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Phase II Trial of CD24Fc for the Prevention of Acute Graft-Versus-Host Disease (GVHD) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) (MK-7110-002)

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ClinicalTrials.gov Identifier: NCT02663622
Recruitment Status : Completed
First Posted : January 26, 2016
Results First Posted : June 18, 2021
Last Update Posted : June 18, 2021
Sponsor:
Collaborators:
Ohio State University
University of Michigan Rogel Cancer Center
Indiana University School of Medicine
Barbara Ann Karmanos Cancer Institute
National Cancer Institute (NCI)
Information provided by (Responsible Party):
OncoImmune, Inc.

Brief Summary:
This is a multicenter prospective phase IIa dose escalation and phase IIa expansion cohort clinical trial designed to evaluate the safety and tolerability of CD24Fc for acute GVHD prophylaxis.

Condition or disease Intervention/treatment Phase
Graft Versus Host Disease Hematopoietic Stem Cell Transplantation Leukemia Drug: CD24Fc Drug: Methotrexate Drug: Tacrolimus Drug: Placebo Phase 2

Detailed Description:

The first part of this study was a phase IIa randomized, double blind, placebo controlled, multi-center study to investigate adding CD24Fc to standard of care tacrolimus and methotrexate in acute graft-versus host disease (GVHD) prophylaxis for allogeneic hematopoietic stem cell transplantation (HCT) with matched unrelated donors in treatment of leukemia and myelodysplastic syndrome. The primary objective was to evaluate the safety, tolerability and dose-limiting toxicities (DLTs) of CD24Fc in participants undergoing matched unrelated donor myeloablative allogeneic HCT for malignant hematologic disorders. Three dose cohorts were planned with 240 mg at day -1, 480 mg at day -1, and the multi-dose cohort of 480-240-240 mg at day -1, day 14 and day 28. The CD24Fc : placebo randomization ratio was 3:1.

The second part was a prospective open label phase IIa expansion cohort trial investigating the addition of CD24Fc to standard acute graft-versus host disease (GVHD) prophylaxis for allogeneic hematopoietic stem cell transplantation (HCT). Based on the phase first part's safety results and the pharmacokinetic data, the phase IIa expansion dose was the multi-dose 480-240-240 mg regimen administered on day -1, day 14 and day 28. The primary objective of phase IIa expansion was to determine if the addition of CD24Fc to standard GVHD prophylaxis improves 180 days post-HCT grade III-IV acute GVHD-free survival (AGFS) when compared to Center for International Blood and Marrow Transplant Research (CIBMTR) database registered control participants who had standard GVHD prophylaxis alone. Eligible participants were those requiring allogeneic HCT for malignant hematologic conditions and receiving a myeloablative conditioning regimen.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Study was double blind for the first 6 participants in each arm. At that point, the recommended phase II dose (RP2D) was determined, and the selected arm enrolled additional participants in an open label fashion.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Trial of CD24Fc for Prevention of Acute Graft-versus-Host Disease Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplant
Actual Study Start Date : September 19, 2016
Actual Primary Completion Date : June 8, 2020
Actual Study Completion Date : May 18, 2021


Arm Intervention/treatment
Experimental: CD24Fc 240 mg
CD24Fc in 240 mg as intravenous (IV) infusion at Day -1 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT)
Drug: CD24Fc
Acute GVHD prophylaxis
Other Name: CD24 Fusion Protein

Drug: Methotrexate
Acute GVHD prophylaxis
Other Name: Trexall

Drug: Tacrolimus
Acute GVHD prophylaxis
Other Names:
  • FK506
  • Prograf

Experimental: CD24Fc 480 mg
CD24Fc in 480 mg as intravenous (IV) infusion at Day -1 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT)
Drug: CD24Fc
Acute GVHD prophylaxis
Other Name: CD24 Fusion Protein

Drug: Methotrexate
Acute GVHD prophylaxis
Other Name: Trexall

Drug: Tacrolimus
Acute GVHD prophylaxis
Other Names:
  • FK506
  • Prograf

Experimental: CD24Fc 960 mg
CD24Fc (480 mg (day -1), 240 mg (day +14) and 240 mg (day +28)) + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT)
Drug: CD24Fc
Acute GVHD prophylaxis
Other Name: CD24 Fusion Protein

Drug: Methotrexate
Acute GVHD prophylaxis
Other Name: Trexall

Drug: Tacrolimus
Acute GVHD prophylaxis
Other Names:
  • FK506
  • Prograf

Placebo Comparator: Placebo
Placebo to CD24Fc (saline IV injection solution) on day -1 or days -1, 14, and 28 + Tacrolimus (begin on day -3. IV [0.03 mg/kg/day] or PO [0.045 mg/kg/dose] dosing is permitted) + Methotrexate (given intravenously at a dose of 15 mg/square meter/dose once daily on Day 1 after HCT, and at a dose of 10 mg/square meter/dose on days 3, 6, and 11 after HCT)
Drug: Methotrexate
Acute GVHD prophylaxis
Other Name: Trexall

Drug: Tacrolimus
Acute GVHD prophylaxis
Other Names:
  • FK506
  • Prograf

Drug: Placebo
100 ml saline IV infusion.
Other Name: Saline Solution




Primary Outcome Measures :
  1. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 32 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to approximately 62 days for the CD24Fc 960 mg arm. ]
    An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. As described in the protocol, AEs reported after the protocol-specified timeframe were not analyzed in this outcome measure: 1 day prior to hematopoietic stem cell transplantation (HCT) through either 30 or 60 days post-HCT, depending on arm as defined in the Time Frame section.

  2. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: 1 day for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to approximately 30 days for the CD24Fc 960 mg arm. ]
    An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented.

  3. Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT) [ Time Frame: Up to 32 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 62 days for the CD24Fc 960 mg arm. ]
    A DLT was defined as: any Grade III or higher non-hematologic toxicity not clearly related to the underlying malignancy, intercurrent infection, or the hematopoietic stem cell transplantation conditioning regimen; any death not related to relapse or intercurrent infection; and failure to engraft by day 30. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Hypersensitivity reactions and other infusion-related reactions were not considered DLTs.

  4. Open Label Expansion Arm Only: Grade III-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS) [ Time Frame: Up to 181 days ]
    AGFS was defined as the time from the date of hematopoietic stem cell transplantation (HCT) to the earliest of Grade III-IV acute GVHD or death due to any cause, whichever occurred first. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants were censored at 181 days.


Secondary Outcome Measures :
  1. Grade II-IV Acute Graft-Versus-Host Disease (GVHD) Free Survival (AGFS) [ Time Frame: Up to 195 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 181 days for the CD24Fc 960 mg arm. ]
    AGFS was defined as the time from the date of hematopoietic stem cell transplantation (HCT) to the earliest of Grade II-IV acute GVHD or death due to any cause, whichever occurred first. Event grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Participants were censored at 195 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 181 days for the CD24Fc 960 mg arm.

  2. Percentage of Participants Experiencing Chronic Graft-Versus-Host Disease (GVHD) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    The percentage of participants who experienced chronic GVHD by approximately 1 year following HCT is presented.

  3. Percentage of Participants Experiencing Relapse Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    The percentage of participants who experienced relapse by approximately 1 year following HCT will be presented.

  4. Percentage of Participants Experiencing Non-Relapse Mortality (NRM) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    The percentage of participants who experienced NRM will be presented as cumulative incidence of NRM. The cumulative incidence (%) of NRM at approximately 1 year following HCT and the 95% CI will be estimated using the cumulative incidence function with relapse as a competing risk. If the maximum observed time is <Study Day 380 for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms or <Study Day 366 for the CD24Fc 960 mg arm, the cumulative incidence at the maximum observed time will presented.

  5. Percentage of Participants Experiencing Infection Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 101 days ]
    The percentage of participants who experienced infection by 101 days following HCT is presented.

  6. Overall Survival (OS) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    OS is defined as the time from HCT to death due to any cause. Participants will be censored at 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 366 days for the CD24Fc 960 mg arm.

  7. Percentage of Participants Experiencing Grade III to IV Acute Graft-Versus-Host Disease (GVHD) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    The percentage of participants who experienced grade III to IV acute GVHD by approximately 1 year following HCT will be presented.

  8. Graft-Versus-Host Disease (GVHD)-Free and Relapse-Free Survival (GRFS) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    GRFS is defined as the time from HCT to GVHD, relapse, or death due to any cause. Participants will be censored at 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 366 days for the CD24Fc 960 mg arm.

  9. Relapse-Free Survival (RFS) Following Hematopoietic Stem Cell Transplantation (HCT) [ Time Frame: Up to 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms. Up to 366 days for the CD24Fc 960 mg arm. ]
    RFS is defined as the time from HCT to relapse or death due to any cause. Participants will be censored at 380 days for the Placebo, CD24Fc 240 mg, and CD24Fc 480 mg arms, and at 366 days for the CD24Fc 960 mg arm.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

4.1.1 A prospective participant for allogeneic hematopoietic stem cell transplantation (HCT) for a malignant hematologic disorder.

4.1.2 The donor and recipient must have a human leukocyte antigen (HLA)-8/8 allelic match at the HLA-A, -B, -C, and - DRB1 loci. High-resolution typing is required for all alleles for unmatched donors. Only matched unrelated donors are acceptable for this trial.

