IKS03 in Patients with Advanced B Cell Non-Hodgkin Lymphomas

Eligibility Criteria

• 1. Males or females, ≥ 18 years of age
• 2. Part 1: documented B cell NHL (any subtype except Burkitt lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia); previously confirmed CD19-positive if feasible
• 3. Part 2: documented B cell NHL (subtypes to be determined); confirmed CD19-positive; possible expansion cohorts may include:
• 1. Diffuse large B cell lymphoma (including germinal center B cell type, activated B cell type)
• 2. Follicular lymphoma (including duodenal-type follicular lymphoma)
• 3. Mantle cell lymphoma
• 4. B cell lymphomas not specified
• 4. If B cell NHL subtype likely to have bone marrow involvement must be willing to undergo bone marrow biopsy in the event of an on-study complete response to confirm response
• 5. NHL that is relapsed, refractory to, or intolerant of existing therapy(ies) with known curative potential, or for which no standard therapy is available; must have received at least 2 prior lines of systemic therapy
• 6. Must be in need of systemic treatment and not require immediate cytoreductive therapy
• 7. Part 1: measurable or non-measurable disease
• 8. Part 2: measurable disease according to The Revised Criteria/Lugano Classification
• 9. Part 1: screening tumor biopsy requested, but optional; Part 2: patient must agree to screening tumor biopsy
• 10. ECOG performance status 0 or 1; anticipated life expectancy ≥ 10 weeks
• 11. Women of childbearing potential and fertile men agreeing to use two effective methods of contraception (including a highly effective method of contraception); women beginning 2 weeks prior to the first dose, men beginning prior to the first dose, and both continuing until 8 months after the last dose of study drug; male patients must also agree to refrain from sperm donation during this period.
• 12. Ability to understand and give written informed consent
• 1. Women who are pregnant or intending to become pregnant before, during, or within 8 months after the last dose of study drug; women who are breastfeeding
• 2. Patients documented to be CD19-negative
• 3. Central nervous system (CNS) lymphoma, leptomeningeal infiltration, or spinal cord compression not controlled by prior surgery or radiotherapy; symptoms suggesting CNS involvement
• 4. Part 2: History of another malignancy within 2 years, with the exception of:
• 1. Treated, non-melanoma skin cancers
• 2. Treated carcinoma in situ (e.g., breast, cervix)
• 3. Controlled, superficial carcinoma of the urinary bladder
• 4. T1a or b prostate carcinoma treated according to standard of care, with PSA within normal limits
• 5. Papillary thyroid carcinoma Stage I treated surgically for cure
• 5. Any of the following hematologic abnormalities at baseline (transfusion allowed \> 5 days previous):
• 1. Hemoglobin \< 8.0 g/dL
• 2. Absolute neutrophil count \< 1,000 per mm3
• 3. Platelet count \< 75,000 per mm3
• 6. Any of the following laboratory abnormalities at baseline:
• 1. Total bilirubin \> 1.5 × upper limit of normal (ULN); \> 3 × ULN if with Gilbert's Syndrome
• 2. AST or ALT \> 3 × ULN; \> 5 × ULN if due to hepatic involvement by tumor
• 3. Estimated GFR ≤ 60 mL/min corrected for BSA
• 4. Albuminuria defined as urine albumin to creatinine ratio \< 30 mg/g or \< 3 mg/mmol) by spot urine albumin
• 7. Any of the following coagulation parameter abnormalities at baseline unless on a stable dose of anticoagulant therapy for a prior thrombotic event:
• 1. PT or INR \> 1.5 × ULN; \> 3× ULN if anticoagulated)
• 2. PTT \> 1.5 × ULN; \> 3× ULN if anticoagulated
• 8. Any of the following laboratory abnormalities at baseline aimed at assessing renal function:
• 1. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min, corrected for BSA.
• 2. Albuminuria defined as urine albumin to creatinine ratio (UACR) ≥ 30 mg/g or ≥ 3 mg/mmol by spot urine albumin
• 9. Patients with:
• 1. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks unless adequately treated and stable
• 2. Active uncontrolled bleeding or a known bleeding diathesis
• 10. Significant cardiovascular disease or condition, including:
• 1. Congestive heart failure or angina pectoris requiring therapy
• 2. Ventricular arrhythmia requiring therapy or other uncontrolled arrhythmia
• 3. Severe conduction disturbance (e.g., 3rd degree heart block)
• 4. QTc interval ≥ 480 milliseconds
• 5. Left ventricular ejection fraction below the lower limit of normal or \< 50% by MUGA scan or echocardiogram
• 6. Class III or IV cardiovascular disease according to the New York Heart Association Functional Classification
• 7. History of acute coronary syndromes (e.g., MI, unstable angina), coronary angioplasty, stenting, or bypass within 6 months
• 11. Significant liver disease, including:
• 1. Non-infectious hepatitis
• 2. Hepatic cirrhosis (Child-Pugh Class B and Class C)
• 12. Significant pulmonary disease or condition, including:
• 1. Significant symptomatic COPD, as assessed by the Investigator
• 2. History or any current evidence on imaging studies of interstitial lung disease, pulmonary fibrosis
• 3. History of pulmonary inflammatory disease, pneumonitis, ARDS
• 4. History of pneumonia within 6 months
• 13. Significant corneal disease or condition, including history of or current evidence of keratitis
• 14. Clinically significant CNS disease or condition including PML, epilepsy, vasculitis, or neurodegenerative disease. Also including TIA or stroke within 6 months
• 15. Known HIV infection or AIDS
• 16. Active hepatitis B virus or hepatitis C virus infection
• 17. Any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever \> 38ºC within 2 weeks
• 18. Autoimmune disease or condition requiring systemic steroids or other immunosuppressive medications
• 19. Unresolved Grade \> 1 AE associated with any prior antineoplastic therapy (except persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, neutropenia, lymphopenia, hypomagnesemia, and/or endocrine end-organ failure being adequately managed by HRT)
• 20. Known or suspected hypersensitivity to any of the excipients of formulated study drug
• 21. Inadequate recovery from a surgical procedure, or a major surgical procedure within 4 weeks
• 22. Any other serious, life-threatening, or unstable preexisting medical condition, including significant organ system dysfunction, or clinically significant laboratory abnormality(ies)
• 23. A psychiatric disorder or altered mental status that would preclude understanding of the informed consent process
• 1. Receipt of:
• 1. Any CD19-targeted therapy within 3 months
• 2. Any tumor vaccine within 6 weeks (must have progressed if previously received)
• 2. Prior autologous/allogeneic CAR-T therapy if known to be CD19-negative after
• 3. Any other antineoplastic agent for the primary malignancy without delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest (except nitrosoureas and mitomycin C within 6 weeks)
• 4. Any other investigational treatments within 4 weeks
• 5. Drugs known to impair renal function, including:
• 1. NSAIDS within 3 days
• 2. Aminoglycoside antibiotics, amphotericin B, etc. within 1 week
• 3. Bisphosphonates within 1 month
• 6. Prior solid organ transplant
• 7. Allogeneic HSCT within 6 months, or:
• 1. If receiving immunosuppression
• 2. If with active evidence of GVHD
• 8. Autologous hematopoietic stem cell transplantation (HSCT) within 3 months
• 9. Radiotherapy:
• 1. To target lesions within 4 weeks unless progression of the lesion has been documented
• 2. To non-target lesions within 1 week
• 10. Live/live-attenuated vaccines against infectious diseases within 4 weeks
• 11. Immunosuppressive or systemic glucocorticoid therapy (\> 10 mg prednisone daily or equivalent) within 2 weeks
• 12. Prophylactic use of hematopoietic growth factors within 1 week
• 13. Herbal therapies and supplements within 2 weeks
• 14. Strong inhibitors of cytochrome P450 within 2 weeks