IRB Study Number 25-633
Status Recruiting
Phase Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
To evaluate whether liso-cel infusion results in improved efficacy, with respect to a theoretical value derived from historical references, in first line therapy for PCNSL in transplant-ineligible patients, based on investigator-assessed 12-month progression-free survival (PFS) probability.
Secondary Objectives
To assess additional parameters of efficacy of liso-cel in first line PCNSL
To assess health-related quality of life (HRQoL) measures in first line PCNSL receiving liso-cel
Inclusion Criteria
Signed Written Informed Consent
1) Participants or their legally acceptable representative must have signed and dated an IRB/IECapproved written ICF in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal patient care. Note: Participants must agree to comply with the requirements and restrictions listed in the informed consent (IC) and in this protocol.
Type of Participant and Target Disease Characteristics
2) Newly diagnosed primary central nervous system lymphoma (PCNSL).
3) Must have received at least 2 cycles of a standard of care (SOC) regimen prior to signing of ICF; corticosteroids used for symptom management before enrollment is allowed and administered at the discretion of the investigator.
4) Confirmed histopathological diagnosis of PCNSL of LBCL histology, assessed by local pathology, without evidence of an underlying systemic disease (ie, secondary CNS lymphoma). If a CNS lesion was not amenable for biopsy, imaging (eg MRI Brain ± MRI Full Spine) with CSF analysis for cytology may be used to confirm diagnosis, in lieu of a biopsy.
5) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6) No prior experimental treatments for PCNSL.
7) Transplant (ASCT)-ineligible based on investigator’s assessment and meeting at least one of the following criteria: age ≥65 years or HCT-CI score ≥3.
8) Suitable to receive a HD-MTX based regimen, based on investigator’s assessment.
9) MTX-sensitive disease at time of enrollment, as documented by a PR or CR on MRI Brain (±MRI Full Spine) per the investigator, based on IPCG criteria
Age of Participant
10) Participant must be 18 years or older of age, inclusive, at the time of signing the ICF.
Reproductive Status
Note: The investigator or designee shall counsel IOCBP participants (as defined in APPENDIX 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
Note: Local laws and regulations may require the use of alternative and/or additional contraceptive methods.
11) Female (as assigned at birth) participants:
Note: Female (as assigned at birth) participants who are not of childbearing potential (as defined in APPENDIX 3), must have documented proof.
Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.
Note: Individuals who are not of childbearing potential are exempt from contraceptive requirements.
a) IOCBP must have a negative highly sensitive pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.
Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.
b) IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
IOCBP are permitted to use hormonal contraceptive methods (as described in APPENDIX 3)
c) A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:
Is not an IOCBP OR
Is an IOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with user independent methods, as described in APPENDIX 3, during the intervention period and for at least 12 months (following the last dose of LDC) and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.
12) Male (as assigned at birth) participants:
Note: Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
a) Male participants are required to use a condom during the intervention period and for at least 12 months (following LDC) after the last dose of study intervention.
b) IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the study intervention period and for at least 12 months (following LDC) after the last dose of study intervention for the male participant.
c) Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) during the intervention period and for at least 12 months (following LDC) after the last dose of study intervention.
d) Male (as assigned at birth) participants must refrain from donating sperm during the intervention period and for at least 12 months (following LDC) after the last dose of study intervention.
e) Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms.
Other Inclusion Criteria
13) Platelets ≥ 75 x109/L
14) Absolute neutrophil count (ANC) ≥ 1.0 x109/L
15) Adequate organ function, defined as adequate bone marrow function to receive LD chemotherapy as assessed by investigator and according to the product label
16) Adequate vascular access for leukapheresis procedure.
17) Able to understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
18) Willing and able to adhere to the study visit schedule and all other protocol requirements.
Exclusion Criteria
Medical Conditions
1) Any condition that confounds the ability to interpret data from the study based on investigator’s or Sponsor’s judgement.
2) History of another primary malignancy that has not been in remission for ≥ 2 years with the exception of the following non-invasive malignancies:
a) Basal cell carcinoma of the skin
b) Squamous cell carcinoma of the skin in situ (Stage 0)
c) Carcinoma in situ of the cervix
d) Carcinoma in situ of the breast
e) Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor nodes, metastasis] clinical staging system) or prostate cancer that has been treated with curative intent
f) Other completely resected Stage 1 solid tumor with a less than 5% risk of recurrence within 2 years.
3) Prior treatment with CAR T-cell or any other gene therapy product that utilizes human genome-editing technology.
4) History of or active human immunodeficiency virus (HIV).
5) Active hepatitis B or active hepatitis C. (Note: Participants with a negative hepatitis B polymerase chain reaction [HepB PCR] assay or a negative hepatitis C virus RNA [HCV RNA] assay for viral load quantification for hepatitis B or C are permitted).
a) Participants positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with a negative viral load are eligible and should be considered for prophylactic antiviral therapy.
b) Participants with a prior history of active or chronic hepatitis C with a negative viral load are eligible and should be considered for prophylactic antiviral therapy.
6) Uncontrolled fungal, bacterial, viral (including SARS-CoV-2, COVID-19, Cytomegalovirus [CMV]; and Epstein-Barr virus [EBV]) or other infection (including tuberculosis) despite appropriate antimicrobials or other infection-directed treatments.
7) Active autoimmune disease requiring immunosuppressive therapy.
8) History of any of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, persistently prolonged corrected QT interval (QTc ≥ 501 ms) despite interventions, symptomatic dysrhythmias that require intervention (eg, atrial fibrillation, atrial flutter, atrioventricular [AV] block), cardiac arrest, unstable angina, history of ischemic stroke, or other clinically significant cardiac disease.
9) History of a symptomatic bleeding disorder within the past 6 months of signing the ICF, including hemorrhagic stroke and acute hemophilia-related bleeding complications.
10) History or presence of or clinically significant central nervous system (CNS) pathology such as epilepsy (a seizure disorder), an isolated seizure within the past 2 years, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson’s disease, Grade 3 or higher tremor, cerebellar disease, organic brain syndrome, or psychosis. If CNS pathology is deemed secondary to underlying PCNSL diagnosis by the investigator, is being actively managed without further clinical progression or deterioration, and in the best clinical judgment of the investigator does not constitute an exclusion criteria, the participant may still be considered eligible.
11) History of prior allogeneic transplant
12) A diagnosis of PIOL/PVRL and isolated CSF disease
13) Progressive vascular tumor invasion, thrombosis, or embolism.
14) Venous thrombosis or embolism not managed on a stable regimen of anticoagulation.
Prior/Concomitant Therapy
15) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7:
Concomitant Therapy.
16) Only protocol-mandated study interventions, “Holding Therapy” and Bridging Therapy are allowed following enrollment. See Section 5.1 and Section 7.7.
17) Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) are not allowed during the Treatment Period.
18) Live vaccines are prohibited for 6 weeks before starting study intervention.
19) Physiologic replacement, topical, and inhaled steroids are permitted. See Table 6.2-1 on washout for additional details.
Allergies and Adverse Drug Reactions
20) History of allergy/hypersensitivity to any component (including excipients) of the study.
21) Known allergy to DMSO and/or dextran.
Other Exclusion Criteria
22) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned while on study may be permitted to continue as a participant. Strict conditions apply.)
23) Ongoing, active, substance abuse (alcohol or other drug addiction).
24) Participation in another clinical trial concurrent with this study.
25) Any major surgery, as defined by the investigator, within 4 weeks prior to study intervention administration.
