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IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia

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ClinicalTrials.gov Identifier: NCT02508324
Recruitment Status : Recruiting
First Posted : July 24, 2015
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE April 7, 2015
First Posted Date  ICMJE July 24, 2015
Last Update Posted Date January 4, 2019
Actual Study Start Date  ICMJE September 10, 2015
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
Safety of cellular immunotherapy [ Time Frame: 6 months ]
evaluate the safety of adoptive immunotherapy with Non-Inherited Maternal Antigen (NIMA) compatible, Inherited Paternal Antigen (IPA) targeted CBU or with haplo-identical stem cells after conventional induction therapy for very high risk AML or MDS.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02508324 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
  • Incidence of Graft Versus Host Disease (GVHD) <10% [ Time Frame: 6 months ]
    To assess the incidence and severity of Graft Versus Host Disease (GVHD), after conventional induction therapy followed by adoptive immunotherapy with NIMA compatible, IPA targeted CBU.
  • Detection of graft chimerism after infusion [ Time Frame: 6 months ]
    To study kinetics of graft chimerism (including umbilical cord blood-microchimerism) after each of these treatments
  • Detection of HLA-antibodies after after infusion <10% [ Time Frame: 6 months ]
    To study development of HLA-antibodies after each of these treatments
  • The response rate of leukemia [ Time Frame: 6 months ]
    To assess response rates and duration of response after each of these treatments
Original Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2015)
  • Incidence of Graft Versus Host Disease (GVHD) <10% [ Time Frame: 6 months ]
    To assess the incidence and severity of Graft Versus Host Disease (GVHD), after conventional induction therapy followed by adoptive immunotherapy with NIMA compatible, IPA targeted CBU.
  • Detection of graft chimerism after infusion [ Time Frame: 6 months ]
    To study kinetics of graft chimerism (including UCBM-microchimerism) after each of these treatments
  • Detection of HLA-antibodies after after infusion <10% [ Time Frame: 6 months ]
    To study development of HLA-antibodies after each of these treatments
  • The response rate of leukemia [ Time Frame: 6 months ]
    To assess response rates and duration of response after each of these treatments
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia
Official Title  ICMJE Parallel Phase II Trial of IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia
Brief Summary

The purpose of this study is to determine the overall safety of adoptive immunotherapy when given after chemotherapy for AML/MDS. Adoptive immunotherapy means using an infusion of cells from a donor to help fight cancer. The donor cells will be either from the umbilical cord blood (UCB) of a newborn baby or they will be cells collected from a relative (haplo-identical cells).

The 2 cohorts that were discussed - adoptive immunotherapy with either UCB or haplo-identical stem cells - will be analyzed separately.

Preliminary data from other centers has suggested that adoptive immunotherapy with cells from a relative is an effective approach that may improve remission rates and survival in AML and MDS, because they exert anti-cancer effects of their own (so called graft vs leukemia effects) and possibly because they hasten recovery of cell counts from chemotherapy. The Investigators are interested in confirming these data, but also in testing umbilical cord blood cells for the same purpose. Preliminary data indicate that umbilical cord blood cells may have more powerful graft vs leukemia effects and cause fewer side-effects.

Detailed Description

This is a phase 2 trial to evaluate the safety of adoptive immunotherapy with Non-Inherited Maternal Antigen (NIMA) compatible, Inherited Paternal Antigen (IPA) targeted CBU or with haplo-identical stem cells after conventional induction therapy for very high risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

The study has 2 cohorts - patients in cohort 1 will receive CBU cells as adoptive immunotherapy. Patients in cohort 2 will receive haplo-identical cells. Both cohorts will be evaluated separately and no formal statistical comparison between cohorts will be performed.

There will be approximately 20 patients in each cohort, and a 95% confidence interval for the proportion of patients experiencing grade III-IV GVHD complications or unexplained prolonged myelosuppression complications in each cohort can be constructed to be within +/- 13.1% of the observed complication proportions. This calculation assumes an expected prevalence of each of these complication proportions of no greater than 10%.

After 10 patients are enrolled in each group, the incidence of the above-defined life-threatening complications will be assessed. If more than one patient out of 10 enrolled patients (i.e., greater than 10%) in a cohort experiences either of these complications, the cohort will be stopped for safety.

All potential recipients will have complete HLA typing and determination of HLA antibodies. An appropriate umbilical cord blood unit (CBU) will be identified or in the absence of an appropriate CBU, a haplo-identical donor will be identified.

Treatment will be as per the treating physician's choice..

The umbilical cord graft or haplo-graft will be administered between 24 - 72 hours after the completion of the chemotherapy regimen.

The Graft Selection Algorithm is as follows:

  1. CBU Unit 5/6 Matched - 1 NIMA match with patient
  2. CBU Unit 5/6 Matched - Shared IPA target(s) with patient
  3. Haplo-identical relative
  4. CBU Unit 4/6 Matched - 1-2 NIMA matches with patient
  5. CBU Unit 4/6 Matched - Shared IPA target(s) with patient

Within 42 days of transplant, the recipient's pre-treatment evaluation includes: medical history and physical examinations, Eastern Cooperative Group Oncology Group (ECOG) score, complete blood count (CBC), HLA antibodies, and cytomegalovirus (CMV) antibody testing.

Patients will continue with the therapy specified in this protocol until one of the following occurs:

  • Achievement of protocol endpoint complete remission (CR) or CR with incomplete platelet recovery (CRp) after induction and cellular therapy;
  • Failure to achieve CR or CRp; or,
  • Extraordinary Medical Circumstances: If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no longer wishes to continue protocol therapy, remove the patient from protocol treatment. In this event.

After removal from protocol therapy, patients will continue to be followed for survival and disease status. Samples for correlative studies will continue to be collected every two months until one year after cell infusion.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • Biological: haplo-identical cells (donor)
    Treatment: Haplo-identical healthy related donor. i.e. Parent, child, sibling, possibly third degree or further removed relative (cousin, aunt, nephew etc). They will be collected using standard methods and approximately 3 x10^6 CD34 cells/kg will be infused within 72 hours after completion of the treatment.
  • Biological: umbilical cord blood unit (CBU)
    Treatment: The CBU unit must supply a minimum of 0.5 x107/kg and a maximum of 2.5x107/kg nucleated cell dose pre-cryopreservation. The unit must match at a minimum of 4 of 6 at HLA-A, -B antigens, -DRB1 alleles with the recipient. Mismatches (0-2) can be at any loci -. Although molecular level typing will be available for the patient and the CBU unit, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1. The CBU donor will also have undergone HLA typing of the mother, thus allowing determination of the CBU-IPA and NIMA. CBU grafts used in this study will be investigational units that meet all criteria for clinical use. Better matching units will be preferred over less matching units as long as the CBU dose exceeds 0.5 x107 nucleated blood cells/kg
Study Arms  ICMJE Intervention

All potential recipients will have complete (HLA) typing and determination of HLA antibodies. An appropriate umbilical cord blood unit (CBU) will be identified or in the absence of an appropriate CBU, a haplo-identical cells (donor) will be identified.

Within 72 hours after completion of the chemotherapy regimen, and no sooner than 24 hours after administration of the last dose of chemotherapy, umbilical cord graft or haplo-graft will be administered.

Interventions:
  • Biological: haplo-identical cells (donor)
  • Biological: umbilical cord blood unit (CBU)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 22, 2015)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients must be 18 years of age or older
  2. Patients with a confirmed diagnosis of AML or MDS, according to World Health Organization (WHO) classification (excluding acute promyelocytic leukaemia) with recurrent or refractory disease as defined below.

    1. For AML:

      1. Primary induction failure (PIF) after ≥ 2 cycles of chemotherapy.
      2. First relapse.
      3. Relapse refractory to salvage chemotherapy
      4. Second or subsequent relapse.
    2. For MDS, either refractory anemia with excess blasts (RAEB) I or RAEB II who failed at least one chemotherapy regimen including either cytarabine or a hypomethylating agent.
  3. Patients must have Karnofsky Performance score of ≥70
  4. Women of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to treatment start
  5. Patients must be capable of understanding and complying with protocol requirements, and must be able and willing to sign a written informed consent form

Exclusion Criteria:

  1. Persistent clinically significant toxicities from previous chemotherapy
  2. Known positive status for human immunodeficiency virus (HIV)
  3. Pregnant and nursing patients
  4. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements
  5. Impairment of hepatic or renal function to such an extent that the patient, in the opinion of the investigator, will be exposed to an excessive risk if entered into this clinical study
  6. Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure. Any New York Heart Association (NYHA) grade 3 or 4.
  7. Any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: June Greenberg 212-746-2651 jdg2002@med.cornell.edu
Contact: Koen van Besien, MD (212) 746-2048 kov9001@med.cornell.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02508324
Other Study ID Numbers  ICMJE 1403014939
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Koen van Besien, MD Weill Medical College of Cornell University
PRS Account Weill Medical College of Cornell University
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP