Post-Transplant Cyclophosphamide, Bortezomib and Abatacept for the Prevention of Graft-versus-Host-Disease (GvHD)

Official title

A Phase I-II Study of High-Dose Post-Transplant Cyclophosphamide, Bortezomib and Abatacept for the Prevention of Graft-versus-Host-Disease (GvHD) Following Allogenic Hematopoietic Stem Cell Transplantation (HSCT)

Overview

This is a phase I-II clinical trial. Adult subjects with hematological malignancies undergoing allogeneic HSCT from an HLA matched sibling or ≥7 out of 8 allele level HLA matched unrelated donor are eligible for the study if they meet the criteria defined in our standard operation procedures (SOPs), meet all inclusion criteria, and do not satisfy any exclusion criteria. Subjects will receive a standard of care conditioning regimen. Subjects will receive investigational PTCy, investigational bortezomib and investigational abatacept as GvHD prophylaxis.

Detailed description

The study will have a phase I and phase II potions. The phase I portion will employ a 3+3 dose escalation design to define the maximum tolerated dose (MTD) of abatacept added to PTCy and bortezomib following HSCT. The phase II portion will consist of two single arm, open label, optimal 2-stage Simon design studies conducted in two separate strata for HLA matched and HLA mismatched donor transplants. Adult patients with hematological malignancies undergoing allogeneic HSCT from an HLA matched sibling or ≥7 out of 8 allele level HLA matched unrelated donor are eligible for the study if they meet the standard criteria defined in our institutional standard operation procedures (SOPs), meet all inclusion criteria, and do not satisfy any exclusion criteria. Subjects will receive a standard of care conditioning regimen followed by peripheral blood hematopoietic stem cells. Subjects with unrelated donors will also receive rabbit anti-thymocyte globulin (rATG). Subjects will receive investigational PTCy, investigational bortezomib and investigational abatacept as GvHD prophylaxis. The phase II portion dose of abatacept will be the MTD as determined in the phase I portion of the study. In the phase II portions, subjects will be stratified based on whether they receive a matched sibling or matched unrelated (matched) donor transplant and ≥7 out of 8, allele level matched (mismatched) unrelated donor transplant.

Interventions

• Drug Cyclophosphamide
  37.5 mg/kg IV over 1 hour on Day +3 and +4
• Drug Abatacept
  Dose level 0: 10 mg/kg IV over 30-60 minutes on day +5 Dose level 1: 10mg/kg IV over 30-60 minutes on day +5 and +14 Dose level 2: 10mg/kg IV over 30-60 minutes on day +5, +14, and +28
• Drug Bortezomib
  1.3 mg/m2 IV 6 hours after graft infusion completion and 72 hours thereafter.

Primary outcome measures

• Phase I:Incidence Dose limiting toxicity (DLT) [Time frame: Day+1 to Day +120]
• Phase II: Grades II-IV Acute GvHD [Time frame: Day+1 to Day +120]

Secondary outcome measures (8)

• Chronic GvHD [Time frame: Day +1 to Day +365]
• Primary graft failure [Time frame: Day +1 to Day +30]
• Poor graft function [Time frame: Day +1 to Day +30]
• Secondary graft failure [Time frame: Day +1]
• Treatment-related mortality (TRM) [Time frame: Day +1 to Day +730]
• Relapse rate (RR) [Time frame: Day +1 to Day +730]
• GvHD and relapse-free survival (GRFS) [Time frame: Day +1 to Day +730]
• Overall survival (OS) [Time frame: Day +1 to Day +730]

Eligibility criteria

Inclusion criteria

• Age ≥14 years
• Karnofsky score ≥70%
• No evidence of progressive bacterial, viral, or fungal infection
• Creatinine clearance >50 mL/min/1.72m2
• ALT and AST <3 x the upper limit of normal
• Total bilirubin <2 x the upper limit of normal (except for Gilbert's syndrome)
• Alkaline phosphatase ≤250 IU/L
• Left Ventricular Ejection Fraction (LVEF) >45%
• Adjusted Carbon Monoxide Diffusing Capacity (DLCO) >50%
• Negative HIV serology
• Negative pregnancy test: Confirmation per negative serum β-human chorionic gonadotropin (β-hCG)
• Willing to comply with all study procedures and be available for the duration of the study.

Exclusion criteria

• 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 90 days after the last dose of study drug. A woman of reproductive capability is one who has not undergone a hysterectomy (removal of the womb), has not had both ovaries removed, or has not been post-menopausal (stopped menstrual periods) for more than 24 months in a row.
• 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. This must be done even if they are surgically sterilized (i.e., post-vasectomy).
• 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 (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Known allergies 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
• Pregnant women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Northwell Health — New Hyde Park

Identifiers

NCT: NCT05289167 · 21-00797

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