Cytopenia
Conditions
Brief summary
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)).
Interventions
DRUGAZD0120
One time administration on Day 0.
DRUGBendamustin
Participants will be given bendamustin for 2 days (study Day -5 and Day -4) followed by 3 days of rest.
Sponsors
Saurabh Dahiya
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | within 28 days after the CAR-T administration | The incidence of adverse events defined as dose-limiting toxicities (DLTs), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events and serious adverse events following infusion | until 28 days after the CAR-T administration | Evaluate the safety of AZD0120 cells by the incidence and severity of adverse events, and serious adverse events, following infusion. Events will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or ASTCT Consensus Grading. |
| Number of CAR-T cells in blood | Day +3, +7, +10, +14, +21, +28 | The CAR T cell expansion and persistence will be followed at designated time points after infusion. Study participants should have detectable CAR T cells in the blood in at least 2 consecutive time points (Day +3, +7, +10, +14, +21, +28). |
| Clinical response rate | At 3, 6, 9, and 12-months post infusion | Measured by complete response (CR), response (R), durable response (DR), and treatment-free remission for each disease arm as determined by published guidelines. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSaurabh Dahiya, MD
Stanford University
Outcome results
None listed