High-Dose Post-Transplant Cyclophosphamide, Bortezomib, and Sitagliptin for the Prevention of GVHD

NCT05895201 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: CTO-IUSCCC-0778
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label Phase I-II study to determine the safe doses of bortezomib, sitagliptin, and PTCy (Phase I) with expansion into a phase II trial to determine efficacy in improving survival.

Conditions

Bone Marrow Transplant Complications; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia, Adult; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia

Keywords

Allogenic peripheral blood stem cell grafts; Phase I; Phase II

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose

  in the first 30 days post-transplant

• proportion of patients developing grades 3-4 non-hematological toxicity defining DLT assessed by CTCAE version 5.0

  in the first 30 days post-transplant

• Proportion of patients alive and free of grade II-IV acute GVHD (graft-versus-host disease)

  Baseline to day +100

• Cumulative incidence of grade II-IV acute GVHD

  through study completion (i.e. up to 5 years)

Secondary Outcomes (13)

• Frequency of Non-Hematological toxicity as assessed by CTCAE version 5.0

  baseline to day +30

• Cumulative incidences of all grades of acute GvHD

  baseline to day +100

• Chronic graft-versus-host disease

  through study completion (i.e. up to 5 years)

• Time to engraftment of neutrophils

  the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (NEUTROPHILS + BANDS) is at least 0.5 x109/l.

• Time to engraftment of platelets

  the time to engraftment of platelets is defined as the time from day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support.

Study Arms (1)

Sitagliptin + Bortezomib + Cyclophosphamide

EXPERIMENTAL

Drug: Sitagliptin; Drug: Bortezomib; Drug: Cyclophosphamide

Interventions

Sitagliptin DRUG

600 or 400 (or MTD) mg PO every 12 hours on days -1 to +14 depending on dose level assignment.

Sitagliptin + Bortezomib + Cyclophosphamide

Bortezomib DRUG

1.3 or 1.0 mg/m2 (or MTD) IV push 6 hours after graft infusion completion (day 0), and 72 hours thereafter depending on dose level assignment.

Sitagliptin + Bortezomib + Cyclophosphamide

Cyclophosphamide DRUG

50 mg/kg IV over 1 hour on days +3 and +4

Sitagliptin + Bortezomib + Cyclophosphamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with any of the following hematologic malignancies:
• Acute myeloid leukemia (AML) in first remission (CR1) if they have with intermediate or high-risk cytogenetic and/or molecular features, or patients in second or subsequent complete remission (CR2, CR3, etc.). Complete remission is defined as presence of \<5% blasts in the bone marrow Version 09/30/2022 25 with no morphological evidence of leukemia. Patients in CR with incomplete count recovery may be included.
• Acute lymphoblastic leukemia (ALL) with any of the following in CR1 or subsequent complete remission (CR2, CR3, etc.). Complete remission is defined as presence of \<5% blasts in the bone marrow with no morphological evidence of leukemia. Patients in CR with incomplete count recovery may be included.
• Myelodysplastic disorder (MDS) with a revised International Prognostic System Score (IPSS-R)104 of greater than 3 at diagnosis. Patients must have \<10% blasts in the bone marrow documented within 30 days of transplant.\*
• Therapy-related myelodysplastic disorder (t-MDS). Patients must have \<10% blasts in the bone marrow documented within 30 days of transplant.\*
• Chronic myelomonocytic leukemia (CMML) type 1 or 2. Patients must have \<10% blasts in the bone marrow documented within 30 days of transplant.\* \*Patients with MDS, t-MDS, and CMML will be included only in the phase I portion of the study.
• Patient age ≥ 18 years
• Karnofsky Performance status ≥ 70%
• Patients must also be suitable to receive a reduced-intensity (RIC) conditioning regimen at the discretion of the treating physician. While there are not universally accepted or validated cut-off criteria of age, performance status, or hematopoietic cell transplantation-comorbidity index (HCT-CI) for suitability for RIC, RIC transplants should be considered for patients 60 years and older, and for patients \<60 years who are "less fit", e.g., KPS \<90% and/or HCT-CI ≥ 3 due to lower non-relapse mortality associated with RIC.
• Patients receiving allogeneic peripheral blood stem cell (PBSC) grafts from HLA-matched (5/6 and 6/6 matches) siblings or matched unrelated donors (7/8 or 8/8 matches at HLA-A, B, C, DRB1 by high resolution typing) are included. All grafts will be unmanipulated (i.e., no T cell depleted or CD34 selected grafts). In addition, donors should meet institutional criteria for donation of PBSC, as well as the screening and eligibility criteria of the National Marrow Donor Program (NMDP) for unrelated donors, and the requirements of the United States Food and Drug Administration for Human Cell, Tissue, or Cellular or Tissue-based Products (HCT/P) (21 CFR Part 1271).
• Required baseline laboratory values within 16 days prior to admission:
• Estimated creatinine clearance \>60 ml/min/1.72 m2
• Serum total bilirubin ≤ 2 x upper limit of normal value (except for Gilbert's disease)
• AST and ALT ≤ 3 x upper limit of normal value
• Alkaline phosphatase (ALP) ≤ 250 IU/l

You may not qualify if:

• Pregnant or nursing females or women of reproductive capability who are unwilling to completely abstain from heterosexual sex or practice 2 effective methods of contraception from start of conditioning through a minimum of 90 days after the last dose of study drug.
• Male subjects who refuse to practice effective barrier contraception from the start of conditioning through a minimum of 90 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
• Inability to provide informed consent.
• Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Patients with active central nervous system leukemia
• Prior allogeneic HSCT or an autologous hematopoietic stem cell transplant in past 12 months
• Patients with diabetes mellitus requiring insulin secretagogues and/or insulin at time of enrollment.
• Patients with a history of pancreatitis
• Patients with symptomatic cholelithiasis
• Known hypersensitivity to any of the components of the investigational treatment regimen.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma, an in-situ malignancy, or low-risk prostate cancer after curative therapy.
• Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
• Prisoners

Sponsors & Collaborators

• Indiana University: lead

Study Sites (1)

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Interventions

Sitagliptin Phosphate; Bortezomib; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2023
• First Posted: June 8, 2023
• Study Start: November 1, 2023
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: April 29, 2024

Record last verified: 2023-10

Locations

US (1)