Clofarabine Pre-conditioning Followed by Stem Cell Transplant for Non-remission AML

Clofarabine Pre-conditioning Followed by Hematopoietic Stem Cell Transplant With Post-Transplant Cyclophosphamide for Non-remission Acute Myeloid Leukemia

The Investigators would like to study the incidence of complete remission (CR) at day +30 after Clofarabine followed by haploidentical transplant. The conditioning regimen used is Fludarabine, Busulfan (2 doses) or cyclophosphamide (2 doses) and Total Body Irradiation (TBI) with post transplant cyclophosphamide for patients with Acute Myeloid Leukemia (AML) who are not in remission prior to considering allogeneic transplant with haploidentical donors.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Clofarabine; Drug: Fludarabine; Drug: Busulfan; Procedure: Total Body Irradiation (TBI); Drug: Cyclophosphamide; Drug: Granulocyte Colony-Stimulating Factor; Drug: Tacrolimus; Drug: Cellcept

Detailed Description

Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have a Human Leukocyte Antigen (HLA)-matched donor identified by the time of two induction failures.

Salvage chemotherapy with clofarabine appears to be another promising option in relapsed and refractory AML. Clofarabine is a second-generation purine nucleoside analog with substantial single-agent activity in adult patients with AML. It is an effective immunosuppressive agent and several trials have shown the feasibility of conditioning with clofarabine-based regimen.

In the past, a conditioning regimen of clofarabine with busulfan (4 doses) has been successfully used prior to allogeneic stem cell transplantation for non-remission AML with day +30 complete remission rates were 90-100%. However, these patients were transplanted with HLA matched donors. This study will examine those patients undergoing transplantation from haploidentical related donor or matched and mismatched unrelated donors.

Achieving a long-term remission is clearly the goal of AML treatment. The investigators would like to propose a protocol for non-remission AML and expand the patient population to older than 55 years of age as well as those who relapsed after initial allogeneic transplant to improve enrolling patients in the near future. The investigators have many patients achieving remission but for those without remission, clofarabine preconditioning may be a reliable protocol to bring these patients into the early complete remission.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnostic criteria of AML, induction failure without having achieved remission after at least 2 attempts at induction chemotherapy, or relapsed after any complete remission (CR).
2. 18 to 75 years of age.
3. Planned or scheduled to receive an allogeneic HSCT from haploidentical related donors, matched and mismatched unrelated donors.

4. All organ function testing should be done within 28 days of study registration.

   • Performance status: Karnofsky ≥ 70% (Appendix A).
   • Cardiac: LVEF ≥ 50% by MUGA or echocardiogram.
   • Pulmonary: FEV1 and FVC ≥ 50% predicted, DLCO (corrected for hemoglobin) ≥ 50% of predicted.
   • Renal: Creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2
   • Hepatic: Serum bilirubin ≤1.5 x upper limit of normal (ULN); (AST)/(ALT) ≤ 2.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN.
5. Both men and women need to use an approved method of birth control and/or abstinence due to unknown risks to the fetus.

Exclusion Criteria:

1. Acute promyelocytic leukemia (APL)
2. Known history of non-compliance with medication regimens, scheduled clinic visits, or self-care.
3. In the opinion of the investigator, no appropriate caregivers identified.
4. HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive
5. Active Hepatitis B and Hepatitis C orepatitis positive serology including HBsAg, hepatitis B core antibody, and hepatitis C antibody. Hepatitis B surface antibody positive due to vaccination or natural immunity are permitted.
6. In the opinion of the physician investigator, uncontrolled medical or psychiatric disorders.
7. Uncontrolled infections requiring treatment within 14 days of registration.
8. Active central nervous system (CNS) leukemia.
9. Cord blood transplant excluded.
10. Prior allogeneic HSCT within last 6 months.
11. Patients with >= grade 2 acute GVHD.
12. Patients with >=moderate chronic GVHD.
13. Pregnant or Breastfeeding. Women of child bearing potential (WCBP) are required to have a negative serum or urine pregnancy test prior to initiation of conditioning regimen.
14. Haploidentical related donors who are positive for DSA ≥ 5000 MFI by solid phase microarray method (Luminex).
15. Any patient with steroid dose more than 10 mg/day within a week of registration .
16. Autoimmune disorder requiring any active immunosuppression therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Clofarabine 30 mg/m^2; Day -14 through Day -10 Clofarabine 30 mg/m^2, Day - 9 Day of rest, Day - 8 Day of rest, Day - 7 Day of rest, Day - 6 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV (Regimen A, Fludarabine 24 mg/m^2 IV and Cyclophosphamide 14.5 mg/kg IV for Regimen B), Day - 5 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV (Regimen A, Fludarabine 24 mg/m^2 IV and Cyclophosphamide 14.5 mg/kg IV for Regimen B), Day - 4 Fludarabine 40 mg/m^2 IV(Regimen A, Fludarabine 24 mg/m^2 IV for Regimen B), Day - 3 Fludarabine 40 mg/m^2 IV(Regimen A, Fludarabine 24 mg/m^2 IV for Regimen B), Day - 2 Day of Rest, Day -1 Total Body Irradiation 200 cGys, Day 0 stem cell transplant infusion, Day +1 Day of rest, Day +2 Day of rest, Day +3 Cyclophosphamide 50 mg/kg IV, Day +4 Cyclophosphamide 50 mg/kg IV, Day +5 Start G-CSF, Tacrolimus, and MMF.

Drug: Clofarabine; Clofarabine to be administered pre-stem cell transplant infusion ("Day 0") once a day for 5 days total.; Other Names: Clolar; Drug: Fludarabine; Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.; Other Names: Fludara; Drug: Busulfan; Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.; Other Names: Busulfex; Procedure: Total Body Irradiation (TBI); TBI will be administered at a dose of 200cGys on Day -1 prior to transplant; Other Names: TBI; Drug: Cyclophosphamide; Cyclophosphamide will be given once a day for 2 days after the transplant infusion.; Other Names: Cytoxan; Drug: Granulocyte Colony-Stimulating Factor; G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated; Other Names: Filgrastim G-CSF; Drug: Tacrolimus; Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated; Other Names: Prograf; Drug: Cellcept; Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated; Other Names: Mycophenolate Mofetil (MMF)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR) Rate at Day 30 Post HSCT	The CR rate at 30 days (Day +30) post stem cell transplant infusion	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Chronic GVHD	The highest overall grade (1-4) of chronic GvHD experienced by participants as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria	1 year
Non-relapse Related Mortality	Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100)	100 days
Neutrophil Engraftment	Rates of engraftment, defined as the first day of Absolute Neutrophil Count (ANC) greater than 500 for the first of three consecutive days	1 year
Rate of Acute Graft-versus-host Disease (GVHD)	The rate of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 using the Glucksberg criteria.	100 days
Severity of Acute Graft-versus-host Disease (GVHD)	The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 using the Glucksberg criteria	100 days
Rate of Chronic GVHD	The rate of any grade (1-4) of Chronic GvHD as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria.	1 year

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Investigators: Principal Investigator: Seema Naik, MD, Penn State Cancer Institute

Publications and helpful links

Helpful Links

• Penn State Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2020
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): November 7, 2022

Study Registration Dates

• First Submitted: June 24, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (Actual): June 28, 2019

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Clofarabine; Haploidentical stem cell transplantation; matched and mismatched unrelated donors; Non-remission AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Clofarabine; Lenograstim; Fludarabine; Tacrolimus; Mycophenolic Acid; Busulfan
• Other Study ID Numbers: 18-011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: At this time there is no plan to share IPD with other researchers outside of Penn State University

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No