RIC alloBMT With Post-transplant Cyclophosphamide for Refractory Systemic Sclerosis

NCT05298358 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: J19128IRB00292605
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, single arm, open label, single center pilot study to assess a reduced-intensity conditioning regimen, bone marrow transplantation with high dose cyclophosphamide (PTCy) in recipients with refractory systemic sclerosis. This study expects to enroll 15 donor/recipient pairs for a total of 30 participants. The primary objective of this study is to assess the safety of using a reduced intensity condition (RIC) preparative regimen bone marrow transplant (BMT) with post-transplant cyclophosphamide for graft vs host disease (GVHD) prophylaxis as treatment for patients with scleroderma. Safety events are grade III-IV GVHD and treatment related mortality within 1 year. Eligibility includes patients \>18 years who are eligible for transplantation according to the BMT Policy Manual, meet the 2013 ACR/EULAR Criteria for Systemic Sclerosis and display active diffuse cutaneous disease. The trial also includes analyses of the effects of BMT on skeletal and cardiac muscle using systemic scleroderma serum biomarkers of CK, aldolase, and troponin as well as periodic monitoring of circulating scleroderma auto-antibody titers, autoreactive T cells, and flow cytometric signatures over the one-year study period to correlate with response.

Conditions

Systemic Sclerosis

Outcome Measures

Primary Outcomes (4)

• Acute Graft vs Host disease (GVHD) incidence

  Number of safety events defined as CTCAE grade III-IV acute GVHD.

  1 year

• Chronic Graft vs Host disease (GVHD) incidence

  Number of participants with chronic GVHD requiring systemic immune suppression.

  1 year

• Disease relapse or progression incidence

  Number of participants diagnosed with disease relapse or progression.

  1 year

• Incidence of death

  Number of participant deaths by any cause.

  1 year

Secondary Outcomes (12)

• Event free survival- pulmonary hypertension

  1 year

• Event free survival- cardiomyopathy

  1 year

• Event free survival- increased mRSS scoring in diffuse scleroderma patients

  1 year

• Event free survival- renal crisis

  1 year

• Event free survival- pulmonary function assessment

  1 year

Other Outcomes (6)

• Additional exploratory objective- serum CK

  1 year

• Additional exploratory objective- serum aldolase

  1 year

• Additional exploratory objective- serum troponin

  1 year

Study Arms (1)

RIC- alloBMT with high PTCy in SSc

EXPERIMENTAL

Days -9 Thymoglobulin 0.5 mg/kg IV Days -8,-7 Thymoglobulin 2 mg/kg IV daily Days -6, -5 Fludarabine 30 mg/M2 IV Cyclophosphamide 14.5 mg/kg IV Days -4, -3-2 Fludarabine 30 mg/M2 IV Day -1 TBI 400 cGy Day 0 Infuse unmanipulated marrow; begin antimicrobial prophylaxis. Days 3, 4 Cy 50 mg/kg IV and Mesna 40 mg/kg IV Day 5 FK-506 oral and MMF oral and G-CSF Day 30 Assess peripheral blood chimerism Day 35 Discontinue MMF Day 60 Assess peripheral blood chimerism Day 180 Discontinue FK-506 Evaluate disease Assess Chimerism in peripheral blood 1 yr. Evaluate disease by peripheral blood chimerism

Biological: RIC alloBMT w PTCy in refractory SSc

Interventions

RIC alloBMT w PTCy in refractory SSc BIOLOGICAL

The preparative regimen: * Thymoglobulin 0.5 mg/kg IV day -9 * Thymoglobulin 2 mg/kg IV Days -8, -7 * Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6,-5 * Fludarabine 30 mg/m2 IV Days -6, -5, -4, -3,-2 * Total body irradiation (TBI) 400cGy * Day 0- infusion of unmanipulated bone marrow The GVHD prophylaxis regimen: * Cy 50 mg/kg IV Days 3, 4 * Tacrolimus (FK-506) (IV or oral (po)) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Sirolimus may be substituted for tacrolimus. * Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID Day 5 - Day 35 * Filgrastim (G-CSF) 5 µg/kg SQ daily beginning Day 5 until absolute neutrophil (ANC) is greater than 1000/µl over at least 2 days. Supportive care: * Mesna- 10 mg/kg/ IV Day 3, 4 * Patients will receive infection prophylaxis and treatment according to institutional guidelines.

RIC- alloBMT with high PTCy in SSc

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients with moderate-to-severe SSc will be considered for this trial, including women and minorities. SSc is too rare a disease in children for it to be feasible to include them.
• Patients must meet the following criteria to be eligible for participation in this clinical trial:
• ACR/EULAR Criteria for Systemic Sclerosis
• Active diffuse cutaneous disease with an mRSS ≥ 20 - including increasing skin score, new body areas involved, increased thickening in previously affected body areas, severe pruritus, tendon friction rubs OR concern for active interstitial lung disease (ILD) with FVC\<70% of predicted, new fibrosis/GGO on HRCT, and/or falling FVC \>10% of predicted
• Lack of response to first line therapy including mycophenolate mofetil at maximum tolerated dose (up to 1.5 grams BID) after 10 weeks and/or equivalent degree of immunosuppression/immunomodulatory therapy with MTX, CYC, IVIG, or rituximab. Lack of response can include physician judgement based on review of records and patient report.
• Age \>18 years and ≤ 65 years
• Patients should be eligible for transplantation according to the BMT Policy Manual.
• Female patients (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post-transplant. Effective birth control is defined as the following:
• Abstinence
• Consistently use birth control pills or patch
• Use injectable birth control (for example, Depo-Provera or Norplant)
• Have tubal sterilization
• Have placement of an IUD
• Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam every time you have vaginal sex. Male patients (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant. Effective birth control methods include:
• Abstinence

You may not qualify if:

• Pregnant, breast feeding, or considering becoming pregnant during the course of the study;
• Requiring IV antimicrobial treatment or hospitalization within 7 days prior to study enrollment for known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds);
• History of human immunodeficiency virus (HIV) infection;
• Active or unresolved gastric antral vascular ectasia (GAVE) syndrome;
• Active or unresolved scleroderma renal crisis;
• Clinically significant pulmonary hypertension, interstitial lung disease, or other cardiopulmonary disease with inadequate organ function as defined above\*\*;
• Any illness or condition which, in the judgment of the investigator, would inappropriately jeopardize the safety of the subject, interfere with study assessments, or impact the validity of the study results;
• Known malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer;
• Prisoners or subjects who are compulsorily detained (involuntary incarceration) for treatment of either a physical or psychiatric illness;
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements or assessment of immunologic endpoints;
• History of significant allergic reactions, hypersensitivity, or intolerance attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study.
• Patients not meeting eligibility for adequate organ function may still be eligible for the study if deemed reasonably safe and clinically appropriate by the investigator following consultation with the appropriate specialist (e.g., cardiology, nephrology, or pulmonology).

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Scleroderma, Systemic

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Study Officials

• Cole Sterling, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: March 7, 2022
• First Posted: March 28, 2022
• Study Start: November 18, 2022
• Primary Completion: November 13, 2024
• Study Completion: November 21, 2024
• Last Updated: February 4, 2025

Record last verified: 2025-02

Locations

US (1)