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Optimizing PTCy Dose and Timing

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ClinicalTrials.gov Identifier: NCT03983850
Recruitment Status : Recruiting
First Posted : June 12, 2019
Last Update Posted : July 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE June 8, 2019
First Posted Date  ICMJE June 12, 2019
Last Update Posted Date July 15, 2019
Actual Study Start Date  ICMJE July 9, 2019
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2019)
aGVHD protection from PTCy 25 mg/kg [ Time Frame: 60 days ]
The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03983850 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Optimizing PTCy Dose and Timing
Official Title  ICMJE Phase I/II Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide as GVHD Prophylaxis After HLA-Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies
Brief Summary

Background:

Stem cell or bone marrow transplants can cure or control blood cancers. Sometimes the donor cells see the recipient s body as foreign. This can cause complications. A high dose of the drug cyclophosphamide (PTCy) can help reduce these risks. Researchers want to see if a lower dose of PTCy can have the same benefits.

Objective:

To see if a lower dose of PTCy will help people with blood cancers have a more successful transplant and fewer side effects.

Eligibility:

People ages 15-65 with leukemia, lymphoma, or multiple myeloma that is not curable with standard therapy and is at high risk of returning without transplant, and their healthy adult relatives

Design:

Transplant participants will be screened with:

Blood, urine, breathing, and heart tests

Scans

Chest x-ray

Bone marrow samples: A needle inserted into the participant s pelvis will remove marrow and a bone fragment.

Transplant recipients will stay at the hospital and be prepped with chemotherapy over 6 days for the transplant. They will get stem cells through a catheter in the chest or neck. They will get the cyclophosphamide chemotherapy. They will stay in the hospital about 4 more weeks. They will have blood transfusions. They will have frequent blood tests and 2 bone marrow samples within 1 year after the transplant.

Donor participants will be screened with:

Blood, urine, and heart tests

Chest x-ray

Scans

Donor participants will have bone marrow taken from their pelvis or stem cells taken from their blood. For the blood donation, blood will be taken from a vein in one arm, move through a machine to remove white blood cells, and be returned through a vein in the other arm.

Participation will last up to 5 years.

Detailed Description

Background:

  • Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-haploidentical HCT
  • When clinically translated, the dose (50 mg/kg) and timing (days +3 and +4) of PTCy used were partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and were partly empirical
  • In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality
  • In the MHC-haploidentical HCT model, a dose of 25 mg/kg on day +4 was equivalent to 25 mg/kg/day on days +3 and +4
  • In addition to better GVHD prevention, lower dosing of PTCy is associated with less broad reduction of T-cell numbers after PTCy

Objective:

-Determine whether a dose of PTCy 25 mg/kg on day +3 and +4 or on day +4 only can maintain adequate protection against grade III-IV acute GVHD.

Eligibility:

  • Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including one of the following:

    • Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission
    • AML of any risk in second or subsequent morphologic complete remission
    • B-cell acute lymphoblastic leukemia in first or subsequent complete remission
    • T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics
    • Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
    • Primary myelofibrosis of intermediate-2 or higher risk by the Dynamic International Prognostic Scoring System (DIPSS)
    • Chronic myelomonocytic leukemia
    • Chronic myelogenous leukemia resistant to or intolerant of greater than or equal to 3 tyrosine kinase inhibitors or with prior history of accelerated phase or blast crisis
    • B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment
    • Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors
    • Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T- cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines
    • Hematologic malignancy of dendritic cell or histiocytic cell type
    • Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)
  • Age 15-65.
  • At least one potentially suitable HLA-haploidentical donor.
  • Karnofsky performance score greater than or equal to 60
  • Adequate organ function

Design:

  • Open-label, single-center, non-randomized, phase I/II study
  • All patients will receive myeloablative conditioning, HLA-haploidentical bone marrow HCT, and GVHD prophylaxis with PTCy, MMF, and sirolimus.
  • A small pilot of 5 evaluable patients will receive the standard PTCy 50 mg/kg on days +3/+4 to obtain a limited amount of comparative pharmacokinetic and T-cell immunophenotyping and repertoire data
  • Then the study will proceed to a small, two-level [1) 25 mg/kg/day on days +3 and +4, 2) 25 mg/kg on day +4 only] phase I dose de-escalation study based on the standard 3+3 approach
  • Patients will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity and phase II will proceed with the shorter duration of the days of treatment (+3/+4 or +4) which is associated with 0-1 of 6 patients with grade III- IV aGVHD at day +60
  • Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with this decreased PTCy exposure, will be used in the phase II portion of the study which will enroll an additional 14 patients to see if this lower PTCy exposure is associated with a similar rate of grade III-IV acute GVHD as is expected with 50 mg/kg on days +3/+4
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Graft Versus Host Disease
  • Hematologic Neoplasms
Intervention  ICMJE
  • Drug: Busulfan
    Busulfan should be administered intravenously via a central venous catheter as a three hour infusion every 24 hours.
  • Drug: Fludarabine
    Fludarabine will be infused by IV over 60 minutes.
  • Drug: Cyclophosphamide
    IV cyclophosphamide will be administered over 2 hours. Slower rates of infusion may be used to decrease side effects. A fluid intake of greater than 2 L/day is recommended during and for 1 to 2 days after cyclophosphamide administration.
  • Drug: Mycophenolate Mofetil
    Any oral formulation should be taken on an empty stomach, 1 hour before or at least 2 hours after meals. Oral formulations should not be administered simultaneously with antacids. Avoid inhalation or direct contact with skin or mucous membranes of dry powder contained in capsules or suspension. IV solutions should be administered over at least two hours through either a peripheral or central vein and should not be administered by rapid or bolus injection.
  • Drug: Sirolimus
    Oral tablets should be administered approximately 4 hours after cyclosporine administration. Sirolimus is administered orally, once daily, without food. Patients unable to tolerate tablets may take the oral solution formulation.
Study Arms  ICMJE
  • No Intervention: Donor Arm
    Collection of bone marrow and/or PBSC (Up to 40donors)
  • Experimental: Phase I Dose De-escalation
    PTCy at deescalating doses (25 mg /kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess forsafety and determine Phase II dose (up to 12 evaluable patients)
    Interventions:
    • Drug: Busulfan
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Drug: Mycophenolate Mofetil
    • Drug: Sirolimus
  • Experimental: Phase I Pilot for Comparative Data
    Standard PTCy 50 mg/kg/day on days +3 and +4, in asmall pilot (up to 5 evaluable patients) for comparativedata
    Interventions:
    • Drug: Busulfan
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Drug: Mycophenolate Mofetil
    • Drug: Sirolimus
  • Experimental: Phase II Efficacy
    PTCy at shortest duration, safe dose (from Phase I) toassess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients)
    Interventions:
    • Drug: Busulfan
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
    • Drug: Mycophenolate Mofetil
    • Drug: Sirolimus
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: June 11, 2019)
400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 29, 2026
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Inclusion Criteria - Recipient

  • Patients must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation limited to one of the following:

    • Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
    • AML of any risk in second or subsequent morphologic complete remission
    • B-cell acute lymphoblastic leukemia in first or subsequent complete remission
    • T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics (no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration)
    • Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
    • Primary myelofibrosis of intermediate-2 or higher risk by the DIPSS
    • Chronic myelomonocytic leukemia
    • Chronic myelogenous leukemia resistant to or intolerant of greater than or equal to 3 tyrosine kinase inhibitors or with history of accelerated phase or blast crisis
    • B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment
    • Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors
    • Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines
    • Hematologic malignancy of dendritic cell or histiocytic cell type
    • Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)
  • Age 15-65. Patients <18 years old must be at least 50 kg. Note: Because patients 15-17 years old and <50 kg are not able to be cared for on the adult oncology wards and by the investigative team, they are excluded.
  • At least one potentially suitable HLA-haploidentical donor.
  • Karnofsky performance score greater than or equal to 60
  • Adequate organ function defined as possessing all of the following:

    • Cardiac ejection fraction greater than or equal to 45% by 2D ECHO or MUGA;
    • Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of greater than or equal to 50% predicted;
    • Estimated serum creatinine clearance of greater than or equal to 60 ml/minute/1.73m(2) calculated using eGRF in the clinical lab for adults and the Schwartz formula for pediatric subjects;
    • Total bilirubin less than or equal to 2X the upper limit of normal;
    • Alanine aminostransferase and aspartate aminotransferase less than or equal to 3X the upper limit of normal.
  • Myeloablative conditioning is toxic to the developing human fetus and is teratogenic. For this reason, the following measures apply:

    • Women of child-bearing potential (WOCBP) 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-transplant.
    • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
    • WOCBP must have a negative serum or urine pregnancy test within 7 days prior to enrollment.
  • Ability of subject or Legally Authorized Representative to understand and the willingness to sign a written informed consent document. Pediatric patients (<18 years of age) will provide assent, and the parent(s) or legal guardian(s) will provide informed consent.
  • Subjects requiring standard therapies to prepare for HCT should be referred in remission if possible. However, these diseases are often aggressive and require swift evaluation for HCT while concurrently attempting to establish disease control through the administration of standard therapies. If ongoing therapy for the underlying disease outside of the NIH is not in the best interest of the subject according to the clinical judgment of the PI, then the subject may receive up to 2 cycles of standard treatment for his/her underlying hematologic malignancy as a bridge to HCT on this protocol, prior to starting the research phase of the study. The subject must have a Karnofsky performance status of greater than or equal to 60% at the start of the first cycle to proceed. If it becomes apparent that the subject will not be able to proceed to HCT, then he/she must come off study. Subjects receiving standard therapy will be told about the therapy, associated risks, potential benefits, alternatives to the proposed therapy, and the availability of receiving the same treatment elsewhere, outside of a research protocol.

Inclusion Criteria - Related Donor

  • Age greater than or equal to 18
  • Karnofsky performance status of 90-100%
  • Related donors with a single haplotype at HLA-A, B, C, and DR loci that is shared with the recipient by high resolution typing with the other haplotype being non-identical as measured by HLA typing and family tree
  • Ability of subject to understand and the willingness to sign a written informed consent document; medically fit and willing to donate
  • No history of opportunistic infections, autoimmunity, hemoglobinopathy, red cell enzymopathy, or malignancy, apart from non-melanomatous skin cancer or healed cervical cancer in situ.
  • If a hereditary malignancy syndrome affecting the hematopoietic system is known to affect the family and is testable, the donor must not be affected.
  • HIV negative, hepatitis B virus surface antigen negative, and hepatitis C virus antibody negative.
  • Medically fit to undergo anesthesia and bone marrow harvesting.
  • Related donors will undergo the Donor Health History Screen by skilled staff in the Blood Services Section for donors to determine donor eligibility using standard DTM criteria.

EXCLUSION CRITERIA:

Exclusion Criteria - Recipient

  • Patients who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 4 weeks prior to the date of beginning conditioning.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection excluding controlled fungal infection on appropriate treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, endocrinopathy (significant uncontrolled or untreated hypothyroidism, hyperthyroidism, or adrenal insufficiency), or active psychiatric illness/social situations that would limit compliance with study requirements
  • Prior myeloablative conditioning for autologous or allogeneic HCT.
  • An HLA-matched-sibling donor who is available and willing to donate bone marrow. Note: The patient must have access to HCT using this donor for this to be an exclusion criterion.
  • Pregnant women or women who intend to become pregnant during the study are excluded because myeloablative conditioning is toxic to the developing fetus with the potential for teratogenic or abortifacient effects.
  • The potential for some of the study medications to be transmissible via breast milk of nursing mothers is unknown. Because there is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding must be discontinued.
  • Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is: metastatic, or relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment, or limited disease treated with curative intent treatment within the last 2 years. This excludes non-melanoma skin cancers.
  • The severity of the hematologic malignancy does not warrant the potential toxicity of myeloablative allogeneic HCT as judged by the PI.

Exclusion Criteria - Related Donor

  • 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 HCT.
  • Donor to which the recipient has donor-specific anti-HLA antibodies and adequate reduction of recipient anti-HLA alloantibodies cannot be attempted or, if attempted, cannot be successfully achieved.
  • 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.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ellen Carroll, R.N. (240) 760-6158 ecarroll@mail.cc.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03983850
Other Study ID Numbers  ICMJE 190112
19-C-0112
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: Christopher G Kanakry, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date July 9, 2019

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