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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04002115
Recruitment Status : Recruiting
First Posted : June 28, 2019
Last Update Posted : October 11, 2021
Sponsor:
Information provided by (Responsible Party):
Seema Naik, MD, Milton S. Hershey Medical Center

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Clofarabine Drug: Fludarabine Drug: Busulfan Procedure: Total Body Irradiation (TBI) Drug: Cyclophosphamide Drug: Granulocyte Colony-Stimulating Factor Drug: Tacrolimus Drug: Cellcept Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
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)
Primary Purpose: Treatment
Official Title: Clofarabine Pre-conditioning Followed by Hematopoietic Stem Cell Transplant With Post-Transplant Cyclophosphamide for Non-remission Acute Myeloid Leukemia
Actual Study Start Date : June 3, 2020
Estimated Primary Completion Date : June 3, 2022
Estimated Study Completion Date : June 3, 2026


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 Name: Clolar

Drug: Fludarabine
Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.
Other Name: Fludara

Drug: Busulfan
Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.
Other Name: Busulfex

Procedure: Total Body Irradiation (TBI)
TBI will be administered at a dose of 200cGys on Day -1 prior to transplant
Other Name: TBI

Drug: Cyclophosphamide
Cyclophosphamide will be given once a day for 2 days after the transplant infusion.
Other Name: Cytoxan

Drug: Granulocyte Colony-Stimulating Factor
G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Filgrastim G-CSF

Drug: Tacrolimus
Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Prograf

Drug: Cellcept
Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Mycophenolate Mofetil (MMF)




Primary Outcome Measures :
  1. Incidence of complete remission (CR) [ Time Frame: 30 days ]
    Determine the incidence of CR at 30 days (Day +30) post stem cell transplant infusion


Secondary Outcome Measures :
  1. Non-relapse related mortality [ Time Frame: 100 days ]
    Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100)

  2. Neutrophil engraftment [ Time Frame: 1 year ]
    Rates of engraftment, defined as the first day of Absolute Neutrophil Count (ANC) greater than 500 for the first of three consecutive days

  3. Incidence of Acute graft-versus-host disease (GVHD) [ Time Frame: 100 days ]
    The incidence of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 using the Glucksberg criteria.

  4. Severity of Acute graft-versus-host disease (GVHD) [ Time Frame: 100 days ]
    The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 using the Glucksberg criteria

  5. Incidence of Chronic GVHD [ Time Frame: 1 year ]
    The incidence of any grade (1-4) of acute GvHD as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria.

  6. Severity of Chronic GVHD [ Time Frame: 1 year ]
    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



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04002115


Contacts
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Contact: Seema Naik, MD 717-531-8678 snaik@pennstatehealth.psu.edu
Contact: Clinical Research Nurse - Leukemia 717-531-5471

Locations
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United States, Pennsylvania
Penn State Cancer Institute Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Seema Naik, MD    717-531-6585    snaik@pennstatehealth.psu.edu   
Sponsors and Collaborators
Milton S. Hershey Medical Center
Investigators
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Principal Investigator: Seema Naik, MD Penn State Cancer Institute
Additional Information:
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Responsible Party: Seema Naik, MD, Associate Professor of the Penn State Cancer Institute, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT04002115    
Other Study ID Numbers: 18-011
First Posted: June 28, 2019    Key Record Dates
Last Update Posted: October 11, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: At this time there is no plan to share IPD with other researchers outside of Penn State University

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seema Naik, MD, Milton S. Hershey Medical Center:
Clofarabine
Haploidentical stem cell transplantation
matched and mismatched unrelated donors
Non-remission AML
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Mycophenolic Acid
Cyclophosphamide
Busulfan
Fludarabine
Clofarabine
Tacrolimus
Lenograstim
Sargramostim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Calcineurin Inhibitors
Enzyme Inhibitors
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents