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Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03922724
Recruitment Status : Recruiting
First Posted : April 22, 2019
Last Update Posted : October 21, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE April 19, 2019
First Posted Date  ICMJE April 22, 2019
Last Update Posted Date October 21, 2019
Actual Study Start Date  ICMJE April 18, 2019
Estimated Primary Completion Date May 27, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
Progression-free survival (PFS) of HCT recipients on the RIC arm [ Time Frame: 1 year post transplant ]
Number of patients who are alive and with PFS at one year, assessed by Kaplan-Meier with 80% and 95% twosided confidence intervals
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03922724 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
  • Incidence of Acute Graft versus-host disease [ Time Frame: 1 year post transplant ]
    Cumulative incidence of acute graft versus host disease at 1 year post transplant
  • Incidence of Chronic Graft versus-host disease [ Time Frame: 1 and 2 years post transplant ]
    Cumulative incidence of chronic graft versus host disease at 1 and 2 years post transplant.
  • primary graft failure [ Time Frame: 60 days post transplant ]
    Cumulative incidence of secondary graft failure at 60 days post transplant.
  • secondary graft failure [ Time Frame: 1 year post transplant ]
    Cumulative incidence of secondary graft failure at 1 year post transplant.
  • lymphoma relapse [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to disease relapse
  • transplant-related mortality [ Time Frame: 180 days and 1 year post transplant ]
    Time from transplant to transplant-related death
  • kinetics and durability of engraftment [ Time Frame: days +28, +42, +60, +100, +180, and 1 year post transplant ]
    The percentage of donor T-, B-, NK-, and myeloid cell populations
  • kinetics and durability of lineage-specific donor chimerism [ Time Frame: days +21, +28, +35, +42, and + 60 post transplant ]
    Association between early chimerism data and primary or secondary graft failure
  • disease-free survival [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to death of any cause or disease relapse.
  • event-free survival [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to death of any cause or other event, including disease relapse, graft failure
  • overall survival [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to death of any cause
  • incidence of EBV, CMV, JCV, BKV, adenovirus, and HHV6 [ Time Frame: day +100 post transplant ]
    cumulative incidence of EBV, CMV, JCV, BKV, adenovirus, and HHV6 in blood
  • GVHD-free graft failure-free survival (GGFS) [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to primary or secondary graft failure and death due to grade 3-4 acute GVHD not responsive to seven days of high dose steroids
  • GVHD-free relapse-free survival (GRFS) [ Time Frame: 1, 3, and 5 years post transplant ]
    Time from transplant to death from any cause of other event
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma
Official Title  ICMJE Phase II Trial of Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma
Brief Summary

Background:

Lymphoma is a type of blood cancer. Blood cell transplant can cure some people with lymphoma. Researchers want to see if they can limit the complications transplant can cause.

Objective:

To test if a stem cell transplant can cure or control lymphoma. Also to test if new ways of getting a recipient ready for a transplant may result in fewer problems and side effects.

Eligibility:

Recipients: People ages 12 and older with peripheral T cell lymphoma that does not respond to standard treatments

Donors: Healthy people ages 18 and older whose relative has lymphoma

Design:

Participants will be screened with:

Physical exam

Blood and urine tests

Bone marrow biopsy: A needle inserted into the participant s hip bone will remove marrow.

Donors will also be screened with:

X-rays

Recipients will also be screened with:

Lying in scanners that take pictures of the body

Tumor sample

Donors may donate blood. They will take daily shots for 5 7 days. They will have apheresis: A machine will take blood from one arm and take out their stem cells. The blood will be returned into the other arm.

Recipients will be hospitalized at least 2 weeks before transplant. They will get a catheter: A plastic tube will be inserted into a vein in the neck or upper chest. They will get antibody therapy or chemotherapy.

Recipients will get the transplant through their catheter.

Recipients will stay in the hospital several weeks after transplant. They will get blood transfusions. They will take drugs including chemotherapy for about 2 months.

Recipients will have visits 6, 12, 18, 24 months after transplant, then once a year for 5 years.

Detailed Description

Background:

  • Mature neoplasms of T and/or natural killer cells, collectively called peripheral T-cell lymphomas (PTCL), are often poorly responsive to chemotherapy and therefore associated with significant morbidity and mortality.
  • Allogeneic hematopoietic cell transplantation (HCT) has the potential to cure PTCL but the optimal approach to HCT for these diseases requires ongoing investigation

Objectives:

  • For subjects on the reduced-intensity conditioning (RIC arm), to estimate the progression free survival
  • For subjects on the immunosuppression-only conditioning (IOC) arm, because they are high risk patients, to preliminarily estimate the proportion who are progression free at one year.

