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Myeloablative Unrelated Donor Cord Blood Transplantation With T-Cell Depleted Haplo-identical Peripheral Blood Stem Cells for Patients With High Risk Hematological Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01682226
First received: September 6, 2012
Last updated: October 23, 2014
Last verified: October 2014
  Purpose

The purpose of this study is to find out whether the addition of blood stem cells from a close family member, when added to two units of umbilical cord blood will make the transplant safer.


Condition Intervention Phase
Leukemia
Myelodysplastic Syndrome
Lymphoma
Device: CliniMACS Fractionation system (Arm A)
Device: CliniMACS Fractionation system (Arm B)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Myeloablative Unrelated Donor Cord Blood Transplantation With T-Cell Depleted Haplo-identical Peripheral Blood Stem Cells for Patients With High Risk Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • number of days to neutrophil recovery [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The day of neutrophil recovery is defined as the first of 3 consecutive days in which the absolute neutrophil count (ANC) is > 0.5. The cumulative incidence of neutrophil recovery will be reported at day 45 post-transplant. Sustained neutrophil engraftment is neutrophil engraftment without secondary graft failure. This will be analyzed at 1 and 2 years post-transplant.


Secondary Outcome Measures:
  • Disease-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: 2 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 78
Study Start Date: September 2012
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: standard risk group
This is a 2 arm phase 2 study to obtain an estimate of the speed of neutrophil recovery after myeloablative CBT with abrogation of prolonged cytopenia by infusion of haploidentical family member T-cell depleted PBSC in patients with high-risk or advanced hematologic malignancies.
Device: CliniMACS Fractionation system (Arm A)

7 days before transplant Admit to hospital. Line insertion 6 days before transplant Fludarabine (chemotherapy) Cyclophosphamide (chemotherapy) 5 days before transplant Fludarabine Thiotepa 4 days before transplant Fludarabine Thiotepa 3 days before transplant Fludarabine Start CSA and MMF 2 days before transplant Fludarabine and TBI (radiation therapy)

1 day before transplant TBI (radiation therapy) Day of transplant Transplant day (infuse cord blood) Day after cord blood transplant Infuse family member stem cells 7 days after transplant Start G-CSF

Experimental: B: high risk group
This is a 2 arm phase 2 study to obtain an estimate of the speed of neutrophil recovery after myeloablative CBT with abrogation of prolonged cytopenia by infusion of haploidentical family member T-cell depleted PBSC in patients with high-risk or advanced hematologic malignancies.
Device: CliniMACS Fractionation system (Arm B)

8 days before transplant Admit to hospital. Line insertion 7 days before transplant Fludarabine 6 days before transplant Fludarabine Cyclophosphamide 5 days before transplant Fludarabine Cyclophosphamide 4 days before transplant Rest 3 days before transplant TBI x 3 Start CSA and MMF 2 days before transplant TBI x 3

1 day before transplant TBI x 3 Day of transplant TBI x 2 then infuse cord blood

1 day after the cord blood transplant Infuse family member stem cells 7 days after transplant Start G-CSF


  Eligibility

Ages Eligible for Study:   2 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Note: protocol eligible patients according to the criteria outlined below will then be divided according to age, diagnosis, performance status, organ function, prior transplantation, hematopoietic cell transplant comorbidity index (HCT-CI)23, and CB TNC dose into those who are at standard risk (Arm A) or high risk (Arm B) for early post-transplant death for the purposes of applying stopping rules and outcome analysis.

Age:

o 2 - 70 years.

Diagnosis of high risk hematological malignancy:

Any acute leukemia in first complete remission (CR) considered at high risk for relapse, or second or third CR, or relapse/refractory less than 25% blasts in bone marrow, or aplasia post-therapy. This includes de novo acute leukemia or acute leukemia that is therapy related or arising from an antecedent hematologic disorder including myelodysplasia (MDS), chronic myeloid leukemia (CML) or other myeloproliferative disorder.

  • Juvenile myelomonocytic leukemia (JMML) in CR, or relapse with less than 25% bone marrow blasts.
  • CML with tyrosine kinase inhibitor failure in chronic or accelerated phase or evolved to acute leukemia.
  • MDS with life-threatening cytopenia(s), and/or red blood cell or platelet transfusion dependence, or patients with aplasia, or patients with excess blasts less than 25% blasts in the bone marrow at work-up.
  • Aggressive lymphoma: patients in CR1 with disease at high risk of relapse or CR2-3 or PR1-3.
  • Indolent lymphoma or chronic lymphocytic leukemia (CLL): any disease status provided any transformed component is in CR.
  • Hodgkin's lymphoma that is primary refractory or relapsed not suitable for other therapy.

Performance status:

  • Karnofsky score > or = to 70 or Lansky score > or = to 70.

    • Organ function:

  • Left ventricular ejection fraction (LVEF) > or = to 50%.
  • Spirometry & corrected DLCO > or = to 50% predicted. In small children use history and physical and CT scan to determine pulmonary status.
  • Total bilirubin < than or = to 1.5 ULN (unless benign congenital elevated bilirubin); ALT/ AST < than or = to 2.5 x upper limit of normal (ULN).
  • Calculated creatinine (calc. creat.) clearance > than or = to 60 ml/min.
  • Albumin > than or = to 3.0.

Graft:

o Cryopreserved dose will be > than or = to 1.5 x 107 TNC/kilogram in each unit for double unit CB grafts. This will be the CB graft for the majority of patients.

In select pediatric patients with access to CB units that have high TNC (> 5.0 x 10^7/kg), good HLA-match (5/6 or 6/6) and are from good quality CB banks a single unit could be considered with a back-up CB unit on standby.

