Select subtypes of non-Hodgkin lymphoma (NHL): - diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) - high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements - transformed follicular lymphoma (FL) - grade 3b FL - Richter’s transformation of chronic lymphocytic leukemia (CLL) MedDRA version: 20.0 Level: LLT Classification code 10012
Conditions
Interventions
Product Name: Not applicable
Product Code: CTX110
Pharmaceutical Form: Dispersion for infusion
INN or Proposed INN: Not available
CAS Nu
Sponsors
CRISPR Therapeutics AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age =18 years. 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 histologically-confirmed (2016 World Health Organization classification) B-cell non-Hodgkin lymphomas: DLBCL NOS, high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed FL, grade 3b FL, or Richter’s transformation of CLL. • Confirmation of tumor histology from local pathology lab (archival tissue from last relapse [within 3 months of enrollment] or biopsy during screening). • At least 1 lesion that is fluorodeoxyglucose positron emission tomography–positive, as defined by Lugano criteria (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. • For NHL expansion cohort, subjects with Richter’s transformation of CLL will be excluded. 4. Refractory or relapsed disease, as evidenced by 2 or more lines of prior therapy, including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen, AND either 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 progressive disease on last therapy, or have stable disease following at least 2 cycles of therapy with duration of stable disease 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. 5. Eastern Cooperative Oncology Group performance status 0 or 1. 6. Meets criteria to undergo LD chemotherapy and CAR T cell infusion. 7. Adequate organ function: • Renal: Estimated glomerular filtration rate >50 ml/min/1.73 m^2. • Liver: Aspartate transaminase or alanine transaminase 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 contraception from enrollment through at least 12 months after CTX110 infusion. 10. Agree to participate in an additional long-term follow-up study after completion of this study. Participation in the long-term follow-up study requires separate consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 55 F.1.3 Elderly (>=65 years) yes
Exclusion criteria
Exclusion criteria: 1. Eligible for and agrees to autologous HSCT. 2. Treatment with the following therapies as described below: a. Prior treatment with any gene therapy or genetically modified cell therapy, including CAR T cells. b. 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. 4. Prior anaphylactic reaction to cyclophosphamide, fludarabine, or any of the excipients of CTX110 product. 5. Detectable malignant cells from cerebrospinal fluid (CSF) or magnetic resonance imaging indicating brain metastases during screening, or a history of central nervous system (CNS) involvement by malignancy (CSF or imaging). 6. History of a seizure disorder, 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. 8. Presence of bacterial, viral, or fungal infection that is uncontrolled or requires IV anti-infectives. 9. Positive for presence of human immunodeficiency virus type 1 or 2, or active hepatitis B virus or hepatitis C virus infection. Subjects with prior history of hepatitis B or C infection who have documented undetectable viral load (by quantitative polymerase chain reaction or nucleic acid testing) are permitted. 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. 11. Radiation therapy within 14 days of enrollment. 12. Use of systemic anti-tumor therapy or investigational agent within 14 days or 5 half-lives, whichever is longer, of enrollment. An exception is made for prior inhibitory/stimulatory immune checkpoint molecule therapy, which is prohibited within 3 half-lives of enrollment. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1 (dose escalation): To assess the safety of escalating doses of CTX110 in subjects with relapsed or refractory B-cell malignancies to determine the recommended Phase 2 dose (RP2D). Phase 2 (cohort expansion): To assess the efficacy of CTX110 in subjects with relapsed or refractory B-cell malignancies, as measured by objective response rate (ORR). ; Secondary Objective: Phase 1 and 2: To further characterize the efficacy, safety, and pharmacokinetics of CTX110. ; Primary end point(s): Phase 1: The incidence of adverse events, defined as dose-limiting toxicities. Phase 2: The objective response rate (complete response [CR] + partial response [PR]) per the Lugano Response Criteria for Malignant Lymphoma, as determined by independent central radiology review. ; Timepoint(s) of evaluation of this end point: Phase 1: The dose-limiting toxicity (DLT) evaluation period will begin with CTX110 infusion and last for 28 days. If a DLT-evaluable subject has signs or symptoms of a potential DLT, the DLT evaluation period will be extended according to the protocol-defined window to allow for improvement or resolution before a DLT is declared. Phase 2: - The interim analysis for futility will occur when 30 subjects have been enrolled and have 3 months of evaluable tumor response data. - The primary analysis of efficacy will occur after 77 subjects in the modified intention-to-treat (mITT) set have had the opportunity to be assessed for response 3 months after CTX110 infusion. - A final analysis will occur when all subjects complete or withdraw from the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy • Duration of response (central read). • Progression-free survival (central read). • Overall survival. Safety • Incidence and severity of adverse events and clinically significant laboratory abnormalities. ;Timepoint(s) of evaluation of this end point: A final analysis will occur when all subjects complete or withdraw from the study. | — |
Countries
Australia, Canada, Germany, United States
Contacts
Public ContactSteve Caffé
CRISPR Therapeutics
Outcome results
None listed