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    Summary
    EudraCT Number:2018-003916-38
    Sponsor's Protocol Code Number:CRSP-ONC-001
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-05-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2018-003916-38
    A.3Full title of the trial
    A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of Allogeneic CRISPR-Cas9–Engineered T Cells (CTX110) in Subjects with Relapsed or Refractory B-Cell Malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to learn about the safety and efficacy of CTX110(the "study drug product") to treat certain types of blood cancer
    A.4.1Sponsor's protocol code numberCRSP-ONC-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCRISPR Therapeutics AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCRISPR Therapeutics AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCRISPR Therapeutics
    B.5.2Functional name of contact pointSteve Caffé
    B.5.3 Address:
    B.5.3.1Street Address610 Main Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1847347 0018
    B.5.6E-mailclinicaltrials@crisprtx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNot applicable
    D.3.2Product code CTX110
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number Not availabl
    D.3.9.2Current sponsor codeCTX110
    D.3.9.3Other descriptive nameCD19-directed allogeneic Chimeric Antigen Receptor T Cell
    D.3.9.4EV Substance CodeSUB197800
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number25 ×10^6 cells/mL to 85 x10^6 cells/mL
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    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)
    E.1.1.1Medical condition in easily understood language
    Blood cancers
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012820
    E.1.2Term Diffuse large B-cell lymphoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061871
    E.1.2Term Non-Hodgkin's lymphoma transformed recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10080217
    E.1.2Term High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10058728
    E.1.2Term Richter's syndrome
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).
    E.2.2Secondary objectives of the trial
    Phase 1 and 2:
    To further characterize the efficacy, safety, and pharmacokinetics of CTX110.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 <3 x upper limit of normal (ULN); total bilirubin <1.5xULN (for subjects with Gilbert’s syndrome, total bilirubin <2 mg/dL).
    • Cardiac: Hemodynamically stable and left ventricle 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 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    A final analysis will occur when all subjects complete or withdraw from the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Germany
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 95
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After completion of this study, all subjects will be required to participate in a separate long-term follow-up study for an additional 10 years to assess safety and survival.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-12-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-28
    P. End of Trial
    P.End of Trial StatusOngoing
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