| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Adult participants with relapsed and refractory multiple myeloma after
failure of 3 or more different prior lines of therapy, including an
immunomodulatory drug (IMiD), a proteasome inhibitor (PI) and an
anti-CD38 (cluster of differentiation 38) monoclonal antibody (mAb),
and who have measurable disease at enrollment and documented
evidence of progressive disease per IMWG criteria on the last prior
therapy. Participants must be refractory to the last line of therapy. | |
| E.1.1.1 | Medical condition in easily understood language | | relapsed and refractory 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 | Evaluate the efficacy of PHE885 with respect to disease response per independent review committee (IRC) in participants infused with PHE885
| |
| E.2.2 | Secondary objectives of the trial | • Evaluate the efficacy of PHE885 with respect to MRD negativity in bone
marrow measured by next generation sequencing (NGS)
• Assess additional efficacy outcomes including complete response rate
(CRR), time to response (TTR), duration of response (DOR), progressionfree
survival (PFS) per IRC and local investigator assessment
• Assess time to next treatment (TTNT) and overall survival (OS)
• Evaluate rate of minimal residual disease (MRD) negativity in bone
marrow measured by next-generation sequencing (NGS)
• Assess durability of MRD negativity
• Assess patient reported outcomes (PRO)
• Assess the PHE885 manufacturing success rate
• Assess manufacturing turnaround time
• Assess safety of PHE885
• Assess the cellular kinetics of PHE885 in peripheral blood and bone
marrow by qPCR
• Assess immunogenicity (humoral and cellular) to PHE885 | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. ≥18 years of age at the time of informed consent form (ICF) signature.
2. Adult participants with relapsed and refractory multiple myeloma who
have received at least 3 prior lines of therapy including an IMiD (e.g.,
lenalidomide or pomalidomide), a proteasome inhibitor (e.g.,
bortezomib, carfilzomib), and an approved anti-CD38 antibody (e.g.,
daratumumab, isatuximab), and have documented evidence of disease
progression (IMWG criteria).
3. Must be refractory to the last treatment regimen (defined as
progressive disease on or within 60 days measured from last dose of last
regimen).
4. Measurable disease at enrollment as defined by the protocol.
5. Eastern Cooperative Oncology Group (ECOG) performance status that
is either 0 or 1 at screening.
6. Must have a leukapheresis material of non-mobilized cells accepted
for manufacturing. | |
| E.4 | Principal exclusion criteria | 1. Prior administration of a genetically modified cellular product, including prior BCMA CAR-T cell therapy.
2. Participants who have received prior BCMA-directed bi-specific antibodies or anti-BCMA antibody drug conjugate.
3. Hypersensitivity to any product (including its ingredients) to be given to the participant as per the study protocol (e.g., PHE885, tocilizumab and lymphodepleting agents).
4. Prior autologous SCT within 3 months prior to signing informed consent or allogeneic SCT within 3 months prior to signing informed consent.
5. Active Graft-versus-Host Disease (GVHD), grade 2-4 according to the Mount Sinai GvHD International Consortium criteria or requiring systemic treatment.
6. Plasma cell leukemia and other plasmacytoid disorders, non-secretory myeloma without other evidence of measurable disease.
7. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
8. Active CNS involvement by malignancy. Participants whose CNS involvement was treated with resolved symptoms, provided that local treatment was > 4 weeks before enrollment, are eligible.
9. Participants with active neurological auto immune or inflammatory disorders (e.g., Guillain-Barre Syndrome, Amyotrophic Lateral Sclerosis).
10. Participants with Grade ≥ 3 neuropathy, or residual non-hematologic effects of Grade ≥ 2 from previous therapy (excluding alopecia).
11. Chemotherapy, small molecule targeted antineoplastics, or any concomitant anti-cancer therapies (other than protocol allowed LD chemotherapy) within 2 weeks prior to apheresis or prior to PHE885 injection.
12. For participants that received prior antibodies (e.g., daratumumab, isotuximab, elotuzumab) the washout period is 3 weeks prior to apheresis collection.
13. Radiotherapy within 2 weeks prior to enrollment except localized radiation therapy for lytic bone lesions or plasmacytomas.
14. Investigational medicinal product within the 4 weeks prior to screening or within 5-half-lives of the investigational product, whichever is longer. Note: Investigational therapies must not be used at any time while on study until the first progression following PHE885 injection.
15. Participants receiving systemic steroid therapy or other immunosuppressive drugs unless the conditions outlined in the protocol are met.
16. Previous or concurrent malignancy with the following exceptions:
• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
• In situ carcinoma treated curativel
• A primary malignancy which has been completely resected and in complete remission for ≥ 3 years.
17. Impaired cardiac function or clinically significant cardiac disease, including any of the conditions outlined in the protocol.
18. Inadequate organ function during screening (i.e., within 56 days before the first dose of study treatment) as outlined in the protocol.
19. Presence of active hepatitis B or C as indicated by serology.
20. Human immunodeficiency virus (HIV) positivity as indicated by serology.
21. Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.).
22. Use of any live vaccines against infectious disease within 6 weeks of PHE885 injection.
23. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
24. Pregnant or nursing (lactating) women. NOTE: Women of child-bearing potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion (if performed) and prior to PHE885 injection.
25. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from enrollment into this study through at least 12 months after the PHE885 injection and until CAR-T cells are no longer present by qPCR on two consecutive tests. qPCR test results will be available upon request. Highly effective contraception methods are outlined in the protocol.
26. Sexually active males must use a condom during intercourse from enrollment into this study through at least 12 months after the PHE885 injection and until CAR-T cells are no longer present by qPCR on two consecutive tests. qPCR test results will be available upon request. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm. A condom is also required to be used by vasectomized men (as well as during intercourse with a male partner or sterile female partner) as white blood cells (WBCs) are a normal part of semen and transmission of PHE885 transduced cells may occur.
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | Best overall response (BOR) per IRC defined as the best disease
response recorded from PHE885 administration until progressive disease
(PD), death or starting new anticancer therapy whichever comes first,
with possible values of either stringent complete response (sCR),
complete response (CR), very good partial response (VGPR), partial
response (PR), minimal response (MR), stable disease (SD), progressive
disease (PD) or unknown (UNK), according to the International Myeloma
Working Group (IMWG) criteria.
The summary measure for the primary endpoint is overall response rate
(ORR), defined as the proportion of participants with a BOR of PR or
better, assessed in the efficacy analysis set (EAS).Best overall response (BOR) per IRC defined as the best disease
response recorded from PHE885 administration until progressive disease
(PD), death or starting new anticancer therapy whichever comes first,
with possible values of either stringent complete response (sCR),
complete response (CR), very good partial response (VGPR), partial
response (PR), minimal response (MR), stable disease (SD), progressive
disease (PD) or unknown (UNK), according to the International Myeloma
Working Group (IMWG) criteria.
The summary measure for the primary endpoint is overall response rate
(ORR), defined as the proportion of participants with a BOR of PR or
better, assessed in the efficacy analysis set (EAS). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Efficacy interim analysis (6 months after the first 60 pts),
Primary analysis (6 months after 90 pts) | |
| E.5.2 | Secondary end point(s) | • Proportion of participants who achieved MRD negative status at any
time point within 3 months of achieving at least CR until time of PD,
death or starting new anticancer therapy, whichever comes first
• CRR defined as the proportion of participants with BOR of sCR or CR
• TTR defined as time from PHE885 administration to the date of first
documented response (PR or better)
• DOR defined as time from first documented response (PR or better)
until relapse or death due to any cause
• PFS defined as time from PHE885 administration until progression or
death due to any cause
• TTNT defined as time from PHE885 administration until start of new
anti-myeloma therapy or death due to any cause
• OS defined as time from PHE885 administration until death due to any
cause
• Duration from the start of undetectable MRD to the time of
reappearance of detectable MRD
• Summary scores of PRO measured by EQ-5D-5L, EORTC-QLQ-C30 and
EORTC-QLQ-MY20
• Proportion of enrolled participants for whom a PHE885 product was
manufactured that met all release specifications
• Time from pick up of cryopreserved material at the clinic or hospital
until return to the clinic or hospital.
• Type, frequency, and severity of adverse events, serious adverse
events, adverse events of special interest (AESIs) and laboratory
abnormalities
• Transgene of PHE885 concentrations over time in peripheral blood and
bone marrow determined by quantitative PCR
Cellular kinetics parameters: Cmax (maximum serum concentration),
Tmax (time to reach Cmax), AUCs and other cellular kinetic parameters
• Summary of pre-existing and treatment-induced immunogenicity
(cellular and humoral) of PHE885
Correlate levels of pre-existing and treatment-induced immunogenicity
with cellular kinetic parameters, safety and efficacy | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Efficacy interim analysis (6 months after the first 75 pts),
Primary analysis (6 months after 100 pts) and
Final CSR (24 months after all 100 pts) | |
| 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 | Yes |
| 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 | |
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description | |
| 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.8.3 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | | Australia | | Brazil | | Israel | | Japan | | Saudi Arabia | | Singapore | | United States | | France | | Germany | | Greece | | Italy | | Spain | | Korea, Republic of | | 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 all participants have completed Month 24 evaluation or progressed or died earlier or were withdrawn prematurely and analysis of primary and secondary end points of the study are performed. Participants who have completed their Month 24 visit before the end of the study will be followed every 1 year until the end of the study. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
