Ustekinumab for the Prevention of Acute Graft-versus-Host Disease After Unrelated Donor Hematopoietic Cell Transplant

• ClinicalTrials.gov Identifier: NCT04572815
• Recruitment Status: Recruiting
• First Posted: October 1, 2020
• Last Update Posted: March 10, 2023
• Sponsor: Fred Hutchinson Cancer Center
• Information provided by (Responsible Party): Fred Hutchinson Cancer Center

Study Description

Brief Summary:

This phase II trial studies how well ustekinumab works in preventing acute graft-versus-host disease after unrelated donor hematopoietic cell transplant. Sometimes the transplanted cells from a donor can attack the body's normal tissues (called graft-versus-host disease). Giving ustekinumab after the transplant may help prevent acute graft-versus-host disease by controlling the body's immune response.

Condition or disease	Intervention/treatment	Phase
Hematologic and Lymphocytic Disorder; Hematopoietic and Lymphoid System Neoplasm	Drug: Placebo Administration; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Biological: Ustekinumab	Phase 2

Detailed Description:

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive ustekinumab intravenously (IV). Beginning 8 weeks after receiving IV ustekinumab, patients receive ustekinumab subcutaneously (SC) on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse or unacceptable toxicity. NOTE: HCT infusion takes place on day 0.

ARM II: Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive a placebo IV. Beginning 8 weeks after IV placebo, patients receive a placebo SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence grade III-IV acute GVHD, of disease relapse, or unacceptable toxicity. NOTE: HCT infusion takes place on day 0.

After completion of study, patients are followed up at 6, 9, 12, 18, and 24 months post-HCT.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 116 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized, Placebo-Controlled, Phase II Trial Examining Ustekinumab for Prevention of Graft Vs. Host Disease After Allogeneic Hematopoietic Cell Transplantation
• Actual Study Start Date: May 14, 2021
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: March 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (ustekinumab); Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive ustekinumab IV. Beginning 8 weeks after receiving IV ustekinumab, patients receive ustekinumab SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse or unacceptable toxicity. NOTE: HCT infusion takes place on day 0.	Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Biological: Ustekinumab; Given IV and SC; Other Names: CNTO 1275; CNTO1275; Immunoglobulin G1, Anti-(Human Interleukin-12 Subunit beta (IL-12B, CLMF p40, NKSF2)) (Human Monoclonal CNTO 1275 gamma1-chain), Disulfide with Human Monoclonal CNTO 1275 kappa-chain, Dimer; Stelara
Placebo Comparator: Arm II (placebo); Between 4 and 72 hours prior to start of HCT conditioning therapy, patients receive a placebo IV. Beginning 8 weeks after IV placebo, patients receive a placebo SC on days 50 (+/- 5 days), 100 (+/- 7 days), and 160 (+/- 7 days) post-HCT in the absence of grade III-IV acute GVHD, disease relapse, or unacceptable toxicity. NOTE: HCT infusion takes place on day 0.	Drug: Placebo Administration; Given IV and SC; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Grade II-IV acute graft versus host disease (GVHD) survival [ Time Frame: At 6 months post-hematopoietic cell transplantation (HCT) ]
   Will be treated as a binary outcome, and the Cochran-Mantel-Haenszel test will be used to compare the two groups based on the stratification factors.

Secondary Outcome Measures :

