Clinical trial with dasatinib for the prevention of CAR-T side effects in patients with relapsed or treatment-resistant multiple myeloma undergoing therapy with idecabtagene vicleucel

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Wuerzburg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Immune System Diseases [C20]

Decision date (initial)

2024-02-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Bristol-Myers Squibb Pharma · University Hospital of Würzburg

External identifiers

EU CT number

2023-507537-16-00

WHO UTN

U1111-1296-5220

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Prophylaxis, Pharmacokinetic

1. Evaluate the safety and tolerability of dasatinib administration as CRS prophylaxis including number of TEAEs (phase I and II) and DLT rate (phase I)

2. Evaluate the efficacy of dasatinib in preventing the occurrence of CRS

Secondary objectives 13

1. Efficacy of dasatinib in preventing higher-grade CRS
2. Evaluation of CRS onset
3. Duration of CRS
4. Efficacy of dasatinib in preventing the occurrence of ICANS
5. Evaluation of ICANS onset
6. Duration of ICANS
7. Occurrence and duration of prolonged and/or severe cytopenia.
8. Occurrence and duration of severe infections.
9. Disease control: Evaluation of overall response rate, complete response rate and duration of response and progression free survival.
10. Survival: Estimation of progression free survival and overall survival.
11. Hospitalization: Hospital admissions post treatment with ide-cel for subjects with CRS and/or ICANS.
12. Need for intensive care: ICU admissions due to CRS and/or ICANS and duration of stays.
13. Quality of life assessment

Conditions and MedDRA coding

Chimeric antigen receptor T cell therapy-associated cytokine release syndrome

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject has the capacity for consenting, was informed about the nature, the scope, and the relevance of the clinical study, voluntarily agrees in participation and in the study provisions, and duly signed the informed consent form approved by the ethics committee before any study-related procedure is performed.
3. Subject has documented diagnosis of RRMM as defined by International Myeloma Working Group (IMWG) criteria.
4. Subject is eligible for approved CAR T therapy with ide-cel in accordance with the ap-proved indication.
5. An ide-cel production slot is available for the patient.
6. An ide-cel product conforming to release specification is available for the subject; only applicable for day -8 confirmatory Screening.
7. Female subjects of childbearing potential must have a negative pregnancy test (blood) at screening commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, highly effective measures of contraception without interruption, from screening through 1 year following the IMP treatment. A highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly) must be practiced. The subject should be informed of the potential risks associated with becoming pregnant while enrolled in this clinical trial. Reliable methods for this trial are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence is only accepted as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] are not acceptable methods of contraception.) Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile female subjects (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.
8. Male patients must practice true abstinence or agree to use a condom during sexual contact with a pregnant woman or a woman of childbearing potential for the study duration.