4.1.3 The following diagnoses are to be included:

  1. Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) in first or second remission. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including central nervous system (CNS) involvement.
  2. Chronic Myelogenous Leukemia (CML) in first or subsequent chronic phase failing to respond (or intolerant) to at least two different tyrosine kinase inhibitors. CML in accelerated or blast phase (CML-AP/BP) are eligible without requirement to fail tyrosine kinase inhibitor therapy, but must be in remission at time of enrollment. Remission is defined as the absence of blasts in the peripheral circulation at the time of enrollment, < 5% blasts in the bone marrow and absence of extramedullary disease including CNS involvement.
  3. Myelodysplastic syndrome (MDS) with intermediate or high-risk International Prognostic Scoring System (IPSS) or equivalent Revised IPSS (IPSS-R) score with < 10% blasts in the bone marrow.
  4. Chronic Myelomonocytic Leukemia (CMML) with < 10% blasts in the bone marrow.

4.1.4 Males or non-pregnant, non-lactating females, ≥ 18 years of age. Note there is no defined upper age limited, so long as deemed appropriate candidate for myeloablative conditioning.

4.1.5 Karnofsky Performance Status >70%.

4.1.6 Participants must have normal or near normal organ function as defined by their treating institutions bone marrow transplantation (BMT) program clinical practice guidelines. In addition, for purposes of this protocol minimum organ function criteria within 21 days of beginning conditioning include:

TABLE 1: Eligibility According to Pre HCT Organ Function Total bilirubin ≤2.5 mg% (unless from Gilbert's disease or disease-related) Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) (AST[SGOT])/ alanine aminotransferase (serum glutamic-pyruvic transaminase) (ALT[SGPT]) <3.0 X institutional upper limit of normal Estimated or actual glomerular filtration rate (GFR) >50 mL/min/1.73 m2 for participants with creatinine levels above institutional normal (GFR should be corrected for body surface area [BSA]) Pulmonary Function Tests* diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) > 50% DLCO should be corrected for hemoglobin Ejection Fraction* >50% Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) ≤ 5

*May be assessed up to 6 weeks prior to the start of conditioning therapy

4.1.7 Ability to understand and the willingness to sign a written informed consent document.

4.1.8 Women of child bearing potential and men must agree to use contraception prior to study entry and through day 100 post HCT (hormonal or barrier method of birth control; abstinence). Should a woman become pregnant or suspect she is pregnant while she or her partner is on treatment in this study, she should inform her study physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study until day 100 post HCT.

Exclusion Criteria:

4.2.1 Participants may not have presence of active CNS disease or extramedullary disease.

4.2.2 Prior cytotoxic chemotherapy within 21 days from the initiation of HCT conditioning (i.e. intensive induction / consolidation for AML). Note, certain low intensity treatments not intended to induce remission but rather stabilize disease are acceptable up to 24 hrs prior to initiation of HCT conditioning (i.e. Tyrosine Kinase Inhibitor, sorafenib).

4.2.3 Cord blood and haploidentical donors are not eligible.

4.2.4 HLA-mismatch at the HLA-A, -B, -C, and - DRB1 loci. Note, HLA-DQ mismatches are permissible.

4.2.5 Pregnant and nursing mothers are excluded from this study. This is because the risk to the fetus is unknown.

4.2.6 Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the participant or raise concern that the participant would not comply with protocol procedures.

4.2.7 Uncontrolled infections. Participants still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiologic, clinical and/or culture) that the infection is well controlled.

4.2.8 Participants seropositive or polymerase chain reaction (PCR) positive for the human immunodeficiency virus (HIV). Participants with evidence of Hepatitis B or Hepatitis C PCR positivity.

4.2.9 Prior HCT (allograft or prior autograft).

4.2.10 Use of T cell depletion either ex vivo or in vivo (i.e. anti-thymocyte globulin [ATG], alemtuzumab) is prohibited.

4.2.11 Current or prior diagnosis of antecedent Myelofibrosis is excluded.


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): NCT02663622


Locations
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United States, Indiana
Indiana University School of Medicine
Indianapolis, Indiana, United States, 46202
United States, Michigan
The University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
OncoImmune, Inc.
Ohio State University
University of Michigan Rogel Cancer Center
Indiana University School of Medicine
Barbara Ann Karmanos Cancer Institute
National Cancer Institute (NCI)
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by OncoImmune, Inc.:
Publications:
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Responsible Party: OncoImmune, Inc.
ClinicalTrials.gov Identifier: NCT02663622    
Other Study ID Numbers: 7110-002
HUM00107805 ( Other Identifier: University of Michigan )
15-4789 ( Other Identifier: Orphan Drug Designation )
R44CA221513 ( U.S. NIH Grant/Contract )
R44CA246991 ( U.S. NIH Grant/Contract )
UMCC 2015.181 ( Other Identifier: UMCC )
MK-7110-002 ( Other Identifier: Merck Protocol Number )
NCI-2017-00017 ( Other Identifier: National Cancer Institute )
CD24Fc-002 ( Other Identifier: OncoImmune Protocol Number )
First Posted: January 26, 2016    Key Record Dates
Results First Posted: June 18, 2021
Last Update Posted: June 18, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Methotrexate
Tacrolimus
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Calcineurin Inhibitors