A Pediatric Study of a Plerixafor Containing Regimen In Second Allogeneic Stem Cell Transplantation
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Purpose
Patients with refractory hematologic malignancies, including those who develop recurrent disease after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. Novel therapeutic agents that target molecular signaling mechanisms and increase the sensitivity of leukemic cells to apoptosis may clearly play a role in this setting.
This study hypothesizes that interrupting the SDF-1/CXCR4 axis using the selective CXCR4 antagonist plerixafor may be useful as a leukemic stem cell mobilizing agent for patients who are refractory to standard dose chemotherapy and in relapse after an allogeneic transplant. This hypothesis is based on the dependence of leukemia cells on MSCs for survival signals as described above and on the preclinical data that suggest increased efficacy by antileukemia agents when leukemia cells are separated from MSCs.
In the present trial, the study proposes to add plerixafor to enhance the conditioning regimen cytotoxicity. At this time the goal is to determine the maximum tolerated dose (MTD) of plerixafor through the process of dose limiting toxicity (DLT) evaluation. Pharmacokinetic studies will be conducted. Additional studies will quantify and the content of leukemia cells and key regulatory and effector T cell populations in the bone marrow and blood before and after exposure to this medication.
If the observed outcomes of this trial are promising, it could serve as a platform on which to study further use of plerixafor as a complimentary agent with conditioning as well as other chemotherapeutic regimens for patients with relapsed or refractory hematologic malignancies.
| Condition | Intervention | Phase |
|---|---|---|
|
Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Chronic Myeloid Leukemia Myelodysplastic Syndrome Non-Hodgkin's Lymphoma |
Drug: Plerixafor |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase I Pediatric Study of a Plerixafor Containing Regimen In Second Allogeneic Stem Cell Transplantation |
- To determine the dose-limiting toxicity and maximum tolerated dose of plerixafor in combination with fludarabine, thiotepa and melphalan as a conditioning regimen for patients undergoing a second allogeneic transplant procedure. [ Time Frame: 7 days post transplant ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 18 |
| Study Start Date: | May 2010 |
| Estimated Study Completion Date: | October 2013 |
| Estimated Primary Completion Date: | October 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Second Allogeneic Transplant Procedure Recipient
Participants with Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Myeloid Leukemia (CML); Juvenile Myelomonocytic Leukemia (JMML); Non-Hodgkin lymphoma (NHL) with evidence of bone marrow disease, receiving a second allogeneic transplant procedure. Intervention: Plerixafor |
Drug: Plerixafor
Plerixafor in combination with fludarabine, thiotepa and melphalan as a conditioning regimen for patients undergoing a second allogeneic transplant procedure (bone marrow or peripheral blood). A traditional 3+3 phase I design will be employed during this study, where dose escalations are planned in groups of 3 participants. No intra-participant escalation will be allowed and dose escalation will not be considered until toxicity information is available from at least 3 evaluable participants at the current dose level.Plerixafor will be given intravenously (IV) rather than subcutaneously (SQ) to minimize discomfort associated with repeated daily injections (up to 3) to the pediatric population of this study.
Other Names:
|
Detailed Description:
This study will determine the following objectives:
- To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of plerixafor in combination with fludarabine, thiotepa, and melphalan as a conditioning regimen for children and young adults undergoing a second allogeneic stem cell transplant (SCT) procedure.
The study determines the secondary objectives:
- To describe the pharmacokinetic properties of plerixafor in this study population
- To evaluate the content of leukemia cells in bone marrow and in blood before and after exposure to plerixafor
- To evaluate key regulatory and effector T cell populations in bone marrow and in blood before and after exposure to plerixafor
- To estimate the cumulative incidence of relapse and overall survival in study participants at one year after this second transplant procedure
Eligibility| Ages Eligible for Study: | up to 21 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age less than or equal to 21 years old.
- One of the following hematologic malignancies that has relapsed after prior allogeneic hematopoietic stem cell transplantation:
- Acute lymphoblastic leukemia (ALL)
- Acute myeloid leukemia (AML)
- Myelodysplastic syndrome (MDS)
- Chronic myeloid leukemia (CML)
- Juvenile myelomonocytic leukemia (JMML)
- Non-Hodgkin's lymphoma (NHL) with evidence of bone marrow disease
- Has a suitable human leukocyte antigen (HLA) matched family member or unrelated donor available for stem cell donation. A "matched" donor is defined as matching at 5/6 or 6/6 HLA loci.
- Does not have active central nervous system (CNS) malignancy (history of CNS disease allowed).
- No prior neuromuscular dysfunction or all prior grade I-IV neuromuscular dysfunctions have subsided > 4 weeks prior to enrollment.
- Cardiac shortening fraction greater than or equal to 25%.
- Creatinine clearance greater than or equal to 50 ml/min/1.73 m2
- Forced vital capacity (FVC) greater than or equal to 40% of predicted value or pulse oximetry greater than or equal to 92% on room air.
- Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50 .
- Off all treatment for acute or chronic graft-versus-host disease (GVHD) for at least 7 days prior to the initiation of conditioning.
- Bilirubin less than or equal to 3 times the upper limit of normal for age.
- Alanine aminotransferase (ALT) less than or equal to 3.0 times the upper limit of normal for age.
- White blood cell count of less than 50,000/mm3
- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.
- Not lactating.
- All patients of childbearing potential must agree to use an effective birth control method
Exclusion Criteria:
- Pregnant and lactating females are excluded from participation as the short and long-term effects of the preparative agents and infusion on a fetus and a nursing child through breast milk are not entirely known at this time.
Contacts and Locations| United States, Tennessee | |
| St. Jude Children's Research Hospital | |
| Memphis, Tennessee, United States, 38105 | |
| Principal Investigator: | Ashok Srinivasan, MD | St. Jude Children's Research Hospital |
More Information
Additional Information:
No publications provided
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT01068301 History of Changes |
| Other Study ID Numbers: | MOZBMT |
| Study First Received: | February 11, 2010 |
| Last Updated: | December 4, 2012 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by St. Jude Children's Research Hospital:
|
Allogeneic Stem Cell transplantation Plerixafor Acute Lymphoblastic leukemia Acute Myeloid leukemia |
Chronic Myeloid leukemia Myelodysplastic Syndrome Non-Hodgkin's Lymphoma Other Leukemia |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myeloid, Acute Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Lymphoma Lymphoma, Non-Hodgkin Myelodysplastic Syndromes Preleukemia Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases |
Immunoproliferative Disorders Immune System Diseases Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Precancerous Conditions JM 3100 Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions |
ClinicalTrials.gov processed this record on May 23, 2013