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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04002115
• Other study ID #: 18-011
• Status: Terminated
• Phase: Phase 2
• Start date: June 3, 2020
• Est. completion date: November 7, 2022

Study information

• Verified date: September 2023
• Source: Milton S. Hershey Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: November 7, 2022
• Est. primary completion date: August 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Clofarabine
Clofarabine to be administered pre-stem cell transplant infusion ("Day 0") once a day for 5 days total.
• Fludarabine
Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.
• Busulfan
Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.

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

Drug:
• Cyclophosphamide
Cyclophosphamide will be given once a day for 2 days after the transplant infusion.
• Granulocyte Colony-Stimulating Factor
G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated
• Tacrolimus
Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated
• Cellcept
Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated

Locations

Country	Name	City	State
United States	Penn State Cancer Institute	Hershey	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Milton S. Hershey Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Non-relapse Related Mortality	Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100)	100 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Penn State Cancer Institute