Haploidentical Stem Cell Transplantation for Children With Therapy Resistant Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jacek Toporski, Lund University Hospital
ClinicalTrials.gov Identifier:
NCT01025778
First received: December 3, 2009
Last updated: March 30, 2015
Last verified: March 2015
  Purpose

Despite substantial progress in the treatment pediatric acute leukemia a significant number of children will experience primary or secondary resistance to the treatment. In other words it will be not possible to achieve remission using standard chemotherapy (primary resistance) or the patients will develop chemotherapy resistant relapse (secondary resistance). Children failing to achieve remission or children relapsing after previous allogeneic stem cell transplantation have short life expectancy and palliative treatment still remains the most reasonable option as the escalation of conventional chemotherapy is not longer effective.

The role of Graft versus Leukemia effect was postulated as one of the mechanisms contributing to the leukemia control/eradication after transplantation of hematopoietic stem cells.

In this study the investigators combine intensified multiagent Clofarabine containing chemotherapy with post-induction treatment intensification using reduced intensity conditioning followed by haploidentical hematopoietic stem cell transplantation. Introducing a new drug to the treatment of resistant leukemia the investigators want to achieve a response which allows us to proceed to immediate haploidentical transplantation. Using a haploidentical donor the investigators can avoid time consuming search for an unrelated donor and perform the transplantation at the optimal time-point. Combating therapy resistant leukemia the investigators would like to evoke and utilize potential Graft-versus-Leukemia effect which is much more pronounced in the haploidentical setting, as it is well documented that allogeneic transplantation with a matched donor is not effective in resistant disease. The use of best KIR mismatch donor and post-transplant donor lymphocyte infusion will be implemented in order to develop/intensify graft versus leukemia effect.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Drug: Clofarabine for remission induction
Drug: Etoposide for remission induction
Drug: Cyclophosphamide for remission induction
Drug: Clofarabine in conditioning before transplantation
Drug: Thiotepa in conditioning before transplantation
Drug: Melfalan in conditioning before transplantation
Procedure: Haploidentical transplantation of T-cell depleted graft
Procedure: Donor lymphocyte infusion
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Clofarabine Based Remission Induction Followed by Haploidentical Stem Cell Transplantation in Children With Refractory Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Lund University Hospital:

Primary Outcome Measures:
  • Event free survival [ Time Frame: 1 year from transplantation ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluation of induction efficacy by response rate and the number of children proceeding to transplant [ Time Frame: 3 months from induction start ] [ Designated as safety issue: No ]
  • Tolerance, safety and quality of life [ Time Frame: 1 year from transplantation ] [ Designated as safety issue: Yes ]
  • Hematological and immunological recovery [ Time Frame: 100 days fron tranplantation ] [ Designated as safety issue: Yes ]
  • Incidence of graft versus host disease [ Time Frame: 100 days from transplantation ] [ Designated as safety issue: Yes ]

Enrollment: 7
Study Start Date: December 2009
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Remission induction and haplo-SCT
Remission induction with Clofaranie, Etoposide and Cyclophosphamide combination followed by haplidentical stem cella transplantation if remission achieved.
Drug: Clofarabine for remission induction Drug: Etoposide for remission induction Drug: Cyclophosphamide for remission induction Drug: Clofarabine in conditioning before transplantation Drug: Thiotepa in conditioning before transplantation Drug: Melfalan in conditioning before transplantation Procedure: Haploidentical transplantation of T-cell depleted graft Procedure: Donor lymphocyte infusion

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Target population

  1. Refractory acute lymphoblastic leukemia

    • Chemoresistant isolated or combined bone marrow relapse

      • Relapse after during/after conventional treatment
      • Relapse ≥6 months after allogeneic stem cell transplantation
    • Primary induction failure
    • Isolated extramedullary relapse after previous HSCT (>6 months)
  2. Refractory acute myeloblastic leukemia including sAML

    • Chemoresistant relapse

      • Relapse after during/after conventional treatment
      • Relapse ≥6 months after allogeneic stem cell transplantation
    • Primary induction failure

Inclusion criteria to start induction treatment with multidrug regimen

  1. Age ≥ 1 and ≤21 years
  2. Patients with previous HCST ≥ 6 m
  3. Provide signed written informed consent patients', and patients' parents /guardians

    • Older children should be capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent as well.
  4. Cardiac output SF ≥25%
  5. Have adequate renal and hepatic functions as indicated by the following laboratory values:

    • Calculated creatinine clearance ≥90 ml/min/1.73 m2
    • Serum bilirubin ≤1.5 X upper limit of normal (ULN)
    • Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 X ULN
    • Alkaline phosphatase ≤ 2.5 X ULN
  6. Performance score of ≥70% (Lansky or Karnofsky)
  7. A suitable haploidentical family member available for stem cell donation, > 18 years of age, fulfilling institutional criteria for blood and marrow donation.
  8. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Inclusion criteria to proceed to transplant after induction

  1. Cardiac output SF ≥25%
  2. Have adequate renal and hepatic functions as indicated by the following laboratory values:

    • Calculated creatinine clearance ≥90 ml/min/1.73 m2
    • Serum bilirubin ≤1.5 X upper limit of normal (ULN)
    • Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 X ULN
    • Alkaline phosphatase ≤ 2.5 X ULN
  3. Performance score of ≥70% (Lansky or Karnofsky)
  4. A suitable haploidentical family member available for stem cell donation, > 18 years of age, fulfilling institutional criteria for blood and marrow donation.
  5. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
  6. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.
  7. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

  1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
  2. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea.

    The patient must have recovered from all acute toxicities from any previous therapy.

  3. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
  4. 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).
  5. Pregnant or lactating patients.
  6. Any significant concurrent malignant disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01025778

Locations
Sweden
Lund University Hospital
Lund, Sweden, SE-22185
Sponsors and Collaborators
Lund University Hospital
Investigators
Principal Investigator: Jacek Toporski, MD, PhD Lund University Hospital
  More Information

Publications:
Responsible Party: Jacek Toporski, MD, PhD, Head, Section of Pediatric Oncology/Hematology, Lund University Hospital
ClinicalTrials.gov Identifier: NCT01025778     History of Changes
Other Study ID Numbers: BUS2009/1
Study First Received: December 3, 2009
Last Updated: March 30, 2015
Health Authority: Sweden: Regional Ethical Review Board

Keywords provided by Lund University Hospital:
Haploidentical hematopoietic stem cell transplantation
Graft versus host disease
Donor lymphocyte infusion
Graft versus leukemia effect
Immunological recovery
Bridge to transplant approach
Therapy resistant leukemia
Hematological malignancy

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Leukemia, Myeloid
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Clofarabine
Cyclophosphamide
Alkylating Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on August 02, 2015