| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed multiple myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by a single administration of cilta-cel versus VRd induction followed by lenalidomide and dexamethasone (Rd) maintenance in terms of progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
1. To characterize minimal residual disease (MRD) negativity
2. To further compare the efficacy of VRd induction followed by a single administration of cilta-cel versus VRd induction followed by Rd maintenance
3. To characterize the safety of VRd induction followed by a single administration of cilta-cel versus VRd induction followed by Rd maintenance
4. To characterize the pharmacokinetics and pharmacodynamics of cilta-cel
5. To assess the immunogenicity of cilta-cel
6. To determine whether replication competent lentivirus is present in participants that receive cilta-cel
7. To evaluate the patient-reported outcomes (PRO) associated with VRd induction followed by single administration of cilta-cel versus VRd induction followed by Rd maintenance |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age, Type of Participant, and Disease Characteristic
1. ≥18 years of age
2. Documented diagnosis of MM according to IMWG diagnostic criteria
3. Measurable disease at Screening as defined by any of the following:
• Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain MM in whom only measurable disease is by serum free light chain (FLC) levels: Serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio.
4. Not considered for high-dose chemotherapy with autologous stem cell transplant (ASCT) due to:
• Ineligible due to advanced age; or
• Ineligible due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or
• Deferral of high-dose chemotherapy with ASCT as initial treatment.
5. Eastern Cooperative Oncology Group Performance Status grade of 0 or 1
Contraceptive/Barrier Requirements
6. A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy test (-human chorionic gonadotropin) tests prior to starting VRd and must agree to further testing during the study. See Section 10.9, for the definition of females who are not of reproductive potential.
7. When a woman is of childbearing potential, the participant 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, without interruption, from the time of signing the informed consent or for at least 4 weeks before therapy (whichever is earlier) until at least 4 weeks following the last dose of lenalidomide, 3 months after receiving the last dose of bortezomib, or 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later) (Section 10.9). Reliable contraception is indicated even where there has been a history of infertility, unless it is due to hysterectomy. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Examples of highly effective contraceptives include:
• User-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; intrauterine hormone releasing system; 3) vasectomized partner.
• User-dependent method: progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable). Estrogen-containing hormonal contraception is contraindicated due to increased risk of thromboembolic events with lenalidomide.
• Women of childbearing potential must follow the contraception criteria outlined in the global REVLIMID® pregnancy prevention program or equivalent local Risk
Evaluation and Mitigation Strategy, whichever is more stringent, as applicable in their region.
8. A man must commit either to abstaining continuously from heterosexual intercourse or a man
• Who is sexually active with a WOCBP 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), without interruption, from the time of signing the informed consent form (ICF) or for at least 4 weeks before therapy (whichever is earlier) until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later), even if they have undergone a successful vasectomy.
• Should agree to practice contraception according to and for the time frame specified in the global REVLIMID® (lenalidomide) pregnancy prevention program or equivalent local REVLIMID® (lenalidomide) pregnancy prevention program, whichever is more stringent.
9. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine), or 1 year after receiving cilta-cel infusion (whichever is later).
For additional information see section 5.1 of the protocol. |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
Medical Condition
1. Frailty index of ≥ 2 according to Myeloma Geriatric Assessment score
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 (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
• non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
• localized prostate cancer (N0M0):
- with a Gleason score of ≤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. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.
4. The following cardiac conditions:
• New York Heart Association Stage III or IV congestive heart failure
• Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment
• History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• History of severe non-ischemic cardiomyopathy
• Screening 12-lead ECG showing a baseline corrected Prolonged corrected QT interval (QTc) >470 msec (for women) and >450 msec (for men), as assessed by 12-lead ECG, except in participants with a pacemaker.
• Impaired cardiac function (left ventricular ejection fraction <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan.
5. Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM.
6. Stroke or seizure within 6 months of signing ICF.
7. Plasma cell leukemia at the time of screening (>2.0 x 10^9/L plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis.
8. Seropositive for human immunodeficiency virus (HIV).
9. Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd.
10. Hepatitis B infection. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status
11. Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody positive or detectable HCV-RNA) or known to have a history of hepatitis C.
12. Participant must not require continuous supplemental oxygen.
13. Contraindications, known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments, including cyclophosphamide or fludarabine (if known) or any of their excipients, including boron, mannitol, dimethyl sulfoxide.
14. Serious underlying medical condition, such as:
• Evidence of active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection
• Active autoimmune disease
• Overt clinical evidence of dementia or altered mental status
• Any history of Parkinson’s disease or other neurodegenerative disorder Prior/Concomitant Medications
15. Prior treatment with CAR-T therapy directed at any target.
16. Any therapy that is targeted to BCMA.
17.
•Any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent, see Section 10.13). or maximum 1 cycle of VRd therapy prior to enrollment, in
a dosing regimen that is consistent with the protocol regimen for VRd induction (including dose modifications consistent with protocol guidelines (Section 6.5), if applicable).
•Radiation therapy for treatment of plasmacytoma within 14 days before enrollment (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of enrollment). However, if the radiation portal covered ≤5% of the bone marrow reserve (see Appendix 10.31), the subject is eligible irrespective of the end date of radiation therapy
For additional information see section 5.2 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) with progression defined by IMWG criteria, or death, whichever occurred first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From the date of randomization to the date of first documented progressive disease (PD), as defined in the IMWG criteria, or death due to any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
1. Sustained minimal residual disease (MRD) negative complete response (CR), as determined by next generation sequencing (NGS) with sensitivity of 10^-5 and defined by MRD negative CR plus at least 12 months durability of the MRD negative CR status.
2. MRD negative CR at 9 months is defined as the participants who achieve MRD negative status at 9±3 months after the randomization date
3. Overall MRD negative CR
4. Overall survival (OS)
5. CR or better
6. Time to subsequent anti-myeloma therapy
7. PFS on next-line therapy (PFS2)
8. Incidence and severity of AEs, laboratory results and other safety parameters
9. Pharmacokinetic and pharmacodynamic markers, by protein, DNA, or RNA analyses, including, but not limited to changes in soluble BCMA, systemic inflammatory cytokine concentrations, markers of CAR-T cell expansion (proliferation) and persistence via monitoring CAR-T positive cells and CAR transgene level.
10. Presence of anti-cilta-cel antibodies
11. Presence of replication competent lentivirus.
12. Mean change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q), EuroQol Five Dimension Questionnaire (EQ-5D-5L) subscale scores, and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items
13. Time to worsening of symptoms, functioning, and overall well-being
14. Proportion of participants with a meaningful improvement in the EORTC QLQ-C30 and MySIm-Q subscale scores using the Patient Global Impression of Severity (PGIS) to calculate the meaningful change threshold
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Followed until the end of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarker assessments, Immunogenicity assessments, PROs and Cytogenetic assessments |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Ireland |
| Norway |
| Portugal |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is when approximately 300 OS events have been accumulated in the study or 10 years after the last participant is randomized, whichever happens earlier. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 15 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 15 |
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