Clinical trial NCT02433483: Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients
Official title: A Phase II Study of Microtransplantation in Patients With Refractory or Relapsed Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Keywords: Adolescent
Children
Microtransplant
Leukemia
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Cookies for Kids' Cancer
First posted: 2015-05-05
Enrollment: 4
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Allogeneic transplant can sometimes be an effective treatment for leukemia. In a traditional allogeneic transplant, patients receive very high doses of chemotherapy and/or radiation therapy, followed by an infusion of their donor's bone marrow or blood stem cells. The high-dose chemotherapy drugs and radiation are given to remove the leukemia cells in the body. The infusion of the donor's bone marrow or blood stem cells is given to replace the diseased bone marrow destroyed by the chemotherapy and/or radiation therapy. However, there are risks associated with allogeneic transplant. Many people have life-threatening or even fatal complications, like severe infections and a condition called graft-versus-host disease, which is caused when cells from the donor attack the normal tissue of the transplant patient.

Recently, several hospitals around the world have been using a different type of allogeneic transplant called a microtransplant. In this type of transplant, the donor is usually a family member who is not an exact match. In a microtransplant, leukemia patients get lower doses of chemotherapy than are used in traditional allogeneic transplants. The chemotherapy is followed by an infusion of their donor's peripheral blood stem cells. The objective of the microtransplant is to suppress the bone marrow by giving just enough chemotherapy to allow the donor cells to temporarily engraft (implant), but only at very low levels. The hope is that the donor cells will cause the body to mount an immunologic attack against the leukemia, generating a response called the "graft-versus-leukemia" effect or "graft-versus-cancer" effect, without causing the potentially serious complication of graft-versus-host disease.

With this research study, the investigators hope to find out whether or not microtransplantation will be a safe and effective treatment for children, adolescents and young adults with relapsed or refractory hematologic malignancies

Detailed description: PRIMARY OBJECTIVES:

* To assess the safety and feasibility of standard chemotherapy plus GCSF-mobilized Hematopoietic Progenitor Cell, Apheresis (HPC-A) in pediatric patients with relapsed or refractory hematologic malignancies.
* To estimate the response rates to standard chemotherapy plus GCSF-mobilized HPC-A in pediatric patients with relapsed or refractory hematologic malignancies.

SECONDARY OBJECTIVES:

* To describe the event-free and overall survival of patients treated with standard chemotherapy plus GCSF-mobilized HPC-A.
* To estimate the time to neutrophil and platelet recovery after treatment with standard chemotherapy plus GCSF-mobilized HPC-A.
* To determine the cumulative incidence of acute and chronic graft-versus-host disease (GVHD).

OTHER PRESPECIFIED OBJECTIVES:

* To characterize donor chimerism and microchimerism.

Patients will receive standard chemotherapy followed by infusion of donor peripheral blood mononuclear cells 2 days after the completion of chemotherapy. Patients who have at least a partial response are eligible to receive a second cycle.

Diagnostic lumbar puncture and intrathecal (IT) chemotherapy will be given prior to cycle 1. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly IT therapy (age-adjusted methotrexate, hydrocortisone, and cytarabine) until the cerebrospinal fluid (CSF) becomes free of leukemia (minimum of 4 doses).

Bone marrow aspiration (BMA) and biopsy to assess response will be performed on approximately day 29 of therapy.

For hematopoietic stem cell mobilization, donors will receive G-CSF (Filgrastim) (Neupogen®) each day for 5 days given subcutaneously (SQ) prior to HPC-A collected by leukapheresis on day 6.

Eligibility criteria: INCLUSION CRITERIA - AML and MDS PARTICIPANTS

* Participants must have a diagnosis of AML or myelodysplastic syndrome (MDS), ALL, and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after HSCT.

  * Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy.
  * Patients with AML must have ≥ 5% leukemic blasts in the bone marrow or have converted from negative minimal residual disease (MRD) status to positive MRD status in the bone marrow as assessed by flow cytometry. If an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood.
* Participant is ≤ 21 years of age (i.e., has not reached 22nd birthday).
* Adequate organ function defined as the following:

  * Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin is \> ULN, direct bilirubin is ≤ 1.5 mg/dL
  * AST (SGOT)/ALT (SGPT) \< 5 x ULN
  * Calculated creatinine clearance \> 50 ml/min/1.73m\^2 as calculated by the Schwartz formula for estimated glomerular filtration rate \>
  * Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%.
* Has an available HPC-A donor.
* Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are \> 16 years old.
* Does not have an uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable.
* Patient has fully recovered from the acute effects of all prior therapy and must meet the following criteria.

  * At least 14 days must have elapsed since the completion of myelosuppressive therapy.
  * At least 24 hours must have elapsed since the completion of hydroxyurea, low-dose cytarabine (up to 200 mg/m\^2/day), and intrathecal chemotherapy.
  * At least 30 days must have elapsed since the use of investigational agents.
  * For patients who have received prior HSCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HSCT. Patients cannot be receiving therapy, including steroids, for GVHD.
* Post-menarchal female has had negative serum pregnancy test within 7 days prior to enrollment.
* Male or female of reproductive potential has agreed to use effective contraception for the duration of study participation.
* Not breastfeeding

INCLUSION CRITERIA - HPC-A CELL DONOR

* At least 18 years of age.
* Family member (first degree relatives).
* Not pregnant as confirmed by negative serum or urine pregnancy test within 7 days prior to enrollment (if female).
* Not breast feeding.
* Meets donation eligibility requirements as outlined by 21 CFR 1271.

Primary outcomes:
measure: Number of Participants by Stratum Who Complete 2 Cycles of Therapy
timeFrame: At the end of therapy cycle 2 (approximately 2-3 months)
measure: Proportion of Participants Who Experience Therapeutic Success
timeFrame: At the end of therapy cycle 2 (approximately 2-3 months)
Secondary outcomes:
measure: 3-year Event Free Survival (EFS)
timeFrame: 3 years after enrollment of the last participant
measure: 3-year Overall Survival (OS)
timeFrame: 3 years after enrollment of the last participant
measure: Median Time to Neutrophil Recovery
timeFrame: From start of therapy to completion of therapy (approximately 1 year)
measure: Time to Platelet Recovery
timeFrame: From start of therapy to completion of therapy (approximately 1 year)
measure: 1-year Cumulative Incidence of Acute Graft Versus Host Disease (GVHD)
timeFrame: From start of therapy through completion of therapy (approximately 1 year)
measure: 1-year Cumulative Incidence of Chronic Graft Versus Host Disease (GVHD)
timeFrame: From start of therapy through completion of therapy (approximately 1 year)
Other outcomes:
measure: Percent Donor Chimerism
timeFrame: At weeks 1, 2, 3, and 4 after infusion of HPC-A
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Jeffrey E. Rubnitz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: