Clinical Trials /

Trial of DFP-10917 vs Non-Intensive or Intensive Reinduction for AML Patients in 2nd/3rd/4th Salvage

NCT03926624

Description:

Phase III, multicenter, randomized study with two arms (1:1 ratio) enrolling patients with AML relapsed/refractory after 2, 3, or 4 prior induction regimens: Experimental arm: DFP-10917 14-day continuous intravenous (IV) infusion at a dose of 6 mg/m²/day followed by a 14-day resting period per 28-day cycles. Control arm: Non-Intensive Reinduction (LoDAC, Azacitidine, Decitabine, Venetoclax Combination Regimens) or Intensive Reinduction (High and Intermediate Dose Cytarabine Regimens), depending on the patient's prior induction treatment.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Trial of DFP-10917 vs Non-Intensive or Intensive Reinduction for AML Patients in 2nd/3rd/4th Salvage
  • Official Title: Phase 3 Randomized Trial of DFP-10917 vs Non-Intensive Reinduction (LoDAC, Azacitidine, Decitabine, Venetoclax Combination Regimens) or Intensive Reinduction (High & Intermediate Dose Cytarabine Regimens) for Acute Myelogenous Leukemia Patients in Second, Third, or Fourth Salvage

Clinical Trial IDs

  • ORG STUDY ID: D18-11141
  • NCT ID: NCT03926624

Conditions

  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
DFP-10917Experimental
CytarabineControl
AzacitidineControl
DecitabineControl
MitoxantroneControl
EtoposideControl
FludarabineControl
IdarubicinControl
VenetoclaxControl
CladribineControl

Purpose

Phase III, multicenter, randomized study with two arms (1:1 ratio) enrolling patients with AML relapsed/refractory after 2, 3, or 4 prior induction regimens: Experimental arm: DFP-10917 14-day continuous intravenous (IV) infusion at a dose of 6 mg/m²/day followed by a 14-day resting period per 28-day cycles. Control arm: Non-Intensive Reinduction (LoDAC, Azacitidine, Decitabine, Venetoclax Combination Regimens) or Intensive Reinduction (High and Intermediate Dose Cytarabine Regimens), depending on the patient's prior induction treatment.

Detailed Description

      Study to compare the rate of complete response (CR) and duration of CR, in patients with
      relapsed or refractory AML to two, three, or four prior induction regimens that may have
      included intensive chemotherapy (e.g., "7+3" cytarabine and daunorubicin), epigenetic therapy
      (i.e., azacitidine or decitabine), or targeted therapy (e.g., FLT-3, IDH-1/2, BCL-2,
      monoclonal antibody), who will receive DFP-10917 versus non-intensive reinduction (LoDAC,
      azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive
      reinduction (high and intermediate dose cytarabine regimens) as a second, third, or fourth
      salvage treatment.

      Experimental Arm DFP-10917 Dose: 6 mg/m²/day administered by continuous infusion for 14 days
      followed by a 14-day resting period per 28-day treatment cycle. If a patient experiences a
      significant treatment-related AE, the patient may undergo one dose reduction of DFP-10917 to
      4 mg/m²/day x 14 days for subsequent treatment cycles

      Control arm: Non-Intensive Reinduction (LoDAC, Azacitidine, Decitabine, Venetoclax + LoDAC or
      Azacitidine or Decitabine) or Intensive Reinduction (High and Intermediate Dose Cytarabine
      Regimens), depending on the patient's prior induction treatment as well as the patient's
      clinical condition and comorbidities. Control treatment is to be selected only from among the
      following. Institutional practice for administering these treatments are permitted, but the
      dose and days of drug administration should be followed as below.

      Non-Intensive Reinduction:

        -  LoDAC: 20 mg Cytarabine administered by subcutaneous (SC) injection, twice daily (BID)
           for 10 days, plus best supportive care per 28-day treatment cycle

        -  Azacitidine: 75 mg/m²/day administered by SC for 7 consecutive days (or 5+2), plus best
           supportive care per 28-day treatment cycle

        -  Decitabine: administered as continuous intravenous (CIV) infusion 20 mg/m² x 5 days plus
           best supportive care per 28 day treatment cycle

        -  Venetoclax + LoDAC or Azacitidine or Decitabine: In combination with LoDAC, Venetoclax
           will be administered via a daily ramp-up to a final 600 mg once daily dose. During the
           ramp-up, patients are to receive TLS prophylaxis and may be hospitalized for monitoring.
           Cytarabine will be administered subcutaneously at a dose of 20 mg/m² once daily on Days
           1-10 of each 28-day cycle beginning Cycle 1 Day 1. In combination with Azacitidine or
           Decitabine, Venetoclax will be administered via a daily ramp-up to a final 400 mg once
           daily dose. Azacitidine will be administered intravenously or subcutaneously at a dose
           of 75 mg/m² on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1. Decitabine will
           be administered via IV at a dose of 20 mg/m² on Days 1-5 or 1-10, as per institutional
           practice, of each 28-day cycle beginning Cycle 1 Day 1.

