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

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ClinicalTrials.gov Identifier: NCT03926624
Recruitment Status : Recruiting
First Posted : April 24, 2019
Last Update Posted : December 21, 2020
Sponsor:
Information provided by (Responsible Party):
Delta-Fly Pharma, Inc.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: DFP-10917 Drug: Cytarabine Drug: Azacitidine Drug: Decitabine Drug: Mitoxantrone Drug: Etoposide Drug: Fludarabine Drug: Idarubicin Drug: Venetoclax Drug: Cladribine Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized, controlled
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 22, 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Experimental
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
Drug: DFP-10917
DFP-10917 Powder for Injection. Active ingredient: 4-amino-1-(2-cyano-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone monohydrochloride

Active Comparator: Control

Non-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
Drug: Cytarabine
cytosine arabinoside (ara-C)

Drug: Azacitidine
Azacitidine

Drug: Decitabine
Decitabine

Drug: Mitoxantrone
Mitoxantrone

Drug: Etoposide
Etoposide

Drug: Fludarabine
Fludarabine

Drug: Idarubicin
Idarubicin

Drug: Venetoclax
Venetoclax

Drug: Cladribine
Cladribine




Primary Outcome Measures :
  1. Complete remission (CR) rate [ Time Frame: 3 years ]
    The rate of CR based on International Working Group (IWG) Guidelines for bone marrow and blood response

  2. Duration of complete remission [ Time Frame: 3 years ]
    Number of days from time of initial CR until disease recurrence or death


Secondary Outcome Measures :
  1. The rate of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp [ Time Frame: 3 years ]
    CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L

  2. The duration of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp [ Time Frame: 3 years ]
    CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L + platelet count < 100x10^9/L

  3. Overall survival [ Time Frame: 3 years ]
    Number of days from date of first dose to date of death

  4. Transition rate to hematopoietic stem cell transplantation (HSCT) [ Time Frame: 3 years ]
    Number of subjects who transition to HSCT

  5. Overall response rate (ORR) [ Time Frame: 3 years ]
    The rate of CR + CRi + CRp + PR

  6. Duration overall response [ Time Frame: 3 years ]
    The duration of CR + CRi + CRp + PR

  7. Rate of disease related co-morbidities [ Time Frame: 3 years ]
    Number and severity of expected leukemia-related adverse events

  8. Adverse events [ Time Frame: 3 years ]
    Number of patients with adverse events



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03926624


Contacts
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Contact: Tapan Kadia, MD 713-792-7026 tkadia@mdanderson.org

Locations
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Sponsors and Collaborators
Delta-Fly Pharma, Inc.
Investigators
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Principal Investigator: Tapan Kadia, MD M.D. Anderson Cancer Center
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Responsible Party: Delta-Fly Pharma, Inc.
ClinicalTrials.gov Identifier: NCT03926624    
Other Study ID Numbers: D18-11141
First Posted: April 24, 2019    Key Record Dates
Last Update Posted: December 21, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Etoposide
Azacitidine
Decitabine
Mitoxantrone
Venetoclax
Idarubicin
Cladribine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents