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

Sponsor
Delta-Fly Pharma, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03926624
Collaborator
(none)
450
39
2
36.3
11.5
0.3

Study Details

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.

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
Anticipated Enrollment :
450 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
randomized, controlledrandomized, 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 :
Nov 22, 2019
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 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 [3 years]

    The rate of CR based on International Working Group (IWG) Guidelines for bone marrow and blood response

  2. Duration of complete remission [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 [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 [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 [3 years]

    Number of days from date of first dose to date of death

  4. Transition rate to hematopoietic stem cell transplantation (HSCT) [3 years]

    Number of subjects who transition to HSCT

  5. Overall response rate (ORR) [3 years]

    The rate of CR + CRi + CRp + PR

  6. Duration overall response [3 years]

    The duration of CR + CRi + CRp + PR

  7. Rate of disease related co-morbidities [3 years]

    Number and severity of expected leukemia-related adverse events

  8. Adverse events [3 years]

    Number of patients with adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

  1. Aged ≥ 18 years.

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

  3. 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).

  4. 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.

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

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

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

  8. 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):

  6. Less than 3 months since HSCT

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

  8. Chronic GvHD >Grade 1

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

  10. A pregnant or lactating woman.

  11. 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.

  12. Patient has acute promyelocytic leukemia (APL).

  13. 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.

  14. Documented or known clinically significant bleeding disorder.

Contacts and Locations

Locations

Site City State Country Postal Code
1 O'Neal Comprehensive Cancer Center Birmingham Alabama United States 35294
2 Banner MD Anderson Gilbert Arizona United States 85234
3 HonorHealth (VGPCC Cancer Transplant Institute) Scottsdale Arizona United States 85258
4 The University of Arizona Cancer Center Tucson Arizona United States 85724-5024
5 University of California Irvine California United States 92697
6 UCLA Los Angeles California United States 90095
7 UF-Health Cancer Center Gainesville Gainesville Florida United States 32608
8 Baptist MD Anderson Jacksonville Florida United States 32207
9 UF-Health Jacksonville Jacksonville Florida United States 32209
10 AdventHealth Medical Group Blood and Marrow Transplant at Orlando Orlando Florida United States 32804
11 Georgia Cancer Center at Augusta University Augusta Georgia United States 30912
12 Rush University Chicago Illinois United States 60612
13 Decatur Memorial Hospital-Cancer Care Specialists of Central IL Decatur Illinois United States 62526
14 Loyola University Medical Center Hines Illinois United States 60153
15 Franciscan Health Indianapolis Indianapolis Indiana United States 46237
16 The University of Kansas Cancer Center Westwood Kansas United States 66205
17 University of KY- Markey Cancer Center Lexington Kentucky United States 40536
18 Norton Cancer Institute Louisville Kentucky United States 40241
19 Ochsner Benson Cancer Center Jefferson Louisiana United States 70121
20 Tulane University New Orleans Louisiana United States 70118
21 Henry Ford Cancer Institute Detroit Michigan United States 48202
22 The University of Mississippi Medical Center Jackson Mississippi United States 39216
23 New York Medical College Valhalla New York United States 10595
24 Novant Health Cancer Institute - Elizabeth (Hematology) Charlotte North Carolina United States 28204
25 East Carolina University Greenville North Carolina United States 27834
26 Vidant Oncology Kinston North Carolina United States 28501
27 Novant Health Cancer Institute - Forsyth (Hematology) Winston-Salem North Carolina United States 27103
28 Wake Forest Baptist Comprehensive Cancer Center Winston-Salem North Carolina United States 27157
29 Gabrail Cancer Center Canton Ohio United States 44718
30 University of Cincinnati Cancer Center Cincinnati Ohio United States 45267
31 Seidman Cancer Center, University Hospitals, Cleveland Medical Center Cleveland Ohio United States 44106
32 Prisma Health Cancer Institute Greenville South Carolina United States 29605
33 Avera Medical Group Sioux Falls South Dakota United States 57105
34 UT Southwestern Dallas Texas United States 75390
35 Baylor College of Medicine Houston Texas United States 77030
36 MD Anderson Cancer Center Houston Texas United States 77030
37 University of Vermont Medical Center Burlington Vermont United States 05401
38 University of Virginia Health System Charlottesville Virginia United States 22903
39 Multicare Institute for Research and Innovation Spokane Washington United States 99218

Sponsors and Collaborators

  • Delta-Fly Pharma, Inc.

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Delta-Fly Pharma, Inc.
ClinicalTrials.gov Identifier:
NCT03926624
Other Study ID Numbers:
  • D18-11141
First Posted:
Apr 24, 2019
Last Update Posted:
Dec 28, 2021
Last Verified:
Dec 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
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:

Study Results

No Results Posted as of Dec 28, 2021