      Intensive Reinduction:

        -  High DAC = cytarabine at doses of 1-2 g/m²/day for up to 5 days, with a maximum total
           dose 10 g/m² per course

        -  FLAG = Days 1-5: fludarabine 30 mg/m² IV over 30 minutes, Days 1-5: cytarabine 1 2
           grm/m² over 4 hours daily x 5, and granulocyte colony-stimulating factor 5 mcg/kg or 300
           mcg/m² until Polymorphonuclear Neutrophil (PMN) recovery, with or without idarubicin
           Days 1-3 at 8 mg/m² IV daily x 3 (FLAG-Ida)

        -  MEC = Days 1-6: mitoxantrone 6 mg/m² IV bolus, etoposide 80 mg/m² IV over 1 hour, and
           cytarabine 1 grm/m² IV over 6 hrs (Etoposide may be deleted per institutional
           guidelines, i.e., HAM regimen)

        -  CLAG/M or Ida = cladribine 5 mg/m² on Days 1-5, cytarabine 2 g/m² on Days 1-5,
           granulocyte-colony stimulating factor 300 μg on Days 0-5 (G-CSF starts 24 hr prior to
           chemotherapy), and mitoxantrone 10 mg/m² on Days 1-3 or Idarubicin 10 mg/m² on Days 1-3

        -  Intermediate DAC = cytarabine 20 mg/m² IV daily x 5

      The selection of control arm treatment will be determined by the investigator depending on
      the patient's prior initial induction and salvage treatment regimen(s), as well as the
      patient's clinical condition and comorbidities. The investigator will select the patient's
      control treatment from among the non-intensive or intensive regimens prior to study treatment
      randomization in order to balance treatment allocation between the experimental and control
      treatment arms.
    

Trial Arms

NameTypeDescriptionInterventions
ExperimentalExperimentalDFP-10917 Dose: 6 mg/m²/day administered by continuous infusion for 14 days followed by a 14-day resting period per 28-day treatment cycle. If a patient experiences a significant treatment-related AE, the patient may undergo one dose reduction of DFP-10917 to 4 mg/m²/day x 14 days for subsequent treatment cycles
  • DFP-10917
ControlActive ComparatorNon-Intensive: LoDAC: 20 mg SC BID 10 days Azacitidine: 75 mg/m²/day SC 7 days(or 5+2) Decitabine: CIV 20 mg/m²x5 days Venetoclax + LoDAC/Azacitidine/Decitabine:LoDAC-Venetoclax ramp-up to 600 mgxday. Cytarabine SC 20 mg/m²xday D1-10. Azacitidine or Decitabine-Venetoclax ramp-up to 400 mgxday. Azacitidine IV or SC 75 mg/m² D1-7. Decitabine IV 20 mg/m² on D1-5 or 1-10. Intensive: High DAC: cytarabine 1-2 g/m² up to 5 days, max total dose 10 g/m² FLAG: D1-5: fludarabine 30 mg/m² IV for 30min, D1-5: cytarabine 1-2 g/m² for 4hr daily x 5 & G-CSF 5 mcg/kg or 300 mcg/m² until PMN recovery, with or without idarubicin D1-3 8 mg/m² IV dailyx3 (FLAG-Ida) MEC: D1-6: mitoxantrone 6 mg/m² IV bolus, etoposide 80 mg/m² IV 1hr & cytarabine 1g/m² IV 6hr. CLAG/M or Ida = cladribine 5 mg/m² D1-5, cytarabine 2 g/m² D1-5, G-CSF 300 μg D0-5, mitoxantrone 10 mg/m² D1-3 or Idarubicin 10 mg/m² D1-3. Intermediate DAC: cytarabine 20 mg/m² IV dailyx5
  • Cytarabine
  • Azacitidine
  • Decitabine
  • Mitoxantrone
  • Etoposide
  • Fludarabine
  • Idarubicin
  • Venetoclax
  • Cladribine

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or pathologically confirmed diagnosis of AML based on WHO
             classification that has relapsed after, or is refractory to, two, three, or four prior
             induction regimens that may have included intensive chemotherapy (e.g., "7+3"
             cytarabine and daunorubicin), epigenetic therapy (i.e., azacitidine or decitabine), or
             targeted therapy (e.g., FLT-3, IDH-1/2, BCL-2, monoclonal antibody).

             (Relapse is defined as reemergence of ≥5% leukemia blasts in bone marrow or ≥1% blasts
             in peripheral blood ≥90 days after first CR or CR without complete platelet recovery
             (CRp). Refractory AML is defined as persistent disease ≥28 days after initiation of
             intensive induction therapy (up to two induction cycles) or relapse <90 days after
             first CR or CRp. Refractory disease for patients undergoing hypomethylating agent
             induction is defined as lack of remission following at least 2 cycles of epigenetic
             therapy without reduction in bone marrow blast status.)

             Patients with a history of IPSS-R high or very high risk MDS that transformed to AML
             during treatment with hypomethylating drugs and then relapse following or are
             refractory to a subsequent AML induction regimen may be enrolled as Second Salvage AML
             patients. Additionally, patients with a history of MPN in accelerated phase (MPN-AP)
             or high-risk primary myelofibrosis (PMF) that transformed to AML during treatment with
             hypomethylating drugs and then relapse following or are refractory to a subsequent AML
             induction regimen may be enrolled as Second Salvage AML patients.

          2. Aged ≥ 18 years.

          3. ECOG Performance Status of 0, 1 or 2.

          4. Adequate clinical laboratory values (i.e., plasma creatinine <2.5 x upper limit of
             normal (ULN) for the institution, bilirubin <2.5 x ULN, alanine transaminase (ALT) and
             aspartate transaminase (AST) ≤2.5 x ULN).

          5. Absence of active central nervous system (CNS) involvement by leukemia. Patients with
             previously diagnosed CNS leukemia are eligible if the CNS leukemia is under control
             and intrathecal treatment may continue throughout the study.

          6. Absence of uncontrolled intercurrent illnesses, including uncontrolled infections,
             cardiac conditions, or other organ dysfunctions.

          7. Signed informed consent prior to the start of any study specific procedures.

          8. Women of child-bearing potential must have a negative serum or urine pregnancy test.

          9. Male and female patients must agree to use acceptable contraceptive methods for the
             duration of the study and for at least one month after the last drug administration.

        Exclusion Criteria:

          1. The interval from prior treatment to time of study drug administration is < 2 weeks
             for cytotoxic agents or < 5 half-lives for noncytotoxic agents. Exceptions: Use of
             hydroxyurea is allowed before the start of study and is to be discontinued prior to
             the initiation of study treatment. At the investigator's discretion, for patients with
             significant leukocytosis that develops during the early treatment cycles, hydroxyurea
             may be administered. The hydroxyurea should be discontinued as soon as clinically
             appropriate.

          2. Any >grade 1 persistent clinically significant toxicities from prior chemotherapy.

          3. Inadequate Cardiac (left ventricular ejection fraction ≤40%) function.

          4. White blood cell (WBC) count >15,000/μL (Note: Patients considered for possible
             venetoclax-containing regimen must have WBC ≤10k/μL prior to initiating venetoclax
             treatment).

          5. For patients with prior hematopoietic stem cell transplant (HSCT):

               1. Less than 3 months since HSCT

               2. Acute Graft versus Host Disease (GvHD) >Grade 1

               3. Chronic GvHD >Grade 1

          6. Any concomitant condition that in the opinion of the investigator could compromise the
             objectives of this study and the patient's compliance.

          7. A pregnant or lactating woman.

          8. Current malignancies of another type. Exceptions: Patients may participate if they
             have previously treated and currently controlled prostate cancer, or adequately
             treated in situ cervical cancer or basal cell skin cancer, or other malignancies with
             no evidence of disease for 2 years or more.

          9. Patient has acute promyelocytic leukemia (APL).

         10. Patients with known HIV, active HBV or active HCV infection (note: testing for these
             infections is not required). For patients with evidence of chronic hepatitis B virus
             (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if
             indicated. Patients with a history of hepatitis C virus (HCV) infection must have been
             treated and cured. For patients with HCV infection who are currently on treatment,
             they are eligible if they have an undetectable HCV viral load.

         11. Documented or known clinically significant bleeding disorder.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission (CR) rate
Time Frame:3 years
Safety Issue:
Description:The rate of CR based on International Working Group (IWG) Guidelines for bone marrow and blood response

Secondary Outcome Measures

Measure:The rate of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp
Time Frame:3 years
Safety Issue:
Description:CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L
Measure:The duration of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp
Time Frame:3 years
Safety Issue:
Description:CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L + platelet count < 100x10^9/L
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:Number of days from date of first dose to date of death
Measure:Transition rate to hematopoietic stem cell transplantation (HSCT)
Time Frame:3 years
Safety Issue:
Description:Number of subjects who transition to HSCT
Measure:Overall response rate (ORR)
Time Frame:3 years
Safety Issue:
Description:The rate of CR + CRi + CRp + PR
Measure:Duration overall response
Time Frame:3 years
Safety Issue:
Description:The duration of CR + CRi + CRp + PR
Measure:Rate of disease related co-morbidities
Time Frame:3 years
Safety Issue:
Description:Number and severity of expected leukemia-related adverse events
Measure:Adverse events
Time Frame:3 years
Safety Issue:
Description:Number of patients with adverse events

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Delta-Fly Pharma, Inc.

Last Updated

April 21, 2021