RIC alloBMT With Post-transplant Cyclophosphamide for Refractory Systemic Sclerosis

A Phase I Study of Reduced Intensity Conditioning Allogeneic Bone Marrow Transplant With Post-transplant Cyclophosphamide for Refractory Systemic Sclerosis

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.

The purpose of this study is to find out if the drug cyclophosphamide given after bone marrow transplantation is safe and effective in patients with systemic sclerosis that have not responded to other standard treatments. Systemic sclerosis (scleroderma) is a systemic autoimmune disease associated with high morbidity and mortality, with an estimated prevalence of 50-300 per million persons/year and incidence of 2.3-22.9 per million persons/year. Currently there exists no cure for scleroderma, and medical management is entirely off-label, with no FDA approved drugs for this condition. Treatment is based on symptom management focused on the specific organ system affected such as the lung, skin, musculoskeletal, cardiac, renal, or gastrointestinal systems. Interest in improving response rates and decreasing relapse has turned attention toward allogeneic stem cell transplantation (allo-BMT). The possibility of maintaining control of autoimmunity by means of mixed chimerism in these autoimmune diseases is quite important. These patients may not need full engraftment to have disease modification. There is still concern about the morbidity GVHD for these patients in the allogeneic setting as well as a potentially limited number of available donors. Towards this end, the study was developed with an approach to BMT using post-transplant cyclophosphamide (PTCy) that allows safe performance of allogeneic BMT from matched, mismatched, unrelated or haploidentical donors. Given that there are responses of refractory systemic sclerosis (SSc) to immunosuppressive therapy in some form, eligible patients will be required to have experienced disease progression despite at least one course of immunosuppressive therapy. In general, this will be defined as progression of skin or lung disease despite optimal courses of therapy or failure to tolerate therapeutic doses of immunosuppressive therapy. Potential donors will be excluded if the donors report a history of autoimmunity. The rationale for this comes from the knowledge that gender, a genetically controlled factor, plays a role in the incidence of autoimmune disease. The study regimen includes several days of chemotherapy, immunosuppressant, and a single dose of radiation followed by the bone marrow transplant. After the transplant, recipient patients will receive two doses of the intravenous (IV, through a vein) chemotherapy cyclophosphamide and two oral medications to prevent graft versus host disease and to aid in bone marrow engraftment. After a while, the anti-rejection medications are stopped. During this time, a chimerism assay that defines how much of the blood comes from donor cells and how much of the blood comes from the recipient will be performed at four weeks, eight weeks, six months, one year after the transplant. This test will tell if the donor's transplanted cells are surviving long term in the recipient. If a recipient participant is eligible, the study regimen will begin about 30 days before bone marrow transplantation and participation will continue for up to 1 year after transplant.

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

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.

Number of participants with a new diagnosis of pulmonary hypertension by right heart cardiac catheterization (mean PAP>25 mmHg).

Number of participants with a new diagnosis of cardiomyopathy (Left ventricular function <30% on ECHO).

Number of participants initially diagnosed with diffuse scleroderma with an increase in mRSS score by 5 points.

Number of participant who experience a 10% or greater decrease in forced vital capacity (FVC) OR a 5-10% decrease in FVC AND 15% or greater decrease in diffusing capacity of the lungs for carbon monoxide (DLCO).

Number participants with increased high risk aGVHD according to revised Minnesota high risk aGVHD criteria.

Proportion of participants who are off of immunosuppression without GVHD or disease recurrence at 12 months post transplantation.

Number of participants who have experienced hematologic recovery at 12 months based on neutrophil and platelet counts.

Assess impact of BMT on histologic scleroderma biomarkers by measuring amount of autoreactive T cells

Additional exploratory objective- flow cytometric analysis of HLA-A, B or DR biomarkers on lymphocytes

Assess impact of BMT on histologic scleroderma biomarkers by assessment of flow cytometry. Complete donor chimerism will be defined as >95%.Mixed donor chimerism will be defined as >5%, but <95% CD3+ cells of donor origin.

Recipient Inclusion Criteria: 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: 2013 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 Vasectomy or female partner who had a tubal ligation Use of condoms with contraceptive foam Adequate organ function defined as: Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 45%. Systolic BP between 90- 170 mmHg Pulse between 60 and 100 bpm Respiratory Rate between 10 and 25 breaths per minute O2 saturation >92% on Room Air Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and AST and ALT < 2.0 x ULN. Renal: estimated creatinine clearance ≥ 40 mL/minute (using the Cockcroft-Gault formula and actual body weight). Cockcroft-Gault formula, based on ideal body weight (IBW): CrCl = (140 - age) x IBW (kg) x 0.85 for females/ PCr x 72 Pulmonary: DLCO (corrected/adjusted for hemoglobin) > 50% and FEV1 > 50% predicted (without administration of bronchodilator) and FVC > 60% predicted. Karnofsky performance score>70% Donor inclusion criteria: HLA-matched or -haploidentical, parent, child, sibling, or half-sibling of the recipient Eligible as per donor selection in FDA 21 CFR Part 1271 Meets all requirements for bone marrow donor selection criteria as described in the standard Johns Hopkins BMT Policies and Procedures. Medically healthy with no clinically significant findings in the physical examination, medical history, vital signs No history of any clinically significant immunosuppressive or autoimmune disease including hematologic malignancy or history of solid organ or allogeneic bone marrow transplantation; Ability to understand and provide informed consent for all study procedures including bone marrow harvest. Recipient Exclusion Criteria: Pregnant, breast feeding or considering becoming pregnant. Patients who are pre-terminal or moribund. Administration of an investigational compound either currently or within 30 days of beginning treatment; History of or positive serologic test for HIV, hepatitis B or C by PCR ; or any potentially communicable infectious disease as determined by the Investigator History of or positive serologic test for hepatitis C (exception: successful treatment with confirmation of sustained virologic response or evidence of viral clearance without prior treatment); Current or history of clinically significant diseases except for known scleroderma, including gastrointestinal, renal, hepatic, neurologic (e.g., epilepsy, neuropathy), hematologic, endocrine (e.g., diabetes), oncologic, pulmonary, immunologic, psychiatric, or any other condition, which, in the judgment of the investigator, is considered uncontrolled and would 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. Know additional abnormality suggestive of a disease and/or organ toxicity other than systemic sclerosis Uncontrolled diabetes with an HbA1C of >8% Acute kidney injury within the last 6 weeks/months Prior major surgery or radiation therapy within 4 weeks of beginning treatment; a. Administration of any live vaccine within 4 weeks of beginning treatment; Does not exclude COVID-19 vaccine Current or anticipated concomitant immunosuppressive therapy (excluding inhaled, topical skin and/or eye drop-containing corticosteroids, or low-dose methotrexate). Systemic corticosteroids must be discontinued at least 4 weeks prior to beginning treatment; Prisoner 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 allergic reactions, hypersensitivity, or intolerance attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Myocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities. Either of the following: Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) is <45% of predicted normal. Note that FEV1 testing also is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal. Known moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification. (Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.) Any illness or condition that in the opinion of the investigator may affect the safety of the subject or the evaluation of any study endpoint. Any subject who meets the following European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) cardiopulmonary criteria should be excluded from high dose cyclophosphamide containing HSCT regimens: Evidence of pulmonary arterial hypertension including baseline (resting) PASP > 40 mmHg or mPAP > 25 mmHg or PASP > 45 mmHg or mPAP > 30 mmHg after fluid challenge LVEF < 45% x Cardiographic signs of right ventricular dysfunction such as diastolic septal flattening (D-sign) Constrictive pericarditis or cardiac tamponade Significant atherosclerotic disease Severe untreated arrhythmias Severe ILD defined by the following: FVC < 60% at either screening or baseline. DLCO Hb <50% at either screening or baseline