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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03926624
Other study ID # D18-11141
Secondary ID
Status Recruiting
Phase Phase 3
First received
Last updated
Start date November 22, 2019
Est. completion date December 2022

Study information

Verified date October 2022
Source Delta-Fly Pharma, Inc.
Contact Tapan Kadia, MD
Phone 713-792-7026
Email tkadia@mdanderson.org
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 450
Est. completion date December 2022
Est. primary completion date December 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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 Design


Related Conditions & MeSH terms


Intervention

Drug:
DFP-10917
DFP-10917 Powder for Injection. Active ingredient: 4-amino-1-(2-cyano-deoxy-ß-D-arabinofuranosyl)-2(1H)-pyrimidinone monohydrochloride
Cytarabine
cytosine arabinoside (ara-C)
Azacitidine
Azacitidine
Decitabine
Decitabine
Mitoxantrone
Mitoxantrone
Etoposide
Etoposide
Fludarabine
Fludarabine
Idarubicin
Idarubicin
Venetoclax
Venetoclax
Cladribine
Cladribine

Locations

Country Name City State
United States Georgia Cancer Center at Augusta University Augusta Georgia
United States O'Neal Comprehensive Cancer Center Birmingham Alabama
United States University of Vermont Medical Center Burlington Vermont
United States Gabrail Cancer Center Canton Ohio
United States Novant Health Cancer Institute - Elizabeth (Hematology) Charlotte North Carolina
United States University of Virginia Health System Charlottesville Virginia
United States Rush University Chicago Illinois
United States University of Cincinnati Cancer Center Cincinnati Ohio
United States Seidman Cancer Center, University Hospitals, Cleveland Medical Center Cleveland Ohio
United States UT Southwestern Dallas Texas
United States Decatur Memorial Hospital-Cancer Care Specialists of Central IL Decatur Illinois
United States Henry Ford Cancer Institute Detroit Michigan
United States UF-Health Cancer Center Gainesville Gainesville Florida
United States Banner MD Anderson Gilbert Arizona
United States East Carolina University Greenville North Carolina
United States Prisma Health Cancer Institute Greenville South Carolina
United States Loyola University Medical Center Hines Illinois
United States Baylor College of Medicine Houston Texas
United States MD Anderson Cancer Center Houston Texas
United States Franciscan Health Indianapolis Indianapolis Indiana
United States University of California Irvine California
United States The University of Mississippi Medical Center Jackson Mississippi
United States Baptist MD Anderson Jacksonville Florida
United States UF-Health Jacksonville Jacksonville Florida
United States Ochsner Benson Cancer Center Jefferson Louisiana
United States Vidant Oncology Kinston North Carolina
United States University of KY- Markey Cancer Center Lexington Kentucky
United States UCLA Los Angeles California
United States Norton Cancer Institute Louisville Kentucky
United States Tulane University New Orleans Louisiana
United States AdventHealth Medical Group Blood and Marrow Transplant at Orlando Orlando Florida
United States HonorHealth (VGPCC Cancer Transplant Institute) Scottsdale Arizona
United States Avera Medical Group Sioux Falls South Dakota
United States Multicare Institute for Research and Innovation Spokane Washington
United States The University of Arizona Cancer Center Tucson Arizona
United States New York Medical College Valhalla New York
United States The University of Kansas Cancer Center Westwood Kansas
United States Novant Health Cancer Institute - Forsyth (Hematology) Winston-Salem North Carolina
United States Wake Forest Baptist Comprehensive Cancer Center Winston-Salem North Carolina

Sponsors (1)

Lead Sponsor Collaborator
Delta-Fly Pharma, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Complete remission (CR) rate The rate of CR based on International Working Group (IWG) Guidelines for bone marrow and blood response 3 years
Primary Duration of complete remission Number of days from time of initial CR until disease recurrence or death 3 years
Secondary The rate of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L 3 years
Secondary The duration of complete remission (CR) + (complete remission with incomplete hematologic recovery) CRi+ (complete remission with partial hematologic recovery) CRp CR as above including neutrophil granulocyte count > 0.5x10^9/L & platelet count > 50x10^9/L + platelet count < 100x10^9/L 3 years
Secondary Overall survival Number of days from date of first dose to date of death 3 years
Secondary Transition rate to hematopoietic stem cell transplantation (HSCT) Number of subjects who transition to HSCT 3 years
Secondary Overall response rate (ORR) The rate of CR + CRi + CRp + PR 3 years
Secondary Duration overall response The duration of CR + CRi + CRp + PR 3 years
Secondary Rate of disease related co-morbidities Number and severity of expected leukemia-related adverse events 3 years
Secondary Adverse events Number of patients with adverse events 3 years
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