  • In select patients who have a very poor search and only have one suitable CB unit available, this unit could be given as a single unit. This unit must have a TNC > 2.5 x 10^7 TNC/kilogram.
  • Haploidentical donors will be used as outlined in section 6.4. Related donors with up to 8/10 match to the patient can be used Assignment of conditioning intensity (high dose vs reduced intensity) will be based on patient disease status, age, extent of prior therapy, organ function and presence of significant comorbidities as outlined in Section 9.2.

For the purposes of analysis, patients will be assigned to Arms A and B as summarized below according to their risk of early post-transplant death.

Eligible patients who fulfill all of the following criteria will be assigned to risk Arm A:

Age 2-49 years Diagnosis Any acute leukemia in CR1 - CR2 (includes therapy-related and arising from MDS or myeloproliferative disease). JMML in CR. CML with TKI failure & < 5% blasts. MDS with < 5% blasts at work-up. Lymphoma (including CLL) CR1-2.

Performance Status Karnofsky > or = to 80; Lansky > or = to 80 Organ Function LVEF > or = to 60% Spirometry & corrected DLCO > or = to 80% predicted. Total bilirubin normal; ALT/ AST normal-1.4 x ULN. Calc. creat. clearance > or = to 70 ml/min.

Prior HSC Transplant No HCT-CI score23 0-2 Pre-thaw TNC Dose Each unit > or = to 2.0 x 10^7/kg

Eligible patients who meet any of the following criteria will be assigned to risk Arm B:

Age 50-70 years Diagnosis Any acute leukemia in relapse/ refractory disease in BM or circulating blasts or CR3 or aplasia. JMML not in CR. MDS with aplasia or > or = to 5% blasts. Lymphoma (including CLL) with disease other than CR1-2. Severe myelofibrosis of the bone marrow Performance Status Karnofsky 70; Lansky 70 Organ Function LVEF 50-59%. Spirometry & corrected DLCO 50-79% predicted. Total bilirubin 1.1-1.5 normal; ALT/ AST 1.5-2.5 x ULN. Calc. creat. clearance 60-69 ml/min. Prior HSC Transplant Yes HCT-CI score23 3 or higher Pre-thaw TNC Dose Either or both units 1.5-1.9 x 10^7/kg.

Exclusion Criteria:

  • Active CNS leukemia.

    • Any acute leukemia (including prior myelodysplasia or CML blast crisis) with morphologic relapse or persistent disease > 25% blasts in the BM, or doubling of the blasts in the blood in the 2 weeks preceding admission, or need for hydroxyurea in the 2 weeks prior to admission, or uncontrolled extra-medullary disease.
    • Two prior stem cell transplants.
    • One prior stem cell transplant within the preceding 6 months.
    • Prior radiation therapy rendering patient ineligible for TBI.
    • Uncontrolled viral, bacteria or fungal infection at time of study enrollment.
    • Sero-positive or NAT positive for HIV.
    • Females who are pregnant or breast feeding.
    • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests

Cord Blood Grafts:

Units will be selected based on the HLA-match to the patient and individual cell doses of the units according to current MSKCC unit selection criteria. HLA-testing will be done using molecular techniques. The standard cord blood graft for this protocol will consist of 2 units as a double unit graft. Each unit will be at least 4 of 6 HLA-A, -B antigen and -DRB1 allele matched with the recipient. Each unit will have a cryopreserved dose of at least 1.5 x 10^7 TNC/recipient body weight (TNC/kg). In the occasional pediatric patient with a large well matched good quality single unit or the rare patient with only one unit of suitable match and dose characteristics the cord blood graft can consist of a single unit.

Haploidentical Donor Inclusion Criteria:

A HLA-haploidentical related donor will be selected as available, and if possible using an algorithm designed to maximize NK cell alloreactivity with prioritization according to KIR/HLA genotypes.

  • Donor CMV status will also be taken into account.
  • The donor must meet criteria outlined in the FACT-approved SOP for "DONOR EVALUATION AND SELECTION FOR ALLOGENEIC TRANSPLANTATION" in the Blood and Marrow Transplant Program Manual, document E-1 (see attached, or link to URL: http://mskweb5.mskcc.org/intranet/html/80312.cfm.).
  • The donor must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter.
  • The donor must be >25 kg in weight.

Haploidentical Donor Exclusion Criteria:

Evidence of active infection (including active urinary tract infection, or upper respiratory tract infection) or evidence of viral hepatitis exposure on screening unless only HbsAb+ and HBV DNA negative.

  • Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis.
  • Factors which place the donor at increased risk for complications from leukapheresis or G-CSF therapy (e.g., active autoimmune disease, sickle cell trait, symptomatic coronary artery disease requiring therapy).
  • Pregnancy (positive serum or urine β-HCG) or breastfeeding. Women of childbearing age must avoid becoming pregnant while on the study.
  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: NCT01682226

Contacts
Contact: Juliet Barker, M.B.B.S. 212-639-3468
Contact: Katharine Hsu, M.D., Ph.D. 646-888-2667

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Juliet Barker, MBBS    212-639-3468      
Contact: Katharine Hsu, MD, PhD    646-888-2667      
Principal Investigator: Juliet Barker, MBBS         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Juliet Barker, M.B.B.S. Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01682226     History of Changes
Other Study ID Numbers: 12-153
Study First Received: September 6, 2012
Last Updated: October 23, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
CYCLOPHOSPHAMIDE (CYTOXAN)
CYCLOSPORINE
FLUDARABINE
G-CSF
MYCOPHENOLATE MOFETIL (MMF)
Cord Blood Transplantation
CliniMACS
12-153

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Neoplasms
Precancerous Conditions
Cyclophosphamide
Alkylating Agents
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 November 23, 2014