Phase I/II Study of AD-PluReceptor Plus Tafasitamab-cxix and Lymphodepleting Chemotherapy in Patients With Autoimmune Disorders

Inclusion Criteria

• •A. Diagnosis of SSc defined as follows:
• •i) Fulfilling 2013 American College of Rheumatology (ACR)and European League Against Rheumatism classification (EULAR) criteria for SSc.46 ii) Antinuclear Antibody (ANA) by immunofluorescence positive at titer ≥ 1:80 at screening or prior to screening.
• •B. SSc disease activity i) Diffuse SSc meeting the following criteria:
• •(1) Disease duration ≤ 7 years (from onset of first non-Raynaud manifestation) AND (2) mRSS ≥ 15 at screening (Appendix 1) OR ii) Participants diagnosed with diffuse or limited cutaneous SSc AND presence of ILD changes on HRCT AND Disease duration ≤ 7 years (from onset of first non- Raynaud manifestation) AND either (1) or (2)
• •1. Progressive ILD as defined by Raghu et al47 (≥ 2 of the following):
• •(a) worsening respiratory symptoms (b) physiological evidence of disease progression (≥ 1 of the following): (i) Absolute decline in FVC ≥ 5% predicted within 1 year of follow-up (ii) Absolute decline in DLCO (corrected for Hb) ≥ 10% predicted within 1 year of follow-up radiological evidence of disease progression (c) radiological evidence of disease progression (≥ 1 of the following):
• •(i) Increased extent or severity of traction bronchiectasis and bronchiolectasis.
• •(ii) New ground-glass opacity with traction bronchiectasis (iii) New fine reticulation (iv) Increased extent or increased coarseness of reticular abnormality.
• •(v) New or increased honeycombing (vi) Increased lobar volume loss
• •2. FVC \< 80% predicted or extent of ILD changes on HRCT \> 20%. C. Inadequate response to at least 1 of the following treatments used for at least 3 months: mycophenolate, cyclophosphamide, rituximab, and/or tocilizumab
• •1. A clinical diagnosis of SLE, based on the 2019 EULAR/ ACR classification criteria for adult SLE.
• •2. Positive ANA titer ≥1:80 or positive anti-dsDNA antibody at screening or prior to screening.
• •3. For LN subjects only: Active, biopsy-proven lupus nephritis (kidney biopsy should have been done within 1 year of study enrollment) class III or IV, with or without the presence of Class V, using the 2018 Revised International Society of Nephrology/Renal Pathology Society criteria48.
• •a. For LN subjects: urine protein-to-creatinine ratio (UPCR) ≥0.5 g/g on 2 first morning void urine samples during screening despite prior or current treatment with standard of care therapy for at least 12 weeks, including corticosteroids, MMF/mycophenolic acid (MPA), CY, calcineurin inhibitors, belimumab, and/or rituximab. Patients should have failed at least 2 standard of care immunosuppressive therapies tried for 3 months, b. For non-renal SLE subjects: SLEDAI-2K ≥8 and clinical SLEDAI-2K ≥6 (excluding headache, alopecia, mucosal ulcers, fever, and organic brain syndrome) or ≥ 1 major organ system with a BILAG A score (excluding musculoskeletal, mucocutaneous, and/or constitutional organ system) during screening despite prior or current treatment with standard of care therapy, including corticosteroids, rituximab or other B cell depleting agents, CY, MMF/MPA, azathioprine, methotrexate, 6-mercaptopurine, sirolimus, tacrolimus, thalidomide, leflunomide, mizorbine, anifrolumab, and/or belimumab. Patients should have failed at least 2 standard of care immunosuppressive therapies tried for 3 months, or failed due to intolerance, or unable to obtain medication.
• •5. If a subject is currently receiving:
• •1. A renin-angiotensin-aldosterone inhibitor, (including direct renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor blockers), the subject must be on a stable dose for at least 8 weeks prior to screening. A sodium-glucose cotransporter-2 (SGLT2) inhibitor, the subject must be on a stable dose for at least 8 weeks prior to screening.
• •2. Regarding oral corticosteroid, doses \<0.5 mg/kg prednisone equivalent at the time of enrollment are required. Steroid taper to ≤10 mg prednisone equivalent prior to lymphodepleting chemotherapy is recommended.
• •1. The patient has a history of steroid resistant chronic graft versus host disease (SR- chronic GVHD) or is intolerant of or has unacceptable complications with steroids.
• •Definition of SR-chronic GVHD - Chronic GVHD that does not respond adequately to full-dose prednisone. Any of the following conditions would be considered SR-chronic GVHD:
• •* Progressive symptoms / manifestations of chronic GVHD despite receiving prednisone 1 mg/kg/day (or equivalent) for two weeks
• •* Stable symptoms / manifestations of chronic GVHD after four to six weeks of prednisone ≥0.5 mg/kg/day (or equivalent)
• •* Inability to taper prednisone to \<0.5 mg/kg/day (or equivalent) without worsening of symptoms / manifestations of chronic GVHD
• •2. Disease activity:
• •• Manifestations/symptoms of chronic GVHD rated as moderate to severe on the NIH chronic GVHD global severity score.
• •3. Manifestations/symptoms of chronic GVHD that have not adequately responded or intolerant to both:
• •* Ruxolitinib
• •* Belumosudil.
• •4. May be receiving adrenal replacement doses of corticosteroids
• •1. Able to provide informed consent.
• •2. Age ≥18 to ≤80 years.
• •3. Adequate organ function i) Peripheral blood absolute neutrophil count (ANC) ≥ 1 × 109/L, unless the neutropenia is deemed to be caused by the underlying autoimmune disease.
• •ii) Hemoglobin ≥ 8 g/dl, unless the anemia is deemed to be caused by the underlying autoimmune disease.
• •iii) Platelet count ≥ 50 × 109/L without platelet transfusion support, unless the thrombocytopenia is deemed to be caused by the underlying autoimmune disease. No clinically significant active bleeding.
• •iv) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN) and total bilirubin ≤ 3 × ULN (or direct bilirubin ≤ 3 × ULN with documented Gilbert's syndrome).
• •v) Oxygen saturation (SaO2) ≥ 92% on room air (as measured by forehead probes in SSc patients).
• •vi) Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 45% as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
• •vii) Adequate renal function, defined as serum creatinine ≤ 2x ULN and estimated Glomerular Filtration Rate (eGFR using the CKD-EPI equation) ≥ 30 ml/min/1.73 m2 5. Recovery to ≤ Grade 1 or baseline of any non-hematological toxicities due to prior therapy.
• •6\. Negative pregnancy test in WOCBP. 7. All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of therapy. Acceptable forms of birth control for female patients include hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor. Participant is willing and able to adhere to the study visit schedule and other protocol requirements and willing to sign informed consent.