Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia.

NCT01041508 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: T2008-005IND 101588
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 6

Brief Summary

Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include 1) patients with pre-existing health issues and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem cell transplant; and 3) leukemia patients with advanced disease who have been heavily pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with total body irradiation that can achieve durable donor engraftment without causing excessive toxicity.

Conditions

Leukemia Lymphoblastic, Acute; Acute Myeloid Leukemia; Neoplasm Recurrent

Keywords

ALL; AML; Recurrence; Relapsed; Stem Cell Transplant; Non-myeloablative

Outcome Measures

Primary Outcomes (1)

• Maximum Feasible Dose of Clofarabine

  The primary objective of the study is to determine the maximum feasible dose (MFD) of Clofarabine that can be given in combination with 2Gy total body irradiation as a non-myeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients with relapsed leukemia. The MFD is defined as the highest clofarabine dose associated with both an acceptably low toxicity and low non-engraftment (NE) rate. NE is defined as \< 5% donor T cells at any time point during serial monitoring. Monitoring during the evaluation period is required Day +30, +60 and +100.

  Day +100

Secondary Outcomes (3)

• Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD)

  Days +30, 60, 100, 180

• Transplant Related Mortality (TRM) at Day +100

  Day 100

• Days to Platelet Recovery

  Days +30, 60, 100, 180

Study Arms (2)

Related Donor Arm

EXPERIMENTAL

Patients with related stem cell donors. Patients will receive Clofarabine in combination with 2Gy total body irradiation (TBI) as a preparative regimen for stem cell transplantation, in turn followed by cyclosporine and Mycophenolate Mofetil as GVHD prophylaxis.

Drug: Clofarabine; Radiation: Total Body Irradiation; Other: Stem Cell Transplantation; Drug: Cyclosporine; Drug: Mycophenolate Mofetil

Unrelated Donor Arm

EXPERIMENTAL

Patients with unrelated stem cell donors. Patients will receive Clofarabine in combination with 2Gy total body irradiation (TBI) as a preparative regimen for stem cell transplantation, in turn followed by cyclosporine and Mycophenolate Mofetil as GVHD prophylaxis.

Drug: Clofarabine; Radiation: Total Body Irradiation; Other: Stem Cell Transplantation; Drug: Cyclosporine; Drug: Mycophenolate Mofetil

Interventions

Clofarabine DRUG

Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry (30, 40 or 52 mg/m2).

Also known as: Clolar, Evoltra

Related Donor Arm; Unrelated Donor Arm

Total Body Irradiation RADIATION

Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day "0" according to institutional guidelines.

Also known as: TBI

Related Donor Arm; Unrelated Donor Arm

Stem Cell Transplantation OTHER

Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.

Also known as: SCT

Related Donor Arm; Unrelated Donor Arm

Cyclosporine DRUG

Cyclosporine is given IV based on body weight at: * Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs). * Age \> 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs) Cyclosporine should be started on day -1 after completion of Clofarabine. Levels should be maintained between 300-400 ng/ml.

Also known as: Gengraf, Neoral, Sandimmune

Related Donor Arm; Unrelated Donor Arm

Mycophenolate Mofetil DRUG

MMF will be at 15 mg/kg, based on adjusted body weight, q 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant. Oral doses will be rounded to the nearest 250 mg (capsules are 250 mg). MMF is also available in oral suspension form. MMF will be given until day +40 post transplant and then tapered by 10% per week to be discontinued by day +90.

Also known as: MMF

Related Donor Arm; Unrelated Donor Arm

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Since this is a Phase 1 study, any patient who is a candidate for a non-myeloablative SCT because he/she cannot tolerate the standard myeloablative preparative therapy is eligible for this trial. Briefly, the following groups of patients will be targeted and are eligible for this trial:
• Patients with presence of organ system dysfunction or severe systemic infections that significantly increase the risk of TRM with standard myeloablative regimens.
• History of previous myeloablative allogeneic or autologous transplantation.
• Heavily pre-treated leukemia patients, eg. Patients in CR after failure of ≥2 prior regimens.(eg. ALL CR ≥ 3).
• Combination of toxicities or co-morbidities that leads the investigator to feel that the child is at high risk (\>50%) of TRM with standard ablative regimens.
• The eligibility criteria listed below are interpreted literally and cannot be waived.
• Age: Patients must be \>1 and \< 21 years of age at the of study entry.
• Diagnosis
• Patients must have a diagnosis of ALL or AML.
• ALL patients must be in clinical remission defined as BM morphology \<5% blasts and CNS 1 status.
• AML patients must be in M1 (\<5% blasts) or M2 (\<20% blasts) marrow status with CNS 1 status.
• Patient must have an ANC \> 750/ul.
• Donor Selection: Patient must have one of the appropriate donor types as described below:
• HLA identical sibling donor.
• Complete matched unrelated donor, (matched at A, B, C, DR B1 and DQ, B1 at the allelic level based on high resolution typing for Class I and II antigens, 10/10 match).

You may not qualify if:

• Patients will be excluded if they meet any of the following criteria:
• Infection
• Patients will be excluded if they have evidence of an active, progressive invasive infection. All patients with existing infections at the time study entry should be discussed with the study chair.
• Patients may have stable invasive infections and still be eligible.
• Patients with infections that are responsive to medical or surgical treatment as shown by radiographic and or microbial assessment may still be eligible.
• Patients will be excluded if they have an active, uncontrolled systemic fungal, bacterial, viral or other infection. All patients with existing infections at the time of study entry should be discussed with the study chair.
• An active uncontrolled infection is defined as exhibiting ongoing signs and symptoms related to the infection (fevers, positive blood cultures, chills, tachycardia, etc) despite appropriate antibiotics or other treatment.
• Patient has a diagnosis of CML or MDS.
• Patient has CNS 2 or CNS 3 status.
• Patient is HIV positive.
• Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry.
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney (including dialysis patients), liver, or other organ system that may place the patient at undue risk to undergo treatment.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results.

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (6)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Nationwide Childrens Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt Children's Hospital

Nashville, Tennessee, 37232, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Publications (1)

• Soni S, Abdel-Azim H, McManus M, Nemecek E, Sposto R, Woolfrey A, Frangoul H. Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study. Biol Blood Marrow Transplant. 2017 Jul;23(7):1134-1141. doi: 10.1016/j.bbmt.2017.03.037. Epub 2017 Apr 7.

  PMID: 28396162 RESULT

Related Links

• Therapeutic Advances in Childhood Leukemia \& Lymphoma Consortium web site

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Recurrence

Interventions

Clofarabine; Whole-Body Irradiation; Stem Cell Transplantation; Cyclosporine; Cyclosporins; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Radiotherapy; Therapeutics; Investigative Techniques; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Results Point of Contact

• Title: Peggy Romano, BA, CCRP
• Organization: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) / Children's Hospital Los Angeles

promano@chla.usc.edu

323-361-5505

Study Officials

• Sandeep Soni, MD

  Nationwide Childrens Hospital

  STUDY CHAIR

• Haydar Frangoul, MD

  Vanderbilt University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 29, 2009
• First Posted: December 31, 2009
• Study Start: January 29, 2010
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: February 1, 2024
• Results First Posted: February 1, 2024

Record last verified: 2023-05

Locations

US (6)