Autoimmune Cytopenia Elimination by Chimeric Antigen Receptor T-cell Therapy

A Phase 1, Open-Label, Single Center Study of AZD0120 (Also Known as GC012F), a Chimeric Antigen Receptor T Cell Therapy Targeting CD19 and B Cell Maturation Antigen (BCMA), in Subjects With Relapsed and Refractory Persistent Autoimmune Cytopenia

This is a phase 1 study to evaluate the safety and tolerability of AZD0120 in patients with relapsed or refractory immune mediated cytopenia (primary chronic Immune Thrombocytopenia (ITP) or autoimmune hemolytic anemia (wAIHA)).

Inclusion Criteria:

1. Diagnosis of primary chronic immune thrombocytopenia (ITP) or warm autoimmune hemolytic anemia (wAIHA) according to the published consensus criteria

2. a. 2 or more prior treatments for ITP wherein the following conditions are required to define prior treatments:

   • 1st line treatment includes steroids (dexamethasone, prednisone or equivalent), IVIG, and/or Anti-Rhd Ig. These medications may be administered in combination or in series.
   • 2nd line treatment includes the use of thrombopoietic agents, and anti-CD20 mAbs.

   These medications may be given in combination or in series.

   • A failure to respond to splenectomy is considered an additional line of therapy.

   Thus, in order to be study eligible, a potential participant must have refractory chronic ITP and have received high dose steroids, IVIG, TPO agonists, and anti-CD20mAbs, with evidence of treatment failure, resistance, or relapse following steroids, TPO agonists, and anti-CD20 mAbs. Participants must have failed both steroids and TPO-RA to be eligible. b. 2 or more prior treatments for AIHA wherein the following conditions are required to define prior treatments:

   • 1st line treatment includes high dose-steroids (dexamethasone, prednisone or equivalent), IVIG, and/or Anti-Rhd Ig. These medications may be administered in combination or in series.
   • 2nd line treatment includes the use of corticosteroids, anti-CD20 mAbs. These medications may be given in combination or in series.
   • A failure to respond to splenectomy is considered an additional line of therapy.

   Thus, in order to be study eligible, a potential participant must have refractory AIHA and have received high dose steroids, IVIG, and anti-CD20mAbs, with evidence of treatment failure, resistance, or relapse following steroids and anti-CD20 mAbs.

   Participants must have failed both steroids and anti-CD20 mAbs (i.e., rituximab) to be eligible.

3. Organ and Marrow Function

   • ANC ≥ 1000/uL.

   • Absolute lymphocyte count ≥ 600/uL.

   • Adequate renal, hepatic, pulmonary and cardiac function defined as:

     • Creatinine ≤ 2 mg/dL or creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 50 mL/min.
     • Serum ALT/AST <2.5 times ULN.
     • Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
     • Cardiac ejection fraction ≥ 50%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings.
     • Baseline oxygen saturation > 92% on room air.

4. Testing for i) HBc Ab ii) HCV Ab iii) Hep B surf. AG iv) HIV 1&2 Ab v) Syphilis Screen vi) HTLV Ab I & II vii) NAT MPX (nucleic acid test multiplex) for HIV, HCV, HBV viii) Herpes Simplex Virus 1 & 2 IgG panel ix) VZ IgG x) CMV Total Ab Must be seronegative for HIV-1 RNA PCR; HIV 1 and HIV 2 Ab (antibody); HTLV-1 and HTLV-2 Ab; PCR- or sAg negative (surface antigen for hepatitis B); negative for the Treponema pallidum antibody Syphilis screen; and negative for HIV-1 and hepatitis C by nucleic acid testing (NAT) within 40 days of apheresis procedures.

5. 6. Females of childbearing potential have a negative serum or urine pregnancy test because of the potentially dangerous/unknown effects on the fetus. Women not of child-bearing potential are defined as females who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are post-menopausal. Females will be considered post-menopausal if they have been amenorrhoeic for 12 months prior to the planned date of assignment to treatment arm without an alternative medical cause. A high FSH level in post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. A post-menopausal state is confirmed by 2 consecutive high FSH values (at least 4 weeks apart) in the post-menopausal range.

6. 7. Contraception: Subjects of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment on this study. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For AZD0120: effective contraception must be used for at least 12 months after receiving AZD0120 infusion or CAR T-cell DNA is no longer detectable by PCR, whichever occurs later. For participants who receive only bendamustine for some reason but not AZD0120: males must use contraception for 3 months after last dose; females must use contraception for 6 months after last dose.

7. Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.

