this study (Phase 2 portion) will commence with approval of the Safety Review
      Committee (SRC) after identification of the MTD, or if the MTD is not established, the
      maximum feasible dose has been evaluated in Part 1. Twelve additional patients will be
      enrolled and treated with PD-616 at the MTD (or other biologically relevant dose) in
      combination with low-dose cytarabine according to the same schedule as in Part 1. The safety
      profile, PK, and efficacy of the study drug combination will be further investigated in Part
      2 of this study.

      Each cycle of treatment consists of a treatment period (D1 through D12) and a rest period
      (D13 through D28). During the treatment period, patients are required to return to the study
      center on D1 through D5 and D8 through D12 for study drug to be administered and evaluations
      to be performed. During the rest period, patients are required to return to the study center
      at least once a week for study evaluations. In addition, patients are required to be
      evaluated for peripheral blasts by flow cytometry in the last week of each cycle (D22 to D28)
      and to receive bone marrow examination in the last week (D22 to D28) of C1. Patients with
      evidence of complete response (CR) in peripheral blood by flow cytometry are to have a repeat
      bone marrow examination performed to confirm CR.

      All patients are to attend the Study Drug Discontinuation Visit within 3 days after
      discontinuing study drug. Thereafter, patients will enter the post-study period and be
      followed monthly (±3 days), starting 30±3 days after last study drug administration, through
      1 year post-C1D1. During the post-study period, patients who discontinue for reasons other
      than progressive disease (PD) also will have follow-up blood samples collected for evaluation
      of changes in the percentage of blasts every month until PD or receipt of alternative
      therapy, whichever occurs first, up to 1 year post-C1D1. During the post-study period,
      patients with evidence of CR in peripheral blood by flow cytometry are to have a repeat bone
      marrow examination performed to confirm CR.
    

Trial Arms

NameTypeDescriptionInterventions
PD-616 plus low-dose CytarabineExperimentalPatients will receive low-dose cytarabine (20 mg/m2) subcutaneously (SC) once daily (QD), followed by a 1-hour intravenous (IV) infusion of PD-616 for 5 consecutive days during Week 1 (D1 to D5) and Week 2 (D8 to D12) of a 28-day treatment cycle. Cytarabine is to be administered approximately 30 minutes before PD-616. In Phase 1 part, the starting dose of PD-616 is 0.0875 mg/m2, with sequential increments of 0.0375 mg/m2, to 0.125, and 0.1625 mg/m2. The dose of PD-616 to be administered in Phase 2 part will be the maximum tolerated dose (MTD)determined from Phase 1 part of the study.
  • PD-616

Eligibility Criteria

        Inclusion Criteria:

          -  Patient has newly diagnosed AML and refuses or is not eligible for treatment with
             aggressive chemotherapy and/or SCT; OR AML and has relapsed or been refractory to
             prior therapy; OR High-risk MDS, defined as IPSS intermediate-2 (INT-2) or IPSS
             high-risk, and refuses or is not eligible for standard or aggressive chemotherapy and
             SCT or prior experimental therapies; OR High-risk MDS, defined as IPSS INT-2 or IPSS
             high risk, and has failed or been refractory to deoxyribonucleic acid (DNA)
             hypomethylating agents (azacitidine or decitabine), lenalidomide, standard/aggressive
             chemotherapy, SCT, or prior experimental therapies.

          -  Has a bone marrow examination performed within 14 days before baseline (C1D1).

          -  Has an ECOG performance status score of 0 to 2.

          -  Aged between 18 and 75 years, inclusive.

          -  Has a life expectancy of ≥3 months.

          -  Has the following laboratory parameters within 7 days before baseline (C1D1):Serum
             creatinine ≤2 mg/dL; Total bilirubin ≤2.0 mg/dL; Alanine transaminase (ALT) or
             aspartate transaminase (AST) <3.0×the upper limit of normal (ULN); Left ventricular
             ejection fraction (LVEF) >40%; Forced expiratory volume in 1 second (FEV1) >60% of
             predicted.

          -  If a female of child-bearing potential, has a negative serum pregnancy test result
             within 14 days before baseline and agrees to abstain from heterosexual intercourse or
             use a barrier method for contraception from 14 days before baseline (C1D1) through 30
             days after the last study drug dose.

          -  If male, agrees to use a latex condom during any sexual contact with a female of
             child-bearing potential.

          -  Able to understand and willing to provide written informed consent.

        Exclusion Criteria:

          -  Has received prior treatment with PD-616 or low-dose cytarabine.

          -  Has received chemotherapy (except hydroxyurea), biological therapy, radiotherapy or
             investigational therapy within 4 weeks before baseline (C1D1).

          -  Has active central nervous system (CNS) involvement (documented by radiologic lesions
             and/or malignant cells in the cerebrospinal fluid [CSF]).

          -  Has acute promyelocytic leukemia (APL, FAB M3).

          -  Has another active systemic malignancy treated with chemotherapy within 12 months
             before baseline (C1D1).

          -  Has known human immunodeficiency virus (HIV) infection.

          -  Has active graft-versus-host disease (GVHD).

          -  Has uncontrolled active infection of any kind. (Patients with infections controlled by
             active antibiotic treatment are eligible).

          -  Has significant renal or hepatic disease, uncontrolled or severe cardiovascular or
             pulmonary diseases, or other uncontrolled medical condition that, based on the
             Investigator's assessment, would compromise the patient's ability to tolerate study
             treatment or the assessment of treatment response.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of dose-limiting toxicities in each cohort of PD-616 in combination of low-dose Cytarabine to determine the maximum tolerated dose of PD-616.
Time Frame:Average 28 days after the first dose of treatment
Safety Issue:
Description:Primary outcome measure for the Phase 1 part of the study.

Secondary Outcome Measures

Measure:The pharmacokinetic profile of PD-616 consisting AUC.
Time Frame:1 hour before and 20, 40 and 60 minutes during and 0.5, 1, 2, 4, 6, 10 hours after treatment on Day 1 and Day 5 and before treatment on Day 2, Day 3 and Day 4
Safety Issue:
Description:
Measure:The pharmacokinetic profile of PD-616 consisting Cmax.
Time Frame:1 hour before and 20, 40 and 60 minutes during and 0.5, 1, 2, 4, 6, 10 hours after treatment on Day 1 and Day 5 and before treatment on Day 2, Day 3 and Day 4
Safety Issue:
Description:
Measure:The pharmacokinetic profile of PD-616 consisting Tmax.
Time Frame:1 hour before and 20, 40 and 60 minutes during and 0.5, 1, 2, 4, 6, 10 hours after treatment on Day 1 and Day 5 and before treatment on Day 2, Day 3 and Day 4
Safety Issue:
Description:
Measure:The pharmacokinetic profile of PD-616 consisting Cmin.
Time Frame:1 hour before and 20, 40 and 60 minutes during and 0.5, 1, 2, 4, 6, 10 hours after treatment on Day 1 and Day 5 and before treatment on Day 2, Day 3 and Day 4
Safety Issue:
Description:
Measure:The proportion of patients experiencing adverse events.
Time Frame:One year from the first dose of treatment
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Biosuccess Biotech Co., Ltd.

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