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

October 18, 2022 updated by: Delta-Fly Pharma, Inc.

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / 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.

Study Type

Interventional

Enrollment (Anticipated)

450

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • Recruiting
        • O'Neal Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Sravanti Ranagaraju, MD
    • Arizona
      • Gilbert, Arizona, United States, 85234
      • Scottsdale, Arizona, United States, 85258
        • Recruiting
        • HonorHealth (VGPCC Cancer Transplant Institute)
        • Contact:
        • Principal Investigator:
          • Abraham Kanate, MD
      • Tucson, Arizona, United States, 85724-5024
        • Recruiting
        • The University of Arizona Cancer Center
        • Contact:
        • Principal Investigator:
          • Sharad Khurana, MD, MSc
    • California
      • Irvine, California, United States, 92697
        • Recruiting
        • University of California
        • Contact:
        • Contact:
          • Phone Number: 714-509-2950
        • Principal Investigator:
          • Deepa Jeyakumar, MD
      • Los Angeles, California, United States, 90095
        • Recruiting
        • UCLA
    • Florida
      • Gainesville, Florida, United States, 32608
        • Recruiting
        • UF-Health Cancer Center Gainesville
        • Contact:
          • Christina Cline, RN, BSN, CCRC
          • Phone Number: 352-273-6840
          • Email: clcline@ufl.edu
        • Contact:
        • Principal Investigator:
          • Zeina Al-Mansour, MD
      • Jacksonville, Florida, United States, 32207
        • Recruiting
        • Baptist MD Anderson
        • Contact:
        • Principal Investigator:
          • William Hammond, MD
      • Jacksonville, Florida, United States, 32209
        • Recruiting
        • UF-Health Jacksonville
        • Contact:
        • Principal Investigator:
          • Walter Quan, MD
      • Orlando, Florida, United States, 32804
        • Recruiting
        • AdventHealth Medical Group Blood and Marrow Transplant at Orlando
        • Contact:
        • Principal Investigator:
          • Rashang Patel, MD
    • Georgia
      • Augusta, Georgia, United States, 30912
        • Recruiting
        • Georgia Cancer Center at Augusta University
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Recruiting
        • Rush University
        • Contact:
        • Principal Investigator:
          • Melissa Larson, MD
      • Decatur, Illinois, United States, 62526
        • Recruiting
        • Decatur Memorial Hospital-Cancer Care Specialists of Central IL
        • Principal Investigator:
          • James Wade, MD
        • Contact:
      • Hines, Illinois, United States, 60153
        • Recruiting
        • Loyola University Medical Center
        • Contact:
        • Principal Investigator:
          • Stephanie Tsai, MD
    • Indiana
    • Kansas
      • Westwood, Kansas, United States, 66205
        • Recruiting
        • The University of Kansas Cancer Center
        • Contact:
        • Principal Investigator:
          • Ken Byrd, MD
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • Recruiting
        • University of KY- Markey Cancer Center
        • Contact:
        • Principal Investigator:
          • Gerhard Hildebrandt, MD
      • Louisville, Kentucky, United States, 40241
        • Suspended
        • Norton Cancer Institute
    • Louisiana
      • Jefferson, Louisiana, United States, 70121
        • Active, not recruiting
        • Ochsner Benson Cancer Center
      • New Orleans, Louisiana, United States, 70118
        • Recruiting
        • Tulane University
        • Contact:
        • Principal Investigator:
          • Hana Safah, MD
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Recruiting
        • Henry Ford Cancer Institute
        • Principal Investigator:
          • Philip Kuriakose, MD
        • Contact:
        • Contact:
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • Recruiting
        • The University of Mississippi Medical Center
        • Contact:
        • Principal Investigator:
          • Stephanie Elkins, MD
    • New York
      • Valhalla, New York, United States, 10595
        • Recruiting
        • New York Medical College
        • Contact:
    • North Carolina
      • Charlotte, North Carolina, United States, 28204
        • Recruiting
        • Novant Health Cancer Institute - Elizabeth (Hematology)
        • Contact:
      • Greenville, North Carolina, United States, 27834
        • Recruiting
        • East Carolina University