8. Adequate vital sign criterion with acceptable numerical ranges of:

   • Systolic Blood Pressure (mmHg) ≥ 100 and ≤ 150
   • Diastolic Blood pressure (mmHg) ≥ 60 and ≤ 90
   • To ensure subject safety and stability, any subject who is noted to have a BP > 150/90 mm Hg should be stable on anti-hypertensive medications with repeated BP ≤150/90 for at least one month prior to enrollment in the study
   • Baseline Heart Rate ≥ 60 and ≤ 100 bpm
   • Oral Temperature ≤ 37.7 C/afebrile
   • Respiratory rate ≥ 12 and ≤ 20bpm

9. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening to be eligible for enrollment.

Exclusion Criteria:

1. For ITP - ITP Bleeding Scale Grade 3 or higher at the screening visit (with the exception of menorrhagia controlled with hormonal therapy +/- tranexamic acid)
2. For ITP - Hgb < 8 g/dL (NOTE: Exclusion does not apply to Evans Syndrome).
3. For wAIHA - subjects with signs of hemolysis not attributable to wAIHA are excluded.
4. For wAIHA - platelet count <100,000/uL (NOTE: ITP subjects may be below this threshold if due to active ITP. Exclusion does not apply to Evans Syndrome).
5. For ITP - Secondary ITP (including but not limited to associated with a lymphoproliferative disorder, positive screening tests for HIV, HCV, H. pylori, Common Variable Immunodeficiency)
6. For wAIHA - Secondary wAIHA (including but not limited to associated with lymphoproliferative disorder, positive screening tests for HIV, HCV, Common Variable Immunodeficiency)
7. Prior treatment with any investigational agent within 3 months, or 5 half-lives, whichever is longer. Agents authorized by the FDA for prevention or treatment of SARS-CoV-2 are not considered investigational.
8. Subjects who received immunosuppressants (i.e., mycophenolate mofetil, azathioprine, methotrexate, calcineurin inhibitors, tyrosine kinase inhibitors) within one month prior to the CAR T infusion are excluded.
9. History of sickle cell anemia or other hemoglobinopathy (hemoglobinopathy trait is not an exclusion criteria).
10. Coagulation abnormalities defined by: INR > 1.6, PT > 15 seconds, PTT > 45 seconds to the exclusion criteria. Patients with positive antiphospholipid antibodies, including anti-cardiolipin, or lupus anticoagulant.
11. Presence of fungal, bacterial, viral, or other infection that is not controlled and/ or requiring hospitalization or treatment with IV antimicrobials within 4 weeks of screening. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
12. Psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the Stanford Transplant team caring for this potential patient would place the patient at an unacceptable risk. Participant has significant neurological or psychiatric condition (active or history of) including but not limited to severe brain injury, dementia, cerebellar disease, Parkinson's disease, clinical evidence of dementia or altered mental status, or stroke, intracranial hemorrhage, or seizure within 6 months before signing ICF. Participants with existing stable, mild neurological conditions that have not progressed in the last 6 months (e.g., essential tremor) may be considered eligible at the Investigator's discretion, following appropriate neurological consultation.
13. Presence or history of liver cirrhosis.
14. Presence or history of MDS; presence of bone marrow failure and malignant bone marrow disorders confirmed by bone marrow examination (aspirate and/or biopsy).
15. Patients without a bone marrow aspirate and/or biopsy performed within 12 months prior to screening to confirm the primary cause of the disease.
16. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) or localized prostate cancer requiring no treatment unless disease free for at least 2 years.
17. Active infection with HIV, hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study may pose unacceptable risk. A prior history of hepatitis B or hepatitis C is permitted providing the viral load is undetectable per quantitative PCR and/or nucleic acid testing. Hepatitis B surface antibody following hepatitis B immunization is not considered to be evidence of past infection.
18. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease (uncontrolled congestive heart failure) within 3 months of enrollment. Subjects with stable cardiac disease fulfilling inclusion criteria are allowed.
19. History of Crohn's, rheumatoid arthritis, systemic lupus that required continued systemic immunosuppression/systemic disease modifying agents within the 2 years prior to trial enrollment.
20. A primary immune deficiency disease.
21. In the investigator's judgment, the subject is unlikely to complete protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
22. History of severe immediate hypersensitivity reaction to any of the agents used in this study. This includes contraindications or life-threatening allergies, hypersensitivity, or intolerance to AZD0120 or its excipients, including dimethyl sulfoxide; bendamustine; or tocilizumab.
23. Any medical condition that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of study treatment.
24. Prior treatment with autologous cellular immunotherapy (e.g., CAR T) or gene therapy directed at any target.
25. Treatment with anti-CD20+, CD19+ or BCMA+ monoclonal antibody therapy within 3 months of trial initiation or with B cell counts less than 50% of the lower limit of normal.
26. Prior history of solid organ transplantation
27. QTc >450msec in males or >470msecs in females