Eligibility:

  • Patients age greater than or equal to 12 years
  • PTCL that is relapsed or refractory to prior therapy and/or PTCL of a risk score where upfront allo HCT in first remission is reasonable (PIT score of intermediate-low risk or higher or supported by clinical practice guidelines1)
  • At least one potentially suitable 7-8/8 HLA-matched related or unrelated donor (at HLA A, B, C, and DR), or an HLA-haploidentical related donor
  • Adequate end-organ function
  • Not pregnant or breastfeeding

Design:

  • There will be two arms that vary in conditioning intensity an immunosuppression-only conditioning (IOC) arm for high-risk subjects and a reduced-intensity conditioning (RIC) arm for those deemed not high-risk and able to tolerate RIC.
  • IOC arm: equine anti-thymocyte globulin (e-ATG) 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m2/day IV on days -9 and -5, low-dose cyclophosphamide (5 mg/kg) orally daily on days -9 through -2
  • RIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m2/day IV on days -11 and -7, low-dose cyclophosphamide (5 mg/kg) orally daily on days -11 through - 4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.

    --Subjects will be assigned to the IOC arm if there is significant end-organ dysfunction present and it is felt that a conditioning regimen that includes busulfan would likely be associated with intolerable or life-threatening toxicities for the patient. Patients will also be assigned to the IOC arm if they possess a DNA repair defect, telomere maintenance defect, or familial cancer predisposition syndrome that necessitates limiting chemotherapy as much as possible to prevent future cancer risk.

  • Peripheral blood stem cells are the preferred graft source, although bone marrow is permitted
  • GVHD prophylaxis: High-dose, post-transplantation cyclophosphamide (PTCy) on days +3 and +4 (50 mg/kg/day on RIC arm and 25 mg/kg/day on IOC arm), sirolimus on days +5 through +60, and mycophenolate mofetil (MMF) on days +5 through +25.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Peripheral T-cell Lymphomas
  • Lymphoproliferative Disorders
  • Immune System Diseases
Intervention  ICMJE
  • Drug: IOC

    e-ATG40 mg/kg/day IV on days -14 and -13. Pentostatin 4 mg/m2

    /day IV on days -9 and -5. Cyclophosphamide 5 mg/kg orally daily on days -9 through -2

  • Drug: GVHD prophylaxis
    High-dose, posttransplantation cyclophosphamide (PTCy) on days +3 and +4 (50 mg/kg /day on RIC arm and 25 mg/kg/day on IOC arm), sirolimus on days +5 through +60, and mycophenolate mofetil (MMF) on days +5 through +25.
  • Drug: RIC
    e-ATG 40 mg/kg/day IV on days -14 and -13. Pentostatin 4 mg /m2/day IV on days -11 and -7. Cyclophosphamide 5 mg/kg orally daily on days -11 through -4. Busulfan IV, pharmacokinetically dosed, on days -3 and -2.
  • Procedure: allo HCT
    Stem cell transplant
Study Arms  ICMJE
  • Experimental: 1/RIC Arm
    Reduced Intensity Conditioning Arm, plus allogeneic HCT with GVHD prophylaxis
    Interventions:
    • Drug: GVHD prophylaxis
    • Drug: RIC
    • Procedure: allo HCT
  • Experimental: 2/IOC Arm
    Immunosuppression Only Conditioning, plus allogeneic HCT with GVHD prophylaxis
    Interventions:
    • Drug: IOC
    • Drug: GVHD prophylaxis
    • Procedure: allo HCT
  • No Intervention: 3/Donor Arm
    Donors for Recipients in Arm 1 or Arm 2
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: April 19, 2019)
165
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2024
Estimated Primary Completion Date May 27, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 2.1.1 INCLUSION CRITERIA-RECIPIENT:

2.1.1.1 Age greater than or equal to 12 years

2.1.1.2 Diagnosis of PTCL, confirmed by NCI pathology review, that is relapsed or refractory to prior therapy, and/or PTCL where upfront allo HCT in first remission is reasonable (PIT score of intermediate-low risk or higher or supported by clinical practice guidelines1)

--ALK-positive ALCL patients will only be eligible if relapsed or refractory

2.1.1.3 At least one potential 7-8/8 HLA-matched related (excluding an identical twin) or unrelated donor (at HLA-A, -B, -C, and DR), or an HLA-haploidentical related donor, based on initial low resolution unrelated donor search and/or at least one iologicallyrelated family member who has at least a 25% chance of being at minimum an HLAhaploidentical match and is potentially suitable to donate based on reported family history. HLA typing of potential donors and/or mutation testing does not need to be completed for eligibility.