      • Kinston, North Carolina, United States, 28501
        • Recruiting
        • Vidant Oncology
        • Contact:
        • Principal Investigator:
          • Misbah Qadir
      • Winston-Salem, North Carolina, United States, 27157
        • Recruiting
        • Wake Forest Baptist Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Timothy Pardee, MD
      • Winston-Salem, North Carolina, United States, 27103
        • Recruiting
        • Novant Health Cancer Institute - Forsyth (Hematology)
        • Contact:
        • Principal Investigator:
          • James Dugan, MD
    • Ohio
      • Canton, Ohio, United States, 44718
        • Recruiting
        • Gabrail Cancer Center
      • Cincinnati, Ohio, United States, 45267
        • Recruiting
        • University of Cincinnati Cancer Center
        • Contact:
        • Principal Investigator:
          • Emily Curran, MD
      • Cleveland, Ohio, United States, 44106
        • Recruiting
        • Seidman Cancer Center, University Hospitals, Cleveland Medical Center
        • Contact:
    • South Carolina
      • Greenville, South Carolina, United States, 29605
        • Recruiting
        • Prisma Health Cancer Institute
        • Principal Investigator:
          • Elizabeth Cull, MD
        • Contact:
    • South Dakota
      • Sioux Falls, South Dakota, United States, 57105
        • Recruiting
        • Avera Medical Group
        • Contact:
        • Principal Investigator:
          • Roberto Ferro, MD
    • Texas
      • Dallas, Texas, United States, 75390
        • Recruiting
        • UT Southwestern
        • Contact:
        • Principal Investigator:
          • Prapti Patel, MD
      • Houston, Texas, United States, 77030
        • Recruiting
        • Baylor College of Medicine
        • Contact:
        • Contact:
          • Phone Number: 713-798-9048
        • Principal Investigator:
          • Gustavo A Rivero, MD
      • Houston, Texas, United States, 77030
    • Vermont
      • Burlington, Vermont, United States, 05401
        • Recruiting
        • University of Vermont Medical Center
        • Contact:
        • Principal Investigator:
          • Diego Adrianzen-Herrera, MD
    • Virginia
      • Charlottesville, Virginia, United States, 22903
        • Recruiting
        • University of Virginia Health System
        • Principal Investigator:
          • Michael Keng, MD
        • Contact:
    • Washington
      • Spokane, Washington, United States, 99218
        • Recruiting
        • MultiCare Institute for Research and Innovation
        • Principal Investigator:
          • Brett Gourley, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: Fludarabine
Fludarabine
Drug: Mitoxantrone
Mitoxantrone
Drug: Decitabine
Decitabine
Drug: Azacitidine
Azacitidine
Drug: Venetoclax
Venetoclax
Drug: Cytarabine
cytosine arabinoside (ara-C)
Drug: Etoposide
Etoposide
Drug: Idarubicin
Idarubicin
Drug: Cladribine
Cladribine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
3 years
Duration of complete remission
Time Frame: 3 years
Number of days from time of initial CR until disease recurrence or death
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
3 years
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 years
Overall survival
Time Frame: 3 years
Number of days from date of first dose to date of death
3 years
Transition rate to hematopoietic stem cell transplantation (HSCT)
Time Frame: 3 years
Number of subjects who transition to HSCT
3 years
Overall response rate (ORR)
Time Frame: 3 years
The rate of CR + CRi + CRp + PR
3 years
Duration overall response
Time Frame: 3 years
The duration of CR + CRi + CRp + PR
3 years
Rate of disease related co-morbidities
Time Frame: 3 years
Number and severity of expected leukemia-related adverse events
3 years
Adverse events
Time Frame: 3 years
Number of patients with adverse events
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Delta-Fly Pharma, Inc.

Investigators

  • Principal Investigator: Tapan Kadia, MD, M.D. Anderson Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 22, 2019

Primary Completion (Anticipated)

December 1, 2022

Study Completion (Anticipated)

December 1, 2022

Study Registration Dates

First Submitted

April 11, 2019

First Submitted That Met QC Criteria

April 23, 2019

First Posted (Actual)

April 24, 2019

Study Record Updates

Last Update Posted (Actual)

October 20, 2022

Last Update Submitted That Met QC Criteria

October 18, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D18-11141

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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