IRB Study Number 24-591
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To compare the efficacy of DVRd followed by cilta-cel and lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy in terms of PFS and sustained MRD-negative CR
Secondary Objectives
To further compare the efficacy of DVRd followed by cilta-cel and lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy
To characterize the safety of cilta-cel after DVRd therapy followed by lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy
To characterize the PK and pharmacodynamics of cilta-cel
To evaluate the PRO associated with DVRd followed by cilta-cel and lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy
To determine whether RCL is present in participants that receive cilta-cel
Inclusion Criteria
Age
- Criterion modified per Amendment 1
1.1. 18 years of age or older.
Type of Participant and Disease Characteristics
Participants with documented NDMM according to IMWG diagnostic criteria (see Section 10.6), for whom high-dose therapy and ASCT are part of the intended initial treatment plan.
Measurable disease, as assessed by central laboratory, at screening as defined by any of the following:
a. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
b. Light-chain MM without measurable disease in serum or urine: serum Ig free light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio.
Note: Local laboratory assessments may be used to establish measurable disease at screening, with local laboratory result ≥125% of requirements (eg, M-protein ≥1.25 g/dL if using local laboratories).
ECOG performance status of grade 0 or 1 (see Section 10.10).
Criterion modified per Amendment 1
5.1. Have clinical laboratory values meeting the following criteria during the Screening Phase: (See protocol)
Contraceptive/Barrier Requirements
A female participant of childbearing potential must have a negative highly sensitive serum or urine pregnancy test (β-human chorionic gonadotropin) at screening and must agree to further serum or urine pregnancy tests during the study. See Section 10.5 for the definition of females who are not of reproductive potential.
When a female participant is of childbearing potential, she must commit either to abstaining continuously from heterosexual intercourse or agree to practice 2 methods of reliable birth control simultaneously, ie, one highly effective method of contraception (failure rate of <1% per year when used consistently and correctly; see examples below) and one other effective method (ie, male latex or synthetic condom, diaphragm, or cervical cap). The participant must agree to remain on both methods of birth control from the time of signing the informed consent form (ICF) and for a minimum of 4 weeks prior to initiating lenalidomide therapy and until at least 1 year after receiving cilta-cel or until at least 1 year after receiving the conditioning regimen or until at least 4 weeks after discontinuation of lenalidomide or until at least 3 months after discontinuation of daratumumab and/or bortezomib, whichever occurs later. Reliable contraception is indicated even when there is a history of infertility, unless it is due to hysterectomy. Female participants of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed.
Examples of highly effective contraceptives include:
a. User-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; 3) intrauterine hormone-releasing system; 4) vasectomized partner; 5) bilateral
tubal ligation/occlusion.
b. User-dependent methods: 1) progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable); 2) sexual abstinence. Estrogen-containing hormonal contraception is contraindicated due to increased risk of thromboembolic events with lenalidomide.
A female participant of childbearing potential must follow the contraception criteria outlined in the lenalidomide global Pregnancy Prevention Plan (PPP) or local PPP/Risk Evaluation and Mitigation Strategy (REMS) program/Risk Management Plan (RMP) applicable in their region, whichever is more stringent. Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method.
Female and male participants must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for at least 1 year after receiving cilta-cel or for at least 1 year after receiving the conditioning regimen or for at least 4 weeks after discontinuation of lenalidomide or for at least 3 months after discontinuation of daratumumab and/or bortezomib, whichever occurs later.
A male participant must commit either to abstaining continuously from heterosexual intercourse or
c. a male participant who is sexually active with a woman of childbearing potential or a pregnant woman must agree to use a barrier method of contraception (eg, latex or synthetic condom with spermicidal foam/gel/film/cream/suppository) from the time of signing the ICF until at least 1 year after receiving cilta-cel or until at least 1 year after receiving the conditioning regimen or until at least 4 weeks after discontinuation of lenalidomide or until at least 3 months after discontinuation of daratumumab and/or bortezomib, whichever occurs later, even if he has undergone a successful vasectomy.
d. a male participant should agree to practice contraception according to and for the time frame specified in the lenalidomide global PPP or local PPP/REMS program/RMP applicable in their region, whichever is more stringent.
Informed Consent
Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol. PRO Assessments
Must be able to read, understand, and complete PRO instruments, and must intend to comply with completion of PRO.
Exclusion Criteria
Prior/Concomitant Therapy
Prior treatment with CAR-T therapy directed at any target.
Any prior BCMA target therapy.
Any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids (not exceeding 40 mg of dexamethasone or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent, see Section 10.12).
Radiation therapy for treatment of plasmacytoma within 14 days of randomization (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of randomization). If the radiation portal covered ≤5% of the bone marrow reserve (see Section 10.13), the participant is eligible irrespective of the end date of radiation therapy.
Plasmapheresis within 28 days of randomization.
Received a strong cytochrome P450 (CYP)3A4 inducer within 5 half-lives prior to randomization (see https://www.fda.gov/drugs/drug-interactions-labeling/drugdevelopment- and-drug-interactions-table-substrates-inhibitors-and-inducers).
Medical Conditions
- 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:
a. Non-muscle-invasive bladder cancer treated within the last 24 months that is considered completely cured.
b. Skin cancer (nonmelanoma or melanoma) treated within the last 24 months that is considered completely cured.
c. Noninvasive cervical cancer treated within the last 24 months that is considered completely cured.
d. Localized prostate cancer (N0M0):
o with a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance,
o 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,
o or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
e. Breast cancer:
o adequately treated lobular carcinoma in situ or ductal carcinoma in situ,
o or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
f. Malignancy that is considered cured with minimal risk of recurrence.
Peripheral neuropathy or neuropathic pain of ≥Grade 2, as defined by National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
The following cardiac conditions:
a. New York Heart Association Stage III or IV congestive heart failure (see Section 10.14)
b. Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment
c. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
d. History of severe nonischemic cardiomyopathy
e. Screening 12-lead electrocardiogram (ECG) showing a baseline corrected QT interval >470 msec (exception for participants with a pacemaker)
f. Impaired cardiac function (left ventricular ejection fraction <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan performed ≤8 weeks before randomization.
Known active, prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM.
Stroke or seizure within 6 months of signing the ICF.
Criterion modified per Amendment 2
12.1. Plasma cell leukemia at the time of screening (≥5% circulating plasma cells in peripheral blood smears), Waldenström’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome, or primary amyloid light-chain amyloidosis.
Seropositive for human immunodeficiency virus (HIV).
Hepatitis B virus (HBV) infection (defined according to Section 10.15). In the event the infection status is unclear, quantitative levels are necessary to determine the infection status (Hwang 2015).
Hepatitis C virus (HCV) infection (defined as anti-HCV antibody positivity or HCV RNA positivity) or known history of HCV infection. Participants with anti-HCV antibody positivity due to prior resolved disease can be enrolled in case of a negative confirmatory HCV RNA test. For participants with known history of HCV infection, confirmation of sustained virologic response (defined as ≥24 weeks after completion of antiviral therapy) is required for study eligibility.
The following pulmonary conditions:
a. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal (for participants ≥65 years of age, FEV1 <50% or diffusing capacity of the lung for carbon monoxide [DLCO] <50%).
b. Moderate or severe persistent asthma within the past 2 years, or current uncontrolled asthma of any classification. (Participants with current controlled intermittent asthma or current controlled mild persistent asthma are allowed in the study).
- Serious underlying medical condition, such as:
a. Evidence of active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection.
b. Active autoimmune disease.
c. Overt clinical evidence of dementia or altered mental status.
d. Any history of Parkinson’s disease or other neurodegenerative disorder.
Must not require continuous supplemental oxygen.
Gastrointestinal disease that may significantly alter the absorption of oral drugs.
Criterion modified per Amendment 2
20.1. Contraindications, known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments (if known), including cyclophosphamide and fludarabine, or any of their excipients, including boron, mannitol, and dimethyl sulfoxide (refer to the IB for cilta-cel and daratumumab or the local product prescribing information for bortezomib, lenalidomide, and dexamethasone for complete lists of excipients).
Prior/Concurrent Clinical Study Experience
- Criterion modified per Amendment 2
21.1. Received or plans to receive any live, attenuated vaccine within 4 weeks prior to randomization.
- Criterion modified per Amendment 2
22.1. Received an investigational treatment (including an investigational vaccine) or used an invasive investigational medical device within 15 days prior to randomization or is currently enrolled in an investigational study.
Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 1 year after receiving cilta-cel or within 1 year after receiving the conditioning regimen or within 4 weeks after discontinuation of lenalidomide or within 3 months after discontinuation of daratumumab and/or bortezomib, whichever occurs later.
Participant plans to father a child while enrolled in this study or within 1 year after receiving cilta-cel or within 1 year after receiving the conditioning regimen or within 4 weeks after discontinuation of lenalidomide or within 3 months after discontinuation of daratumumab and/or bortezomib, whichever occurs later.
Any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the study site, to understand informed consent, or 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.
Diagnostic Assessments
- Major surgery within 2 weeks prior to randomization, or has surgery planned during the study or within 2 weeks after study treatment administration. Participants with planned surgical procedures to be conducted under local anesthesia may participate.
Other Exclusions
- Unable or unwilling to undergo antithrombotic prophylactic treatment.