Exclusion criteria 13

1. Subject has any significant medical condition, or psychiatric illness (including lab abnormalities) that could interfere with subject's safety or compliance to the study procedures.
2. Subject has received treatment with an IMP within 4 weeks prior to screening.
3. Subject has known relevant pleural or pericardial effusion.
4. Subjects receiving any of the following: a) CYP3A4 metabolized drugs with small therapeutic range including, but not limited to drugs listed in Protocol Appendix I (see Section 11.3) b) Patients receiving potent CYP3A4 inhibitors including, but not limited to drugs listed in Protocol Appendix J (see Section 11.3) c) Patients with concomitant medication of potent CYP3A4 inducers including, but not limited to drugs listed in Protocol Appendix K (see Section 11.3) – with the exemption of 1. cyclophosphamide if administered as part of the pre-treatment lymphodepletion chemotherapy prior to ide-cel or to control high-grade CRS (for details see summary of product characteristics [SmPC] for ide-cel); and 2. dexamethasone if administered for treatment of CRS, ICANS or haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (for details see SmPC for ide-cel) d) Patients who cannot be taken off drugs that have a risk of causing Torsades de pointes, including, but not limited to drugs listed in Protocol Appendix L (see Section 11.3) e) Concomitant medication with H2 inhibitors, proton pump inhibitors or antacids (e.g. aluminium hydroxide/magnesium hydroxide, see Protocol Section 11.3) f) Subjects who have discontinued any of these medications must have a wash-out period of at least 2 days prior to the first dose of dasatinib. If the drugs listed in Protocol Appendices H-K cannot be discontinued in a subject, but the subject is otherwise eligible for participation in the clinical trial, the sponsor should be contacted.
5. Cardiac symptoms or cardiovascular disease, including: a) Myocardial infarction or unstable angina pectoris within 6 months prior to screening b) Congestive heart failure with left ventricular ejection fraction (EF <45% in last cardiologic assessment in the last 3 months) c) Diagnosed or suspected congenital long QT syndrome d) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes) e) Prolonged QTc interval on screening electrocardiogram (greater than 450 msec) on Bazett's correction f) Subject has known pulmonary arterial hypertension.
6. Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C or has active Cytomegalovirus (CMV) infection/reactivation.
7. Subject has systemic and uncontrolled fungal, bacterial, viral or other infection. Uncontrolled defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring intravenous (IV) antimicrobials for management within 14 days of enrolment.
8. Subject with known hypersensitivity to dasatinib or any of the excipients.
9. Subjects with hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
10. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.
11. Subject diagnosed or treated for another malignancy within 5 years before enrolment or previously diagnosed with another malignancy and any evidence of residual disease. Participants with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection, Carcinoma in situ of the breast, Incidental histologic finding of prostate cancer [T1a or T1b] or prostate cancer that is curative.
12. Legal incapacity or limited legal capacity.
13. Employees of the sponsor or employees or relatives of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Number of TEAEs (phase I and II) and DLT rate (phase I):Type, frequency, and severity of TEAEs, will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; Time frame: day -2 to day 30
2. Frequency and severity of any grade CRS. CRS is assessed using American Society for Blood and Marrow Transplantation (ASBMT) CRS Consensus Grading; Time frame: day 0 to day 30

Secondary endpoints 13

1. CRS frequency and severity of Grade 2-5 CRS is assessed using the American Society for Blood and Marrow Transplantation (ASBMT) CRS Consensus Grading; Time frame: day 0 to day 30
2. Time to onset of any grade CRS; Time frame: day 0 to day 30
3. Time between CRS (any grade) onset to CRS resolution. Assessed using ASBMT CRS Consensus Grading. Time frame: day 0 to day 30
4. Frequency and severity of any grade ICANS. ICANS are assessed using the ASBMT ICANS Consensus Grading. Time frame: day 0 to day 30
5. Time to onset of any grade ICANS, assessed using the AS-BMT ICANS Consensus Grading. Time frame: day 0 to day 30
6. Time between onset of any grade ICANS until ICANS resolution, assessed using the ASBMT ICANS Consensus Grading. Time frame: day 0 to day 30
7. Occurrence and duration of prolonged (present at day 30 or later) and/or severe (CTCAE version 5.0 grade 3 or higher) cytopenia. Time frame: day -2 to day 360
8. Occurrence and duration of severe (CTCAE version 5.0 grade 3 or higher) infections. Time frame: day -2 to day 360
9. Overall response rate, complete response rate and duration of response and progression free survival according to IMWG criteria Time frame: day 0 to day 360
10. Progression free survival and overall survival with the Kaplan-Meier method. Time frame: day 0 to day 360
11. Number of hospital admissions post treatment with ide-cel for subjects with CRS and/or ICANS and duration of hospital stays, time of first discharge. Time frame: day 0 to day 360
12. Number of ICU admissions due to CRS and/or ICANS and duration of stays. Time frame: day 0 to day 360
13. Changes in Health-related Quality of Life (HRQoL) assessed by European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30/-MY20). Time frame: day 0 to day 360

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Wuerzburg AöR

Sponsor organisation

Universitaetsklinikum Wuerzburg AöR

Address

Oberduerrbacher Strasse 6, Grombuehl Grombuehl

City

Wuerzburg

Postcode

97080

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Wuerzburg AöR

Contact name

Sekretariat I

Public contact point

Organisation

Universitaetsklinikum Wuerzburg AöR

Contact name

Sekretariat I

Third parties 8

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications