Clofarabine Pre-conditioning Followed by Stem Cell Transplant for Non-remission AML
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Clofarabine; Fludarabine; Busulfan; Total Body Irradiation (TBI); Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Tacrolimus; Cellcept
Intervention description: Clofarabine to be administered pre-stem cell transplant infusion ("Day 0") once a day for 5 days total.; Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.; Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.; TBI will be administered at a dose of 200cGys on Day -1 prior to transplant; Cyclophosphamide will be given once a day for 2 days after the transplant infusion.; G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated; Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated; Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Busulfan; Fludarabine; Clofarabine; Tacrolimus; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Intervention 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)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Clofarabine; Haploidentical stem cell transplantation; matched and mismatched unrelated donors; Non-remission AML

Summary:

      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.
    

Eligibility criteria:

        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.