A first-in-human clinical study to assess feasibility, safety and antitumor activity of genetically modified T-cells in multiple myeloma

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] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

22 Jun 2020 → ongoing

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Universitätsklinikum Würzburg

External identifiers

EU CT number

2024-512643-23-00

EudraCT number

2019-001264-30

WHO UTN

U1111-1309-2091

ClinicalTrials.gov

NCT04499339

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacoeconomic, Pharmacogenetic, Dose response, Pharmacokinetic, Safety, Therapy, Efficacy

1.) Phase I: Safety determination of the treatment with SLAMF7 CAR-T;
2.) Phase I: Determination of the MTD and the recommended phase IIa dose of SLAMF7 CAR-T
3.) Phase IIa: Safety determination of the treatment with SLAMF7 CART;
4.) Phase IIa: Evaluation of the efficacy, defined as overall response rate (ORR) of SLAMF7 CAR-T in patients with MM

Secondary objectives 6

1. 1.) Evaluation of the complete response (CR) of SLAMF7 CAR-T in patients with MM
2. 2.) Determination of the feasibility to ex vivo manufacture of autologous SLAMF7 CAR-T and to administer to patients with MM;
3. 3.) Determination of the expansion and duration of in vivo persistence of adoptively transferred SLAMF7 CAR- T cells in peripheral blood, bone marrow and tumor tissue;
4. 4.) To determine if the adoptive transfer of SLAMF7 CAR-T has an antimyeloma effect;
5. 5.) Determination of the SLAMF7 CAR-T cells impact on patient's overall survival (OS);
6. 6.) To determine if the adoptive transfer of SLAMF7 CAR-T affects the quality of life

Conditions and MedDRA coding

Multiple myeloma

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Signed informed consent form.
2. 2. Patient is ≥18 years of age.
3. 3. Patient is willing and able to adhere to the protocol requirements.3. Patient is willing and able to adhere to the protocol requirements.
4. 4. Patient with diagnosis of MM who has been treated with at least 2 prior lines of treatment, including at least one cycle of high-dose chemotherapy with autologous hematopoietic stem cell transplantation if the patient was eligible, and exposure to an immunomodulatory imide drug (e.g. lenalidomide and/or pomalidomide), a proteasome inhibitor, and an anti-CD38 antibody. (Note: Induction therapy, up to 2 cycles of high-dose chemotherapy with autologous hematopoietic stem cell transplantation, and subsequent consolidation and/or maintenance therapy are considered one line of treatment).
5. 5. At least one of the following subcriteria must be measured in the patient: - Serum M-protein greater or equal to 0.5 g/dL - Urine M-protein greater or equal to 200 mg/24 h - Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal - A biopsy-proven evaluable plasmacytoma - Bone marrow plasma cells >10% of total bone marrow cells (>30% if bone marrow plasma cells are the only marker of measurable disease)
6. 6. Patients previously treated with an anti-SLAMF7 antibody are eligible.
7. 7. Karnofsky performance status ≥60%. If patient has a Karnofsky performance status <60% (e.g. after a spinal cord injury) but is judged to be medically fit by the investigator, patient is eligible.
8. 8. Female patients of childbearing potential must: a) have a negative pregnancy test (blood) at screening. b) either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption, from screening through 1 year following the IMP infusion. 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 patient 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), progestogenonly 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 patients (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled. c) Agree to abstain from breast feeding during the study participation and for 1 year after the IMP infusion.
9. 9. Male patients must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after IMP infusion, even if he has undergone a successful vasectomy.

Exclusion criteria 18

1. 1. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤12 months prior to leukapheresis.
2. 2. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning >12 months, and suffers on chronic Graft-versus-Host Disease and/or is on systemic immune-suppressants.
3. 3. Patient with diagnosis of MM a. in first relapse following an autologous stem cell transplantation or b. in second relapse that subsequently achieves a complete response that is considered being a candidate for an allogeneic stem cell transplantation, unless the patient explicitly denies undergoing an allogeneic stem cell transplantation.
4. 4. Patient has received anti-CD38 and/or anti-SLAMF7 antibodies ≤8 weeks prior to leukapheresis.
5. 5. Ongoing treatment with systemic immune-suppressants (e.g. systemic cyclosporine or systemic steroids at any dose). (Note: Physiologic steroid replacement therapy, topical immunesuppresants as e.g. cyclosporine/tacrolimus eye drops, and topical steroids are permitted.)
6. 6. Echocardiogram with left ventricular ejection fraction <45%.
7. 7. Inadequate renal function defined by creatinine clearance ≤45 mL/min using Cockcroft-Gault equation.
8. 8. Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) and total bilirubin >1.5 x ULN (unless due to Gilbert's syndrome and direct bilirubin is ≤1.5 x ULN; unless due to intrahepatic myeloma lesions as demonstrated by magnetic resonance imaging [MRI] or positron emission tomography [PET]/computed tomography [CT] not older than 4 weeks prior to screening).
9. 9. International ratio (INR) or partial thromboplastin time (PTT) >1.5 x ULN, unless on a stable dose of anti-coagulant.
10. 10. Evidence of human immunodeficiency virus (HIV) infection.
11. 11. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV), excluding - Patients who are hepatitis B surface antigen negative and HBV viral deoxyribonucleic acid (DNA) negative - Patients who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months - Patients who are seropositive because of hepatitis B virus vaccine - Patients with known HBV infection but undetectable HBV viral load and on anti-viral therapy to prevent HBV reactivation.
12. 12. Seropositive for and with active viral infection with hepatitis C virus (HCV), excluding - Patients who had hepatitis C but had received an antiviral treatment and show no detectable HCV viral ribonucleic acid (RNA) for 6 months.
13. 13. Seropositive for syphilis on treponema pallidum hemagglutination test, excluding - Patients with negative treponema pallidum antibody absorption test result
14. 14. Patients with active infection (e.g. asymptomatic and symptomatic severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) or other serious medical or psychiatric disorder on investigators decision.
15. 15. Pregnant or lactating women.
16. 16. Current or previous (within 30 days of enrollment) treatment with another IMP.
17. 17. Known abuse of alcohol, drugs, or medicinal products.
18. 18. Employees of the sponsor, or employees or relatives of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 1.) Phase I: Type, frequency, and severity of adverse events (AEs), including serious adverse events (SAEs), cytokine release syndrome (CRS), and neurotoxicity (i.e. immune effector cell-associated neurotoxicity syndrome [ICANS])
2. 2.) Phase I: MTD of SLAMF7 CAR-T that can be administered in phase IIa will be assessed at the end of phase I
3. 3.) Phase IIa: Type, frequency, and severity AEs, including SAEs, CRS, and neurotoxicity (i.e. ICANS)
4. 4.) Phase IIa: Percentage of patients who achieved partial response (PR) or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion

Secondary endpoints 6

1. 1.) Phase IIa: Percentage of patients who achieved CR or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion
2. 2.) Phase I and IIa: Percentage of myeloma patients enrolled into the trial who receive ex vivo expanded autologous SLAMF7 CAR-T within the 48h shelf-life of the product
3. 3.) Phase I and IIa: Maximum peak in SLAMF7 CAR-T (Cmax), time to peak of SLAMF7 CAR-T (Tmax), area under the curve of CAR-T CD4+ and CD8+ cells (AUC), including maximum expansion and duration of persistence of SLAMF7 CAR-T cells at Baseline, Days 1, 3, 7, 10, 14, 21, 28, Week 6, 8, 12, Months 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
4. 4.) Phase I and IIa: a) Time between first SLAMF7 CAR-T infusion and first documentation of response at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24; b) Time between first response and disease progression PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24 c) Time between SLAMF7 CAR-T infusion and first documentation of PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24 d) Phase I and IIa: Proportion of minimal residual disease (MRD) evaluable patients that are MRD negativ
5. 5.) Phase I and IIa: Time between SLAMF7 CAR-T infusion and time of death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
6. 6.) Patient-reported outcomes as measured by EORTC-QLQ-C30/-MY20 at Screening, Baseline, Months 6, 12, 24

Investigational products

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

Test 5

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 4

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 9 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