2.1.1.4 Adequate end-organ function, as measured by:

  • For RIC: Left ventricular ejection fraction (LVEF) greater than or equal to 40% by 2D echocardiogram (ECHO) or MUGA, left ventricular shortening fraction greater than or equal to 20% by ECHO, or LVEF greater than or equal to 30% if the patient has radiologic evidence of aortic, renal, or coronary artery vasculitis. For IOC: LVEF greater than or equal to 30% by 2D ECHO or MUGA.
  • Pulmonary function tests: DLco (corrected for hemoglobin) and FEV1 greater than or equal to 40% of predicted for the RIC arm, and greater than or equal to 30% predicted for the IOC arm; or in pediatric patients, if unable to perform pulmonary function tests, there should be no evidence of dyspnea at rest, no requirement for supplemental oxygen, and oxygen saturation >92% on room air. Calculations will be based on the USA-ITS-NIH reference.
  • Bilirubin less than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or hemolysis) for patients receiving RIC and bilirubin less than or equal to 5.0 mg/dL for patients receiving IOC (unless due to Gilbert s syndrome or hemolysis); ALT and AST less than or equal to 10 x ULN for patients receiving RIC or IOC. Patients who are above these bilirubin, ALT, or AST thresholds may be eligible for the RIC or IOC arm if evaluated by a hepatologist who deems the liver function test abnormalities to be potentially disease related, either because of direct involvement by PTCL, due to an associated process such as hemophagocytic lymphohistiocytosis, or as sequelae of prior chemotherapy that is thought to improve with time.
  • Estimated creatinine clearance of greater than or equal to 50 mL/min/1.73 m2, calculated using eGFR in the clinical lab for adults and the Schwartz formula for pediatrics.

2.1.1.5 Adequate central venous access potential

2.1.1.6 Karnofsky (adults) or Lansky (children) performance status of greater than or equal to 50% or ECOG performance status of 2 or less for the RIC arm and Karnofsky (adults) or Lansky (children) greater than or equal to 30% or ECOG performance status of 3 or less for the IOC arm

2.1.1.7 Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document

2.1.1.8 Not pregnant or breastfeeding.

2.1.1.9 As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-allo HCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately.

2.1.2 EXCLUSION CRITERIA-RECIPIENT:

2.1.2.1 Patients who are receiving any other investigational agents, with the exception of virus specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HCT.

2.1.2.2 History of allergic reactions to horses or attributed to compounds of similar chemical or biologic composition to agents (e-ATG, steroids, cyclophosphamide, busulfan, pentostatin, sirolimus, MMF, G-CSF) used in the study

2.1.2.3 Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol or which does not allow for appropriate informed consent

2.1.3 INCLUSION CRITERIA-RELATED DONOR:

2.1.3.1 Age greater than or equal to 18 and weight of greater than or equal to 15 kg

2.1.3.2 Karnofsky performance status of 90-100% (adults)

2.1.3.3 Related donors with at least a haplotype at HLA-A, B, C, and DR loci that is shared with the recipient by high resolution typing, excluding an identical twin, or unrelated donors matched 7-8/8 at HLA-A, B, C, and DR loci by high resolution typing

2.1.3.4 Ability of subject or guardian to understand and the willingness to sign a written informed consent document; medically fit and willing to donate

2.1.3.5 Related donors: No history of opportunistic infections, autoimmunity, hemoglobinopathy, red cell enzymopathy, or malignancy, apart from non-melanomatous skin cancer or healed cervical cancer in situ.

2.1.3.6 HIV negative, hepatitis B virus surface antigen negative, and hepatitis C virus antibody negative.

2.1.3.7 Related donors undergoing bone marrow harvest should be deemed fit for the operative procedure and related donors undergoing apheresis should be deemed fit for the collection procedure.

2.1.3.8 Related donors will undergo the Donor Health History Screen by skilled staff in the Blood Services Section for adult donors to determine donor eligibility using standard DTM criteria.

2.1.4 EXCLUSION CRITERIA-RELATED DONOR:

2.1.4.1 Donors must not be pregnant. Donors of childbearing potential must use an effective method of contraception, including one or more of the following: intrauterine device, hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner s vasectomy, barrier methods (condom, diaphragm, or cervical cap), or abstinence from the day of signing consent through day +60 of the recipient s allo-HCT.

2.1.4.2 History of a psychiatric disorder which in the opinion of the PI may compromise compliance with the transplant protocol, or which does not allow for appropriate informed consent.

2.1.4.3 Other medical constraints that in the opinion of the PI constitute exclusion. Donors will be asked in the consent to refrain from certain activities prior to and during participation (e.g. foreign travel, tattoos); however, these do not automatically exclude the donor and will be reviewed by the PI.

2.1.5 INCLUSION CRITERIA (UNRELATED DONOR):

2.1.5.1 Unrelated donors will be evaluated in accordance with existing NMDP Standard Policies and Procedures, available at: http://bethematch.org/About-Us/Global-transplantnetwork/ Standards/, except for the additional requirement of EBV serostatus testing for clinical purposes of donor selection. Note that participation in this study is offered to all unrelated donors but not required for clinical donation, so it is possible that not all unrelated donors will enroll on this study. Unrelated donors only enroll if they contribute research specimens, which is optional

2.1.6 EXCLUSION CRITERIA (UNRELATED DONOR):

2.1.6.1 Unrelated donors: failure to qualify as a National Marrow Donor Program (NMDP) donor per current NMDP Standards, available at: http://bethematch.org/About-Us/Globaltransplant- network/Standards/. Exceptions to donor eligibility (e.g. foreign travel, tattoos) do not automatically exclude the donor and will be reviewed by the PI.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 99 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Stephanie N Hicks (Cotton) (301) 435-9679 cottonsn@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03922724
Other Study ID Numbers  ICMJE 190085
19-C-0085
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jennifer A Kanakry, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date October 17, 2019

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