1. Cumulative incidence of grade II-IV and grade III-IV acute GVHD [ Time Frame: At 100 days post-HCT ]
2. Cumulative incidence of grade II-IV and grade III-IV acute GVHD [ Time Frame: At 6 months post-HCT ]
3. Acute GVHD organ staging, overall grading, and classification [ Time Frame: From time of HCT, assessed up to day 100 post-HCT ]
   Minnesota risk criteria will be used to assess organ involvement, individual organ staging, and overall acute GVHD grade. Risk classification will be performed per MacMillan et al.
4. Incidence of overall chronic GVHD [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Will be assessed at serial study visits, and scored according to National Institutes of Health Consensus criteria.
5. Incidence of moderate-severe chronic GVHD [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Will be assessed at serial study visits, and scored according to National Institutes of Health Consensus criteria.
6. Incidence of post-HCT relapse [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Relapse is defined as hematologic relapse or any unplanned intervention (including withdrawal of immune suppression) to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes.
7. Incidence of non-relapse mortality [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Non-relapse mortality indicates death with primary malignancy that served as HCT indication in remission. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes.
8. Relapse-free survival [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Relapse is defined as hematologic relapse or any unplanned intervention (including withdrawal of immune suppression) to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease. Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes.
9. Overall survival [ Time Frame: From time of HCT, assessed up to 2 years post-HCT ]
   Will be compared using either the log-rank test (if no competing risks) or Gray's test (if competing risks are present). For time-to-event endpoints with competing risks, the log-rank test will also be used for exploratory purposes.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age 18 - 70
• Signed informed consent.
• Hematologic malignancy or disorder requiring allogeneic hematopoietic cell transplantation

• Adequate vital organ function:

  1. Left ventricular ejection fraction (LVEF) ≥ 50%
  2. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 50% of predicted values on pulmonary function tests
  3. Transaminases (aspartate aminotransferase [AST], aspartate aminotransferase [ALT]) < 3 times upper limit of normal values
  4. Creatinine clearance ≥ 50 cc/min.
• Performance status: Karnofsky Performance Status Score ≥ 70%.
• HCT donor is at least 8/8 (matched at HLA-A, -B, -C, -DRB1) matched with the recipient
• PBSC (peripheral blood mobilized stem cells) as graft source
• Fully myeloablative, reduced-toxicity ablative, or reduced-intensity conditioning regimens. If melphalan is part of the conditioning regimen, dose must be at least 75mg/m^2

Exclusion Criteria:

• Active infection not controlled with appropriate antimicrobial therapy
• Human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection
• Anti-thymocyte globulin (ATG) as part of the conditioning regimen or GVHD prophylaxis
• Pregnant or nursing women
• Subjects of childbearing age unwilling to use an effective birth control method or refrain from sexual intercourse until 15 weeks after last dose of study drug
• Non-myeloablative conditioning regimens or conditioning regimens that use less than 75mg/m^2 of melphalan
• Prior allogeneic transplant
• Non-malignant blood disorders (e.g. sickle cell disease, aplastic anemia)
• Positive screening test for tuberculosis

Contacts and Locations

Contacts

Contact: Stephanie J. Lee; 206-667-6190; sjlee@fredhutch.org

Locations

United States, California

City of Hope Comprehensive Cancer Center,; Recruiting

Duarte, California, United States, 91010

Contact: Ryotaro Nakamoto 626-256-4673 x82405 rnakamoto@coh.org

Principal Investigator: Ryotaro Nakamoto

United States, Florida

H. Lee Moffitt Cancer Center & Research Institute; Recruiting

Tampa, Florida, United States, 33612

Contact: Joseph Pidala 813-745-2256 joseph.pidala@moffitt.org

Principal Investigator: Joseph Pidala

United States, New York

Roswell Park Cancer Institute; Active, not recruiting

Buffalo, New York, United States, 14263

United States, Washington

Fred Hutch/University of Washington Cancer Consortium; Recruiting

Seattle, Washington, United States, 98109

Contact: Stephanie J. Lee 206-667-6190 sjlee@fredhutch.org

Principal Investigator: Stephanie J. Lee

Sponsors and Collaborators

Fred Hutchinson Cancer Center

Investigators

• Principal Investigator: Stephanie J. Lee; Fred Hutch/University of Washington Cancer Consortium

More Information

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT04572815
• Other Study ID Numbers: RG1005588; NCI-2020-02617 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 10421 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); R01FD006836 ( U.S. FDA Grant/Contract )
• First Posted: October 1, 2020
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hematologic Diseases; Ustekinumab; Interleukin-12; Immunoglobulins; Immunoglobulin G; Immunologic Factors; Physiological Effects of Drugs; Dermatologic Agents; Adjuvants, Immunologic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents