This is an open-label, multicenter, Phase 1 study evaluating the safety and efficacy of CTX110 in subjects with relapsed or refractory B-cell malignancies.
Professor Chan Cheah
CRISPR Therapeutics AG
Adult B Cell ALL
The study may enroll up to 143 subjects in total. CTX110 is a CD19-directed chimeric antigen receptor (CAR) T cell immunotherapy comprised of allogeneic T cells prepared for the treatment of B cell malignancies. The cells are from healthy adult volunteer donors that are genetically modified ex vivo using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9) gene editing components (single guide RNA and Cas9 nuclease).
For all cohorts, unless otherwise specified
1. Age ≥18 years (Cohorts A, B, C, E, and F), or ≥18 to ≤70 years (Cohort D)2. Able to understand and comply with protocol-required study procedures and voluntarily sign a written informed consent document
3. Diagnosed with 1 of the following B cell malignancies: Cohorts A, B, C, E, and F: Histologically confirmed B cell NHLs: DLBCL NOS, high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed FL, or grade 3b FL
• Confirmation of tumor histology from local pathology lab (archival tissue from last relapse/progression [within 3 months of enrollment] or biopsy during screening)
• At least 1 measurable lesion that is FDG PET–positive, as defined by Lugano criteria (Deauville score of 4 or 5 on Lugano criteria 5-point scale). Note: Previously irradiated lesions will be considered measurable only if progression is documented following completion of radiation therapy.
Cohort D: Histologically confirmed B cell ALL
• D1: Bone marrow involvement with ≥5% blasts (see investigational plan in the protocol body)
• D2: Bone marrow MRD-positive (defined as >1 × 10-4 cells detected by flow cytometry or polymerase chain reaction [PCR]) with ≤5% blasts.
4. Refractory or relapsed disease, as evidenced by the following cohort-specific criteria:
Cohorts A, B, C, E, and F (NHL): 2 or more lines of prior therapy, including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen, AND have failed prior autologous hematopoietic stem cell transplantation (HSCT) OR ineligible for or refused prior autologous HSCT. Subjects who have received autologous HSCT must have recovered from HSCT-related toxicities.
• For refractory disease, subjects must have PD on last therapy, or have SD following at least 2 cycles of therapy, with duration of SD of up to 6 months.
• For subjects with transformed FL, subjects must have received at least 1 line of chemotherapy for disease after transformation to DLBCL.
Cohort D (adult B cell ALL):
• 2 or more lines of prior therapy, or
• Any bone marrow relapse after allogeneic HSCT; or
• Philadelphia chromosome–positive (Ph+) if subjects are intolerant to or ineligible for tyrosine kinase inhibitor (TKI) therapy, or have progressed after at least 1 line of TKI therapy
5. Eastern Cooperative Oncology Group performance status 0 or 1
6. Meets criteria to undergo LD chemotherapy (all cohorts), CAR T cell infusion (all cohorts), and daratumumab infusion (Cohort C only)
7. Adequate organ function:
• Renal: Estimated glomerular filtration rate >50 mL/min/1.73 m2
• Liver: Aspartate transaminase or alanine transaminase <3 × upper limit of normal (ULN); total bilirubin <1.5 × ULN (for subjects with Gilbert’s syndrome, total bilirubin <2 mg/dL)
• Cardiac: Hemodynamically stable and left ventricular ejection fraction ≥45% by echocardiogram
• Pulmonary: Oxygen saturation level on room air >91% per pulse oximetry
8. Female subjects of childbearing potential (postmenarcheal with an intact uterus and at least 1 ovary, who are less than 1 year postmenopausal) must agree to use acceptable method(s) of contraception from enrollment through at least 12 months after CTX110 infusion.
9. Male subjects must agree to use effective acceptable method(s) of contraception as specified in the protocol from enrollment through at least 12 months after CTX110.
