Phase II Open-Label, Single Arm, Multicenter Study of Ciltacabtagene Autoleucel in High-Risk Smoldering Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Pethema

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Oct 2024 → ongoing

Decision date (initial)

2024-08-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

J&J Innovative Medicine

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy and safety of Dara-VRD followed by cilta-cel in high-risk SMM

Secondary objectives 6

1. To further evaluate the efficacy of Dara-VRD followed by cilta-cel in high risk SMM patients as measured by ORR as well as different response categories partial response (PR), very good partial response (VGPR), CR, and sCR, and duration of response (DOR)
2. To assess the survival of patients with high-risk SMM
3. To characterize serum M-protein correlation with responses according to IMWG criteria and MRD testing
4. To evaluate the immune-activity of Dara-VRD followed by cilta-cel
5. To assess and compare cellular characteristics in apheresis product and manufacturing samples from Group 1 and Group 2
6. Evaluation of MRD with sensitivity level 10-6

Conditions and MedDRA coding

High-risk smoldering multiple myeloma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
2. High-risk SMM defined as having 1 of the following 2 criteria: 1. High-risk per “Mayo 20-2-20” criteria defined as presence of any ≥2 of the following: a. Serum M-protein ≥2 gm/dL b. Involved to uninvolved FLC ratio ≥20 c. BMPC % ≥20% OR 2. Presence of ≥95% of BMPC with an aberrant phenotype within the BMPC compartment and immunoparesis present defined as a reduction of at least 25% below the lower normal limit for ≥1 uninvolved immunoglobulin isotype (only IgG, IgA and IgM will be considered).
3. Have an ECOG performance status of ≤1.
4. Have an estimated glomerular filtration rate (eGFR), based on the Modified Diet in Renal Disease (MDRD) 4-variable formula (Appendix 11: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in Renal Disease Formula (in mL/min)) or 24-hour urine collection of ≥40 mL/min during the screening period
5. Laboratory values obtained <21 days prior to Screening: • Total bilirubin ≤2.0 mg/dL • Aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) • Alanine transaminase (ALT) ≤3 x ULN
6. Participants should have: • Hemoglobin ≥8.0 g/dL (≥5 mmol/L) (without prior red blood cell [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted).* For participants who meet the inclusion criteria at screening, transfusion of RBCs is permitted after screening as needed to maintain a hemoglobin level 8.0 g/dL • Neutrophils ≥1.0 × 109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test) • Platelets ≥75 × 109/L (must be without transfusion support in the 7 days prior to the laboratory test) • Lymphocyte count ≥0.3 × 109/L
7. Participants should be seronegative for human immunodeficiency virus (HIV) or have controlled disease if seropositive.
8. A participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
9. A participant must be either of the following (as defined in Appendix 5) a. Not of childbearing potential, or b. Of childbearing potential and practicing at least 1 highly effective method of contraception (details in Appendix 5) contraception throughout the study and through 6 months after the last dose of study treatment. Note: If a participant becomes of childbearing potential after the start of the study, the participant must comply with (b.).
10. A participant of chilbearing potential using oral contraceptives should use an additional barrier contraceptive method (details in Appendix 5).
11. A participant with childbearing potential must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the cilta-cel infusion. Participants of childbearing potential should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
12. A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 1 year after receiving the cilta-cel infusion. If the participant’s partner is of childbearing potential, the participant must use condoms (with or without spermicide) and the partner of childbearing potential of the participant must also be practicing a highly effective method of contraception (see Appendix 5). A participant who is vasectomized must still use a condom (with or without spermicide), but the partner is not required to use contraception.
13. A participant must agree not to donate sperm for the purposes of reproduction during the study and for 1 year after receiving the last dose of study treatment. Participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.
14. A participant must agree not to plan to father a child while enrolled in this study or within 1 year after the last dose of study treatment
15. Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
16. An additional ICF will be collected to get participants authorization to collect the necessary samples for performing the Biological studies indicated in this protocol
17. Be willing and able to adhere to the lifestyle restrictions specified in this protocol
18. Not included in other clinical trial or treated with an experimental drug

