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

  • Clinicaltrials.gov identifier

    NCT03926624

  • Recruitment Status

    Recruiting

  • First Posted

    April 24, 2019

  • Last update posted

    June 2, 2021

Study Description

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:Leukemia, Myeloid, Acute
  • Intervention/Treatment: Drug: DFP-10917
    Drug: Cytarabine
    Drug: Azacitidine
    Drug: Decitabine
    Drug: Mitoxantrone
    Drug: Etoposide
    Drug: Fludarabine
    Drug: Idarubicin
    Drug: Venetoclax
    Drug: Cladribine
  • Phase: Phase 3

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 Design

  • Study Type: Interventional
  • 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 2019
  • Estimated Primary Completion Date: December 2022
  • Estimated Study Completion Date: December 2022

Arms and interventions

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

Outcome Measures

  • 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

Eligibility Criteria

  • 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 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.

Contacts and Locations

Contacts

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

Locations

United States, Alabama
O'Neal Comprehensive Cancer Center
Birmingham

United States, Arizona
Banner MD Anderson
Gilbert

United States, Arizona
HonorHealth (VGPCC Cancer Transplant Institute)
Scottsdale

United States, California
University of California
Irvine

United States, California
UCLA
Los Angeles

United States, Florida
UF-Health Cancer Center Gainesville
Gainesville

United States, Florida
Baptist MD Anderson
Jacksonville

United States, Florida
UF-Health Jacksonville
Jacksonville

United States, Florida
AdventHealth Medical Group Blood and Marrow Transplant at Orlando
Orlando

United States, Georgia
Georgia Cancer Center at Augusta University
Augusta

United States, Idaho
St. Luke's Mountain States Tumor Institute
Boise

United States, Illinois
Rush University
Chicago

United States, Illinois
Decatur Memorial Hospital-Cancer Care Specialists of Central IL
Decatur

United States, Illinois
Loyola University Medical Center
Hines

United States, Indiana
Franciscan Health Indianapolis
Indianapolis

United States, Kansas
The University of Kansas Cancer Center
Westwood

United States, Kentucky
Norton Cancer Institute
Louisville

United States, Louisiana
Ochsner Benson Cancer Center
Jefferson

United States, Louisiana
Tulane University
New Orleans

United States, Michigan
Henry Ford Cancer Institute
Detroit

United States, Mississippi
The University of Mississippi Medical Center
Jackson

United States, Missouri
St. Louis University Hospital
Saint Louis

United States, New York
New York Medical College
Valhalla

United States, North Carolina
East Carolina University
Greenville

United States, North Carolina
Vidant Oncology
Kinston

United States, North Carolina
Wake Forest Baptist Comprehensive Cancer Center
Winston-Salem

United States, Ohio
Gabrail Cancer Center
Canton

United States, Ohio
University of Cincinnati Cancer Center
Cincinnati

United States, Ohio
Seidman Cancer Center, University Hospitals, Cleveland Medical Center
Cleveland

United States, South Carolina
Prisma Health Cancer Institute
Greenville

United States, South Dakota
Avera Medical Group
Sioux Falls

United States, Texas
UT Southwestern
Dallas

United States, Texas
Baylor College of Medicine
Houston

United States, Texas
MD Anderson Cancer Center
Houston

United States, Vermont
University of Vermont Medical Center
Burlington

United States, Virginia
University of Virginia Health System
Charlottesville

United States, Washington
Multicare Institute for Research and Innovation
Spokane

Sponsors and Collaborators

Delta-Fly Pharma, Inc.

Investigators

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

More Information

  • Responsible Party: Delta-Fly Pharma, Inc.
  • ClinicalTrials.gov Identifier: NCT03926624 History of Changes
  • Other Study ID Numbers: D18-11141
  • First Posted: April 24, 2019 Key Record Dates
  • Last Update Posted: June 2, 2021
  • Last Verified: June 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: No
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Additional relevant MeSH terms: Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute