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Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04959175
Recruitment Status : Recruiting
First Posted : July 13, 2021
Last Update Posted : August 11, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Certain blood cancers can be treated with blood or bone marrow transplants. Sometimes the donor cells attack the recipient's body, called graft-versus-host disease (GVHD). The chemotherapy drug cyclophosphamide helps reduce the risk and severity of GVHD. Researchers want to learn if using a lower dose of cyclophosphamide may reduce the drug's side effects while maintaining its effectiveness. Such an approach is being used in an ongoing clinical study at the NIH with promising results, but this approach has not been tested for transplants using lower doses of chemotherapy/radiation prior to the transplant.

Objective:

To learn if using a lower dose of cyclophosphamide will help people have a successful transplant and have fewer problems and side effects.

Eligibility:

Adults ages 18-85 who have a blood cancer that did not respond well to standard treatments or is at high risk for relapse without transplant, and their donors.

Design:

Participants may be screened with the following:

Medical history

Physical exam

Blood and urine tests

Heart and lung tests

Body imaging scans (they may get a contrast agent)

Spinal tap

Bone marrow biopsy

Participants will be hospitalized for 4-6 weeks. They will have a central venous catheter placed in a chest or neck vein. It will be used to give medicines, transfusions, and the donor cells, and to take blood. In the week before transplant, they will get 2 chemotherapy drugs and radiation. After the transplant, they will get the study drug for 2 days. They will take other drugs for up to 2 months.

Participants must stay near NIH for 3 months after discharge for weekly study visits. Then they will have visits every 3-12 months until 5 years after transplant.

Participants and donors will give blood, bone marrow, saliva, cheek swab, urine, and stool samples for research.


Condition or disease Intervention/treatment Phase
Hematologic Neoplasms Drug: Mycophenolate Mofetil Procedure: Allogeneic HSCT Drug: Fludarabine Drug: Sirolimus Drug: Filgrastim Drug: Cyclophosphamide Drug: Mesna Procedure: Total Body Irradiation (TBI) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies
Actual Study Start Date : September 23, 2021
Estimated Primary Completion Date : April 27, 2027
Estimated Study Completion Date : April 30, 2027


Arm Intervention/treatment
No Intervention: Donors
Collection of research samples on bone marrow donors
Experimental: Older, HLA-matched
Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor
Drug: Mycophenolate Mofetil
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Fludarabine
30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Drug: Filgrastim
begins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is > 1,000/mm3 over the course of three days or > 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.

Drug: Cyclophosphamide
Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).

Drug: Mesna
25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.

Procedure: Total Body Irradiation (TBI)
400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)

Experimental: Older, HLA-mismatched
Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor
Drug: Mycophenolate Mofetil
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Fludarabine
30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Drug: Filgrastim
begins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is > 1,000/mm3 over the course of three days or > 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.

Drug: Cyclophosphamide
Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).

Drug: Mesna
25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.

Procedure: Total Body Irradiation (TBI)
400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)

Experimental: Younger, HLA-matched
Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor
Drug: Mycophenolate Mofetil
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Fludarabine
30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Drug: Filgrastim
begins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is > 1,000/mm3 over the course of three days or > 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.

Drug: Cyclophosphamide
Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).

Drug: Mesna
25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.

Procedure: Total Body Irradiation (TBI)
400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)

Experimental: Younger, HLA-mismatched
Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor
Drug: Mycophenolate Mofetil
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Fludarabine
30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.

Drug: Filgrastim
begins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is > 1,000/mm3 over the course of three days or > 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.

Drug: Cyclophosphamide
Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).

Drug: Mesna
25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.

Procedure: Total Body Irradiation (TBI)
400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)




Primary Outcome Measures :
  1. determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60 [ 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. In addition, a cumulative incidence curve for this endpoint will be constructed.


Secondary Outcome Measures :
  1. Grade III-IV acute GVHD at day 100 and 200 [ Time Frame: 100 days/200 days ]
    Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, non-relapse mortality, and chronic GVHD will be competing risks for acute GVHD. Grade III-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.

  2. Grade II-IV acute GVHD at day 100 and 200 [ Time Frame: 100 days/200 days ]
    Estimates will be determined using competing risk-based cumulative incidence curves. Grade II-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.

  3. Rate of Fried s Frailty Phenotypes (FP) [ Time Frame: 1 year ]
    Frequency of different phenotypes

  4. Chronic GVHD at one year [ Time Frame: 1 year ]
    Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, and non-relapse mortality will be competing risks for chronic GVHD.

  5. Progression/relapse at one year [ Time Frame: 1 year ]
    Estimates will be determined using Kaplan-Meier curves. Relapse and non-relapse mortality will be competing risks for each other.

  6. Non-relapse mortality at 100 days and one year [ Time Frame: 100 days and 1 year ]
    Estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other.

  7. Overall survival, progression-free survival, and disease-free survival at one year [ Time Frame: 1 year ]
    Estimates will be determined using Kaplan-Meier curves.

  8. Estimation of platelet engraftment, neutrophil engraftment. [ Time Frame: day 28 and day 100 ]
    Rate and timing will be evaluated descriptively, including fractions who attain each condition at day 28 and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting participants.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 85 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

-INCLUSION CRITERIA - Recipient

  1. Subjects must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including, but not limited to, one of the following:

    • Acute myeloid leukemia in morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
    • B-cell acute lymphoblastic leukemia in first or subsequent complete remission
    • T-cell acute lymphoblastic leukemia in first or subsequent complete remission
    • 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 >=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, after autologous transplantation or has progressed through at least 2 lines of therapy
    • Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory 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 higher60 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)
  2. Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning. Reasons for unfitness for myeloablative conditioning include:

    • Prior myeloablative HCT
    • Prior exposure to inotuzumab, gemtuzumab, or other agent that increases the risk for sinusoidal obstruction syndrome.
    • Significant organ dysfunction (e.g., creatinine or liver enzymes above the upper limit of normal or EGFR <=70 ml/min/1.73sq.m; prior sinusoidal obstruction syndrome, hepatic fibrosis, hepatic steatosis, or nodular regenerative hyperplasia; reduced ejection fraction <55% or focal hypokinesis, FEV1 or adjusted DLCO <75% of predicted)
    • Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) >= 3
    • Subject refusal of MAC (including subjects insistent on trying to maintain fertility)
    • Pre-frail or frail by Fried s frailty phenotype
    • Karnofsky performance score <80
    • Significant life-threatening toxicities associated with prior chemotherapy
    • Co-morbidity considered by the treating physician to be exclusionary of MAC
  3. At least one potentially suitable HLA-matched related, HLA-haploidentical first degree or collateral related, HLA-matched unrelated, or >=5/10 HLA-mismatched unrelated donor.
  4. Karnofsky performance score >=60
  5. Ability of subject to understand and the willingness to sign a written informed consent document.
  6. Adequate organ function defined as possessing all of the following:

    • Cardiac ejection fraction >=35%;
    • Forced expiratory volume-1, forced vital capacity, and diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) all of >=40% predicted;
    • Serum creatinine clearance of >=45 ml/minute calculated using the Cockcroft-Gault equation;
    • Total bilirubin <=2X the upper limit of normal;
    • Alanine aminotransferase and aspartate aminotransferase <=5X the upper limit of normal.
  7. Nonmyeloablative 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.
  8. For NIH treated subjects only: 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 NIH PI, then the subject may receive 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. 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.

EXCLUSION CRITERIA - Recipient:

  1. Subjects who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 2 weeks prior to the date of beginning conditioning.
  2. Poorly controlled malignant indication for transplantation such as:

    • Leukemia not having achieved morphologic remission (i.e. bone marrow blasts >5% or active extramedullary disease)
    • Lymphoma not having achieved at least a partial response to prior chemotherapy or radiation
  3. Uncontrolled intercurrent illness that in the opinion of the site PI would make it unsafe to proceed with transplantation.
  4. 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.
  5. Active malignancy of non-hematopoietic type which is: metastatic, 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 nonmelanoma skin cancers.

INCLUSION CRITERIA - Related Donor:

Related donor (age >=12) deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, bone marrow, and stool for research.

Related donors will be evaluated in accordance with existing institutional Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.

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 60 days after donation.

EXCLUSION CRITERIA - Related Donor:

None


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04959175


Contacts
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Contact: Amy H Chai (301) 219-7105 amy.chai@nih.gov
Contact: Christopher G Kanakry, M.D. (240) 760-6171 christopher.kanakry@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY dial 711    ccopr@nih.gov   
United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Shannon McCurdy    215-614-0698    shannon.mccurdy@pennmedicine.upenn.edu   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christopher G Kanakry, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04959175    
Other Study ID Numbers: 10000359
000359-C
First Posted: July 13, 2021    Key Record Dates
Last Update Posted: August 11, 2022
Last Verified: August 9, 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
myeloablative conditioning
Chronic Graft-Versus-Host Disease
hematopoietic cell transplantation
Fludarabine
TOTAL BODY IRRADIATION
Additional relevant MeSH terms:
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Hematologic Neoplasms
Neoplasms
Neoplasms by Site
Hematologic Diseases
Mycophenolic Acid
Sirolimus
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Antifungal Agents