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

Penn State Health

Status and phase

Terminated

Phase 2

Conditions

Acute Myeloid Leukemia

Treatments

Drug: Fludarabine

Drug: Tacrolimus

Drug: Granulocyte Colony-Stimulating Factor

Drug: Cellcept

Drug: Cyclophosphamide

Drug: Busulfan

Drug: Clofarabine

Procedure: Total Body Irradiation (TBI)

Study type

Interventional

Funder types

Other

Identifiers

NCT04002115

18-011

Details and patient eligibility

About

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.

Full 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.

Enrollment

2 patients

Sex

All

Ages

18 to 55 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

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).
18 to 75 years of age.
Planned or scheduled to receive an allogeneic HSCT from haploidentical related donors, matched and mismatched unrelated donors.
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.
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

Acute promyelocytic leukemia (APL)
Known history of non-compliance with medication regimens, scheduled clinic visits, or self-care.
In the opinion of the investigator, no appropriate caregivers identified.
HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive
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.
In the opinion of the physician investigator, uncontrolled medical or psychiatric disorders.
Uncontrolled infections requiring treatment within 14 days of registration.
Active central nervous system (CNS) leukemia.
Cord blood transplant excluded.
Prior allogeneic HSCT within last 6 months.
Patients with >= grade 2 acute GVHD.
Patients with >=moderate chronic GVHD.
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.
Haploidentical related donors who are positive for DSA ≥ 5000 MFI by solid phase microarray method (Luminex).
Any patient with steroid dose more than 10 mg/day within a week of registration .
Autoimmune disorder requiring any active immunosuppression therapy.

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Sequential Assignment

Masking

None (Open label)

2 participants in 1 patient group

Clofarabine 30 mg/m^2

Experimental group

Description:

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.

Treatment: