CARLOTTA01: A Phase I Trial to Establish the Safety and Maximum Tolerated Dose of High-affinity Autologous BCMA-targeting CAR T-cells in Patients With Relapsed and Refractory B-cell Malignancies
Study Details
Study Description
Brief Summary
The purpose of this phase I study is to determine whether MDC-CAR-BCMA001 (BCMA directed CAR T-cells) is safe and tolerable in the treatment of relapsed and refractory B-cell malignancies
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: MDC-CAR-BCMA001 MDC-CAR-BCMA001 will be administered intravenously in ascending dose levels. This trial will test a total of 4 dose levels in order to identify the MTD and/or RP2D for MDC-CAR-BCMA001. |
Genetic: MDC-CAR-BCMA001 (BCMA directed CAR T-cells)
Single-dose interavenous infusion of MDC-CAR-BCMA001 at the respective dose level following a conditioning chemotherapy
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose (MTD) of MDC-CAR-BCMA001 [appr. 24 months]
The MTD will be defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
- Incidence and severity of adverse events and serious adverse events graded according to CTCAE V5.0 and ASTCT consensus criteria for CRS and ICANS [appr. 24 months]
- Incidence of DLT during DLT-evaluation period and beyond [appr.24 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female patients aged ≥ 18 years
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Written informed consent of the subject
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Able and willing to adhere to the trial protocol
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ECOG performance status 0-2
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Either Multiple Myeloma (MM):
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relapsed or refractory disease after at least 2 lines of treatment including an IMiD, a proteasome inhibitor and an anti-CD38 an-tibody or anti-CD319 (SLAMF7; Elotuzumab) antibody AND
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not eligible for treatment with other regimen available accord-ing to local standard of care and known to confer clinical ben-efit according to the investigator's discretion, prior treatment with other BCMA-targeting immunotherapies (including T-cell engaging antibodies, CAR T-cells and antibody-drug immuno-conjugates) is allowed AND
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measurable disease defined by serum M-Protein ≥ 10 g/l OR urine M-Protein ≥ 200 mg/24h OR serum free light chain > 100 mg/l of involved FLC and abnormal serum free light chain ratio
OR
Diffuse large B-cell lymphoma (DLBCL):
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Relapsed after or refractory to standard curative therapy (such as R-CHOP) and refractory to at least one course of standard salvage chemotherapy OR
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Relapsed within one year after high-dose chemotherapy and autologous stem cell support OR
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Relapsed after allogeneic stem-cell transplantation or ap-proved anti-CD19 CAR T-cell therapies.
AND (applicable to all DLBCL patients)
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Not be eligible for treatment with other regimen available ac-cording to local standard of care and known to confer clinical benefit. This includes but is not limited to anti-CD19 directed CAR T-cell therapies with approved constructs AND (applicable to all DLBCL patients)
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Measurable disease according to Lugano criteria
- Adequate organ function defined as:
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Neutrophils ≥ 0.5 Gpt/l and Platelets ≥ 50 Gpt/l (unless due to subtotal infiltration of the bone marrow by underlying malig-nancy)
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Lymphocytes ≥ 0.1 Gpt/l
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ALAT and ASAT ≤ 3.0x ULN
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Bilirubin ≤ 1.5x ULN
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Creatinine ≤ 1.5x ULN
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Adequate cardiac function i.e. LVEF ≥ 50%, no major valve abnormalities or dyskinesias
- A female of childbearing potential* may be enrolled providing she has a negative pregnancy test at screening and is routinely using a highly effective method of birth control (pearl index of ≤ 1 required) resulting in a low failure rate (e.g. hormonal contraception, intrauterine device, total sexual abstinence or sterilization). Male patients must also prac-tice a highly effective method of birth control and should not father a child at least until 12 months after infusion of CAR T-cells
Exclusion Criteria:
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Any CNS-involvement by underlying disease
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History of seizure or cerebrovascular ischemia / hemorrhage within the last 12 months
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History of any autoimmune CNS disease (e.g. multiple sclerosis, amy-otrophic lateral sclerosis, optic neuritis)
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Ongoing neurologic conditions that in the opinion of the investigator might increase the risk for neurotoxicity or impair the assessment of CAR-associated neurotoxicity
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Inadequate pulmonary function (i.e. need for continuous oxygen sup-port)
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Patients on hemodialysis
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Any contraindications to Fludarabine and/or Cyclophosphamide as given in the SmPC
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Any other active malignancy requiring active treatment or interfering with the assessment of primary or secondary trial endpoints, adjuvant hormonal therapy is allowed
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Positivity for anti-human immunodeficiency virus (HIV) immunoglobulin
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Active or chronic infectious hepatitis B (HBV) and C (HCV) virus unless serology demonstrates clearance of infection (i.e. PCR undetectable viral load for hepatitis)
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Active infection with SARS-CoV2 or history of SARS-CoV2 infection within the past 3 months or active long COVID syndrome
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Uncontrolled bacterial, viral or fungal infections defined as infections needing in-patient and/or i.v. antimicrobial treatment*
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Active Graft versus Host Disease defined as active symptoms of GvHD or ongoing immunosuppressive treatment or prophylaxis within the last 30 days prior to application of MDC-CAR-BCMA001
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Psychologic disorders, drug abuse or any other condition which might significantly impair a patient's ability to comply with the trial protocol
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Patients who are expected to deteriorate during the time needed for manufacturing MDC-CAR-BCMA001 in spite of bridging therapy in the opinion of the investigator including
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Any condition requiring systemic treatment with immunosuppressive drugs (including but not limited to steroids exceeding 20 mg Predniso-lone per day)
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Any antineoplastic treatment within 7 days prior to leukapheresis or within 2 weeks or 5 half-lives (whatever is shorter) of the start of lym-phodepleting chemotherapy (palliative radiotherapy to lesions not es-sential for response assessment is allowed without a minimal washout period)
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Any investigational therapy within 4 weeks or 5 half-lives (whatever is shorter) prior to apheresis or the start of lymphodepleting chemothera-py
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History of allergic reactions to any drug or its ingredients / impurities foreseen to be given as part of this trial according to the protocol*
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Receipt of live vaccines within 2 weeks prior to leukapheresis and start of lymphodepleting chemotherapy
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Pregnant or breastfeeding women. Breastfeeding has to be discontin-ued before onset of and during treatment and should be discontinued for at least 3 months after end of treatment.
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Women of childbearing potential, except women who meet the following criteria:
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post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum FSH > 40 U/ml)
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postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy)
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regular and correct use of a contraceptive method with an Pearl Index < 1% per year
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sexual abstinence
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Vasectomy of the partner
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Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure
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Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)
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Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences
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Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Technische Universität Dresden, NCT/UCC, Early Clinical Trial Unit | Dresden | Germany | 01307 |
Sponsors and Collaborators
- Technische Universität Dresden
- German Cancer Research Center
Investigators
- Principal Investigator: Martin Wermke, Prof., Technische Universität Dresden (TUD)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TUD-BCMACA-078