E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Multiple Myeloma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
1. To characterize the safety of JNJ68284528 and establish the dose (RP2D) (Phase 1b)
2. To evaluate the efficacy of JNJ-68284528 (Phase 2)
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E.2.2 | Secondary objectives of the trial |
1. To characterize the safety of JNJ68284528(Phase 2)
2. To characterize the pharmacokinetics and pharmacodynamics of JNJ-68284528
3. To assess the immunogenicity of JNJ-68284528
4. To further characterize the efficacy of JNJ-68284528
5. To compare the patient-reported outcomes (PRO) after treatment to subject’s reported health state prior to treatment and to assess the sustained benefit of subject’s perceived health related quality of life (HRQoL) (Phase 2 only)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 years of age.
2.Documented diagnosis of multiple myeloma according to IMWG diagnostic criteria.
3.Measurable disease at Screening as defined by any of the following:
- Serum monoclonal paraprotein (M-protein) level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours; or
- Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain greater than or equal to 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
4.Received at least 3 prior multiple myeloma treatment regimens or are double refractory to an IMiD and PI (refractory multiple myeloma as defined by IMWG consensus criteria). Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen.
-Undergone at least 1 complete cycle of treatment for each regimen, unless PD was the best response to the regimen.
5. Received as part of previous therapy a PI, an IMiD, and an anti-CD38 antibody (prior exposure can be from different monotherapy or combination regimens).
6. Subject must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG criteria on or within 12 months of their last regimen. Confirmation may be from either central or local testing. Also, subjects with documented evidence of progressive disease (as above)
within the previous 6 months and who are refractory or non-responsive to their most recent line of treatment afterwards are eligible.
7. ECOG Performance Status grade of 0 or 1
8. Clinical laboratory values as specified in the protocol
9. Women of childbearing potential must have a negative pregnancy test at screening and prior to the first dose of cyclophosphamide and fludarabine using a highly sensitive serum pregnancy test (β human chorionic gonadotropin [β-hCG]).
10. When a woman is of childbearing potential the following are required:
-Subject must agree to practice a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agree to remain on a highly effective method of contraception from the time of signing the informed consent form (ICF) until at least 100 days after receiving a JNJ-68284528 infusion.
-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 methods: 1) combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral or intravaginal or transdermal; 2) progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable)
In addition to the highly effective method of contraception a man:
-Who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) from the time of signing the ICF until at least 100 days after receiving a JNJ-68284528 infusion
- Who is sexually active with a woman who is pregnant must use a condom
Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 100 days after the last dose of study treatment.
Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method.
11. Subject must sign an ICF indicating that he or she 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 subject’s disease.
12. Willing and able to adhere to the prohibitions and restrictions specified in this protocol. |
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E.4 | Principal exclusion criteria |
1. Prior treatment with CAR-T therapy directed at any target.
2. Any therapy that is targeted to BCMA.
3. Diagnosed or treated for invasive malignancy other than multiple myeloma, except:
-Malignancy treated with curative intent and with no known active disease present for greater than or equal to 2 years before enrollment; or
-Adequately treated non-melanoma skin cancer without evidence of disease.
4. Prior antitumor therapy as follows, prior to apheresis:
-Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half lives, whichever is less
-Monoclonal antibody treatment for multiple myeloma within 21 days.
-Cytotoxic therapy within 14 days.
-Proteasome inhibitor therapy within 14 days.
-Immunomodulatory agent therapy within 7 days.
-Radiotherapy within 14 days. However, if the radiation portal covered less than or equal to 5% of the bone marrow reserve, the subject is eligible irrespective of the end date of radiotherapy.
5. Toxicity from previous anticancer therapy must resolve to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
6. The following cardiac conditions:
-New York Heart Association (NYHA) stage III or IV congestive heart failure
-Myocardial infarction or coronary artery bypass graft (CABG) less than or equal to 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
-Impaired cardiac function (LVEF <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan (performed less than or equal to 8 weeks of apheresis).
7. Received a cumulative dose of corticosteroids equivalent to ≥70 mg of prednisone within the 7 days prior to apheresis
8. Received either of the following:
-An allogenic stem cell transplant within 6 months before apheresis. Subjects who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease (GVHD).
-An autologous stem cell transplant less than or equal to 12 weeks before apheresis
9. Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.
10. Stroke or seizure within 6 months of signing ICF.
11. Plasma cell leukemia at the time of screening (>2.0 x 109/L plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary AL amyloidosis.
12. Seropositive for human immunodeficiency virus (HIV).
13. Vaccinated with live, attenuated vaccine within 4 weeks prior to apheresis.
14. Hepatitis B infection as defined in the protocol. In the event the
infection status is unclear, quantitative levels are necessary to determine the infection status.
15. Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA positive) or known to have a history of hepatitis C. For subjects with known history of HCV infection, confirmation of sustained virologic response [SVR] is required for study eligibility, defined as ≥24 weeks after completion of antiviral therapy.
16. Supplemental oxygen use to maintain adequate oxygenation.
17. Known life threatening allergies, hypersensitivity, or intolerance to JNJ-68284528 or its excipients, including DMSO.
18. Serious underlying medical condition, such as:
-Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection
-Active autoimmune disease or a history of autoimmune disease within 3 years
-Overt clinical evidence of dementia or altered mental status
19. Any issue that would impair the ability of the subject to receive or tolerate the planned treatment at the investigational 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 subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
20. Pregnant or breast-feeding, or planning to become pregnant while enrolled in this study or within 100 days after receiving study treatment.
21. Plans to father a child while enrolled in this study or within 100 days after receiving study treatment.
22. Major surgery within 2 weeks prior to apheresis, or has surgery planned during the study or within 2 weeks after study treatment administration. (Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Phase 1b: Number of Participants with Adverse Events
2. Phase 1b: Number of Participants with Adverse Events by Severity
3. Phase 2: Overall Response Rate (ORR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Minimum 2 years after JNJ-68284528 infusion (Day 1)
2. Minimum 2 years after JNJ-68284528 infusion (Day 1)
3. Minimum 2 years after JNJ-68284528 infusion (Day 1)
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E.5.2 | Secondary end point(s) |
1. Phase 2: Number of Participants with Adverse Events
2. Levels of B-Cell Maturation Antigen (BCMA) Expressing Cells and Soluble BCMA
3. Systemic Cytokine Concentrations
4. Levels of CAR-T Cells
5. Level of JNJ-68284528 T Cell Expansion (proliferation), and Persistence
6. Number of Participants with Anti-JNJ68284528 Antibodies
7. Very Good Partial Response (VGPR) or Better Rate
8. Percentage of Participants who Achieve Clinical Benefit Rate
9. Duration of Response (DOR)
10. Progression-free Survival (PFS)
11. Overall Survival (OS)
12. Percentage of Participants With Negative Minimal Residual Disease (MRD)
13. Time to Response (TTR)
14. Change from Baseline in Health-related Quality of Life (HRQoL) as Measured by EORTC QLQ-C30
15. Change from Baseline in HRQoL as Measured by EORTC QLQ-MY20
16. Change from Baseline in Participant reported Health Status Measured by EQ-5D-5L
17. Change from Baseline in Global Health Status Using PGIC Scale
18. Change from Baseline in Pain Measured by PGIS Scale
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-13: Minimum 2 years after JNJ-68284528 infusion (Day 1)
14-18: Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1)
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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 |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 12 |
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 |
Belgium |
France |
Israel |
Netherlands |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The end of the study will be defined as 2 years after the last subject has received his or her initial dose of JNJ-68284528. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 25 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 30 |