For all cohorts, unless otherwise specified
1. Eligible for and agrees to autologous HSCT
2. Treatment with the following therapies as described below:
• Prior treatment with any gene therapy or genetically modified cell therapy, including CAR T cells
• Prior treatment with a CD19-directed antibody, bispecific T cell engager, or antibody-drug conjugate, unless there is confirmed CD19 expression (by immunohistochemistry or flow cytometry) after progression or relapse following most recent CD19-directed treatment
3. Prior allogeneic HSCT: For subjects with B cell ALL, prior allogeneic HSCT is permissible if it has been more than 6 months from HSCT at the time of enrollment; there is no evidence of acute or chronic GvHD; and the subject has recovered from HSCT-related toxicities, has been off immunosuppressive therapies for at least 3 months prior to enrollment, and has not received donor lymphocyte infusion for at least 2 months prior to enrollment.
4. Known contraindication to daratumumab (Cohort C only), cyclophosphamide, fludarabine, or any of the excipients of CTX110 product
5. Detectable malignant cells from cerebrospinal fluid (CSF) or magnetic resonance imaging (MRI) indicating brain metastases during screening, or a history of central nervous system (CNS) involvement by malignancy (CSF or imaging).
• Subjects with B cell ALL with a prior history of CNS involvement with no evidence of current CNS disease during screening may be included after SRC approval, based on safety data from the first 6 B cell ALL subjects with no CNS disease history treated in the dose escalation part of the study.
6. History of a seizure disorder, major cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement. 7. Unstable angina, clinically significant arrhythmia, or myocardial infarction within 6 months of enrollment, or grade 3 or higher pericardial effusion at the time of enrollment.
8. Presence of active bacterial, viral, or fungal infection that is uncontrolled, based on investigator judgment in consultation with the medical monitor
9. Positive for presence of human immunodeficiency virus (HIV) type 1 or 2, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects with prior history of HBV or HBC infection who have documented undetectable viral load (by quantitative polymerase chain reaction [PCR] or nucleic acid testing) are permitted. Infectious disease testing (HIV-1, HIV-2, HCV antibody and PCR, HBV surface antigen, HBV surface antibody, HBV core antibody) performed within 45 days of enrollment may be considered for subject eligibility.
10. Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma, adequately resected and in situ carcinoma of cervix, or a previous malignancy that was completely resected and has been in remission for ≥5 years of enrollment.
11. Radiation therapy within 14 days of enrollment
12. For Cohorts A, B, C, E, and F (NHL): Use of systemic antitumor therapy or investigational agent within 14 days or 5 half-lives, whichever is longer, of enrollment. Exceptions: 1) prior inhibitory/stimulatory immune checkpoint molecule therapy, which is prohibited within 3 half-lives of enrollment; and 2) rituximab use within 30 days prior to enrollment is prohibited (however PET/CT needs to occur at least 2 weeks after last rituximab dose).
For Cohort D (adult B cell ALL): Use of systemic antitumor therapy within 7 days of enrollment. Exceptions: 1) immunotherapy agents (i.e., rituximab, inotuzumab) must be stopped within 14 days of enrollment; 2) long-acting chemotherapy agents (e.g., pegylated asperigenase, methotrexate >25 mg/m2) must be stopped within 14 days of enrollment; and 3) investigational agent must be stopped after 5 half-lives have passed before enrolling. Subjects must have recovered to grade 1 CTCAE from acute toxicity (except hematological) of all previous therapy prior to enrollment. Steroids are permitted until 2 days before starting LD chemotherapy for maintenance or to allow for control of peripheral blood blasts.
13. Primary immunodeficiency disorder or active autoimmune disease requiring steroids and/or other immunosuppressive therapy
14. Diagnosis of significant psychiatric disorder or other medical condition that, in the opinion of the investigator, could impede the subject’s ability to participate in the study
15. Women who are pregnant or breastfeeding
16. Life expectancy of less than 6 weeks
For Cohort D only
17. Diagnosis of Burkitt’s lymphoma/leukemia
18. Isolated extramedullary disease