Exclusion criteria 11

1. History of uncontrolled illness, including but not limited to MGUS, standard risk smoldering myeloma, active myeloma by current IMWG definition, light chain amyloidosis with organ involvement or patients with extramedullary disease
2. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: • Non-muscle-invasive bladder cancer treated within the last 24 months that is considered completely cured. • Skin cancer (nonmelanoma or melanoma) treated within the last 24 months that is considered completely cured. • Noninvasive cervical cancer treated within the last 24 months that is considered completely cured. • Localized prostate cancer (N0M0): • with a Gleason score ≤6, treated within the last 24 months or untreated and under surveillance, • with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence, • or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence • Breast cancer: • adequately treated lobular carcinoma in situ or ductal carcinoma in situ, • or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence. • Malignancy that is considered cured with minimal risk of recurrence
3. Known allergies, hypersensitivity, or intolerance to cilta-cel or its excipients (refer to the IB).
4. Participant had major surgery or had significant traumatic injury ≤14 days prior to C1D1
5. If any of the following exist at screening, participant will be excluded because this trial involves an investigational agent whose genotoxic, mutagenic, and teratogenic effect on the developing fetus and newborn are unknown: a) Pregnant participants; b)Nursing participants; c) Participants of childbearing potential who are unwilling to employ adequate contraception (per protocol)
6. Other comorbidity which would interfere with participant's ability to participate in trial, eg, uncontrolled infection, uncompensated heart, or lung disease
7. Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
8. History of neurodegenerative disease (eg, Parkinson or other neurodegenerative disorders) including overt clinical evidence of dementia or altered mental status or; stroke (within 6 months).
9. Medical history of treatment for another malignancy <2 years before trial enrollment, other concurrent chemotherapy, or any ancillary therapy considered investigational. Note: Bisphosphonates are considered supportive care rather than therapy and are thus allowed while on protocol treatment
10. Known seropositive for or active viral infection with HIV, HBV, hepatitis C virus (HCV), or SARS CoV 2 (Coronavirus Disease 2019 [COVID-19]). • Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody, hepatitis B core antibody (HBc), or hepatitis B surface antigen (HBsAg) must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. • Participants who are positive for HIV1 or 2 infections, with undetectable viral load and on stable antiretrovirals, will not be excluded. • Participants with past HCV infection need at least 12 months of sustained virologic response and be negative for RNA to enter. • Patients with a high-risk of HBV reactivation (eg, negative for HBV antigen but positive for chronic HBV, with or without anti-serum HBV) must be monitored with DNA and ALT/AST
11. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. To evaluate the proportion of high risk SMM patients with undetectable MRD at 6 months (defined as an MRD-negative at 6m), 12 months (defined as an MRD-negative at 12m), and thereafter every 12m up to 5y after cilta-cel administration as well as the sustained undetectable MRD rate (defined as MRD-negative for at a minimum 12 months duration) in the ITT population. MRD will be evaluated in the bone marrow by Next-Generation Flow and N-G Sequencing with sensitivity level of 10‐5 and 10-6.
2. Nature, frequency, severity, and timing of adverse events (AEs), discontinuations due to AEs, and serious adverse events (SAEs).
3. Selected safety laboratory tests: IgG levels, CBC cytopenia, CD4/CD8 lymphocyte panel and CAR-T chemistry.

Secondary endpoints 12

1. To evaluate the proportion of high risk SMM patients who achieve a PR or better according to IMWG criteria
2. To evaluate the proportion of high risk SMM patients who achieve PR, VGPR, CR, and sCR according to IMWG criteria
3. To evaluate the duration of response in patients who achieve PR or better according to IMWG criteria
4. To assess PFS until progression to myeloma (with myeloma-defining events).
5. To assess PFS to biochemical progression
6. To assess PFS2
7. To assess time to progression (IMWG criteria; Appendix 9) from the date of the first administration of study treatment
8. To assess overall survival from the date of the initial infusion of cilta-cel to the date of the participant's death
9. To evaluate mass spectrometry quantification of M-protein to be correlated with the conventional responses as well as MRD testing
10. Immune profiling at baseline and sequentially after cilta-cel administration, sequentially (in peripheral blood and bone marrow) and by 12-color multidimensional flow cytometry and single cell RNA (scRNA) seq
11. Cellular characterization of apheresis product and manufacturing samples from Group 1 and Group 2 by using genomic sequencing, proteomics and/or flow cytometry approaches
12. Proportion of high-risk SMM patients who achieved undetectable MRD and sustained undetectable MRD by using Next-Generation Flow and Next-Generation Sequencing with sensitivity level of 10‐6

Investigational products

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

Test 5

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Pethema

Sponsor organisation

Fundacion Pethema

Address

Calle De Santa Balbina 2 Oficinas 3 4 5

City

Madrid

Postcode

28023

Country

Spain

Scientific contact point

Organisation

Fundacion Pethema

Contact name

Evidenze Health España

Public contact point

Organisation

Fundacion Pethema

Contact name

Evidenze Health España

Third parties 8

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

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

Documents 14 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