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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Fludarabine
* Drug: Busulfan
* Procedure: Total Body Irradiation (TBI)
* Drug: Cyclophosphamide
* Drug: Granulocyte Colony-Stimulating Factor
* Drug: Tacrolimus
* Drug: Cellcept


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose de-escalation: Enrollment will begin at 30 mg/m2 to analyze any grade 4-5 organ toxicities as defined in Section 12.2. If the trial is stopped due to excessive toxicities, then dose de-escalation to 20 mg/m2 will occur for the next cohort of participants. For each participant, the observation period is from start of treatment through post-transplant day +30. Adverse effects will be continuously monitored as patients are enrolled. The trial will be stopped when the toxicity rate exceeds 20% with a posterior probability of 80% and a margin of no more than 5%. This leads to the following stopping rule: the trial will be stopped if 2 of the first 3 subjects experience grade 4-5 organ toxicity, or 3 out of 6, 4 out 9, 5 out of 12, 6 out of 16, or 7 out 19.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clofarabine 30 mg/m^2<br>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<br>* Clofarabine to be administered pre-stem cell transplant infusion (Day 0) once a day for 5 days total.<br>* Other names: Clolar;Drug: Fludarabine<br>* Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.<br>* Other names: Fludara;Drug: Busulfan<br>* Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.<br>* Other names: Busulfex;Procedure: Total Body Irradiation (TBI)<br>* TBI will be administered at a dose of 200cGys on Day -1 prior to transplant<br>* Other names: TBI;Drug: Cyclophosphamide<br>* Cyclophosphamide will be given once a day for 2 days after the transplant infusion.<br>* Other names: Cytoxan;Drug: Granulocyte Colony-Stimulating Factor<br>* G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated<br>* Other names: Filgrastim G-CSF;Drug: Tacrolimus<br>* Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated<br>* Other names: Prograf;Drug: Cellcept<br>* Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated<br>* Other names: Mycophenolate Mofetil (MMF);|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clofarabine, Haploidentical stem cell transplantation, matched and mismatched unrelated donors, Non-remission AML