IRB Study Number 25-151
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
2.1. Primary Objective
To determine recommended phase II dose of human LMY-920 in patients with relapsed or refractory CLL/SLL.
2.2. Secondary Objectives
To establish toxicity profile for the infusion of LMY-920.
To determine the objective response rate per international workshop in Chronic Lymphocytic Leukemia22 after treatment with LMY-920 in patients with relapsed or refractory CLL/SLL.
To determine the complete response rate per international workshop in Chronic Lymphocytic Leukemia22 after treatment with LMY-920 in patients with relapsed or refractory CLL/SLL.
To determine the duration of response in patients with relapsed or refractory CLL/SLL treated with LMY-920.
To determine the progression-free survival in patients with relapsed or refractory CLL/SLL lymphoma treated with LMY-920.
To determine the overall survival in patients with relapsed or refractory CLL/SLL treated with LMY-920.
Inclusion Criteria
- Histologically confirmed chronic lymphocytic leukemia (including small lymphocytic lymphoma)
o Relapsed after 2 or more lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.
No evidence of CNS lymphoma.
Male or female ≥ 18 years of age.
ECOG Performance status ≤ 2 [See Appendix 1].
Presence of Presence of active disease for patients with CLL and SLL and presence of measurable disease for patients with SLL.
A. CLL/SLL (note that SLL patients must have both measurable disease and active disease): Active disease as defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), with at least one of the following criteria21:
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hb <10 g/dL or platelet counts <100 × 109/L are generally regarded as indication for treatment.
Massive (i.e., ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
Massive nodes (i.e., ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine, etc.).
Disease-related symptoms as defined by any of the following:
o Unintentional weight loss ≥10% within the previous 6 months.
o Significant fatigue (ie, ECOG performance scale 2 or worse; cannot work or unable to perform usual activities).
o Fevers ≥100.5°F or 38.0°C for 2 or more weeks without evidence of infection.
o Night sweats for ≥1 month without evidence of infection.
B. Measurable disease for patients with SLL: At least one measurable lesion according to Lugano Revised Response Criteria for Malignant Lymphoma1.
>2 weeks since prior radiation therapy or 5 half-lives for systemic therapy at the time of leukapheresis, whichever is shorter (Note: Obinutuzumab pre-treatment of CLL/SLL patients must start at the latest 14 days prior to apheresis).
Total bilirubin ≤ 1.5 X upper institutional limit of normal (except in patients with Gilbert’s syndrome, active hemolysis or disease involvement of the liver).
AST (SGOT)/ALT ≤ 2.5 X institutional upper limit of normal.
Calculated creatinine clearance ≥ 30ml/min.
Cardiac ejection fraction of ≥50%
Adequate pulmonary function as defined as pulse oximetry ≥ 92% on room air.
Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document.
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 90 days after the BAFF CAR-T cell infusion. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormonereleasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the BAFF CAR-T cell infusion. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the BAFF CAR- T cell infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria
ASCT within 6 weeks of informed consent.
History of allogeneic hematopoietic stem cell transplantation.
Active graft-versus-host disease.
Active central nervous system or meningeal involvement by lymphoma or leukemia. Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced MRI imaging for at least 90 days prior to registration.
Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast).
Known active additional malignancies which require systemic treatment (non-immediately morbid malignancies receiving only low-toxicity regimens such as hormone suppression for prostate or breast cancer may be allowed at the judgment of the investigator).
Less than 28 days elapsed between prior treatment with investigational agent(s) and the day of lymphocyte collection.
New York Heart Association class IV congestive heart failure.
Cardiovascular disorders including unstable angina pectoris, clinically significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack, or other ischemic event) within 6 months prior to registration.
Active infection requiring intravenous systemic treatment.
HIV seropositivity.
Pregnant or breastfeeding women are excluded from this study because LMY-920 therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMY-920, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study.
Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy.
Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
Patients with history of active and clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson’s disease.
Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
History of autoimmune disease (i.e., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medications (other than low dose steroids) within 6 months.
