| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose escalation (Part 1):
- To establish the safety and tolerability of EOS884448 (EOS-448) alone, and in combination with iberdomide with and without dexamethasone (DEX), in participants with relapsed/refractory multiple myeloma (RRMM)
- To determine the recommended phase 2 dose (RP2D) of EOS-448 alone and the RP2D of the combination of EOS-448 with iberdomide with or without DEX in participants with RRMM.
Expansion (Part 2):
- Further evaluate the safety and tolerability of EOS-448 in the corresponding expansion cohorts either alone, or in combination with iberdomide with or without DEX, in participants with RRMM
- Assess the clinical activity of EOS-448 in the corresponding expansion cohorts either alone or in combination with iberdomide with or without DEX in participants with R RMM |
|
| E.2.2 | Secondary objectives of the trial |
Dose escalation (Part 1): Assess the clinical activity in participants receiving EOS-448 alone or in combination with iberdomide with or without DEX in participants with RRMM
All Parts: Further evaluate the clinical activity according to time-to-events of EOS-448 alone or in combination with iberdomide with or without DEX in participants with RRMM; Assess the PK and immunogenicity of EOS-448 (alone or in combination with iberdomide with or without DEX) in blood
Exploratory
All Parts: To further assess clinical activity in terms of overall survival;T o assess the pharmacodynamic (PD) activity of EOS-448 (alone or in combination with iberdomide with or without DEX) as well as other exploratory biomarkers in blood and bone marrow aspirate samples; To Assess Minimal Residual Disease (MRD) in complete and very good partial responders
Expansion (Part 2): In Part 2 (Arms 2B and 2C), to assess PK of iberdomide (in combination with EOS-448 with or without DEX) in blood samples |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria:
Participants are eligible to be included in the study if all the following criteria are met:
1. Written informed consent signed in accordance with federal, local, and institutional guidelines, including consent for bone marrow aspirate (BMA) before and during administration of study treatment.
2. Age greater than or equal to (≥) 18 years at the time of informed consent.
3. Documented diagnosis of MM.
4. Have received at least 3 prior lines of myeloma therapy including an IMiD, a proteasome inhibitor, and an anti-CD38 antibody in any order during the course of treatment for multiple myeloma (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one line) and not be candidate for regimens known to provide clinical benefit in this setting.
5. Must have progressed on their last line of myeloma therapy.
6. Measurable disease as defined by at least one of the following:
a. Serum M-protein ≥ 0.5 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitative IgA
b. Urinary M-protein of at least 200 mg/24 hours by urine protein electrophoresis (UPEP)
c. Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided that FLC ratio is abnormal
d. If SPEP is felt to be unreliable for routine M-protein measurement (example, for IgA or IgD MM), then quantitative immunoglobulin (Ig) levels by nephelometry or turbidometry are acceptable
7. Any non-hematological toxicities that patients had from prior treatments must have resolved to less than or equal (≤) Grade 1 by C1D1 with the exception of alopecia.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
9. Adequate hepatic function within 28 days prior to C1D1: Total bilirubin ≤ 1.5 X ULN (except patients with Gilbert's syndrome (hereditary indirect hyperbilirubinemia) who must have a total bilirubin of ≤ 3 X ULN) and both AST and ALT ≤ 2.5X ULN
10. Adequate renal function within 28 days prior to C1D1. Creatinine clearance (CrCl) > 45 mL per minute or greater using the formula of Cockroft and Gault (1976):
a. CrCl (female) = (([140-age] x weight in kg)/(serum creatinine x 72)) x 0.85;
b. CrCl (male) = ([140-age] x weight in kg)/(serum creatinine x 72)
11. Adequate hematopoietic function within 28 days prior to C1D1: total white blood cell count ≥ 1,500/millimeter cube (mm^3), absolute neutrophil count (ANC) ≥ 1,000/mm^3, hemoglobin ≥ 8.0 g/dL. Platelet count ≥ 75,000/mm^3 for Part 1. For Part 2: platelet count ≥ 75,000/mm^3 for participants in whom < 50% of bone marrow nucleated cells are plasma cells, otherwise platelet count ≥ 50,000/mm^3
12. Females of childbearing potential (FCBP) must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the participant practices true abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting study treatment, during the study treatment, and for at least 60 days after the last dose of study treatment. Contraception requirements are detailed in Section 9.5 and the current version of the Pregnancy Prevention Program.
Note: A FCBP is a female who: 1) has achieved menarche at some point and, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months
13. Male participants must:
a. Practice true abstinence* or agree to use a condom (see current version of the Pregnancy Prevention Program) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 100 days after the last dose of study treatment even if he has undergone a successful vasectomy.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.]
14. Male participants must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 100 days following last dose.
15. Participants must agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.
16. All male and female participants must follow all requirements defined in the current version of the Pregnancy Prevention Program. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded if any of the following criteria applies:
1. MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded).
2. Documented active systemic amyloid light chain amyloidosis.
3. Active plasma cell leukemia.
4. Clinical evidence of central nervous system or pulmonary leukostasis, disseminated intravascular coagulation, or CNS MM.
5. Red Blood Cell transfusions and blood growth factors within 14 days of C1D1.
6. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy or plasmapheresis within 2 weeks prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patients on long-term glucocorticoids during Screening do not require a washout period. Prior radiation is permitted for treatment of fractures or to prevent fractures as well as for pain management.
7. Treatment with an investigational anti-cancer therapy within 4 weeks prior to C1D1, last infusion with CAR-T cell therapy within 12 weeks prior to C1D1.
8. Treatment with granulocyte colony-stimulating factor (G-CSF) within 4 weeks prior to C1D1.
9. History of Grade ≥2 pneumonitis, active autoimmune disease, or persistent immune-mediated toxicity caused by immune checkpoint inhibitor therapy of Grade ≥2 with the exception of residual endocrinopathy adequately substituted, vitiligo, Type 1 diabetes mellitus, or psoriasis not requiring systemic therapy.
10. Active neuropathy >Grade 2 (CTCAE v5.0). or Grade ≥ 2 neuropathy with pain at Screening (within 28 days prior to C1D1).
11. History of life-threatening toxicity related to prior immune therapy or any toxicity that resulted in permanent discontinuation of prior immune therapy.
12. Prior autologous stem cell transplantation < 3 month, or allogeneic stem cell transplantation < 12 months prior to C1D1.
13. Active graft versus host disease after allogeneic stem cell transplantation.
14. Major surgery within 4 weeks prior to C1D1.
15. Active, unstable cardiovascular function:
a. Symptomatic ischemia, or uncontrolled angina within the past 6 months
b. Myocardial infarction within 3 months prior to C1D1
c. Uncontrolled, clinically significant conduction abnormalities
d. Stroke/transient ischemic attack within 1 year prior to C1D1.
e. History of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with NYHA Class III-IV, pericarditis, significant pericardial effusion, or myocarditis or any grade)
f. Ejection fraction < 50% at Screening determined by echocardiogram or other approved method of evaluation
g. ECG with corrected QT interval (QTcF) of > 470 milliseconds or any clinically significant abnormal electrocardiogram (ECG) finding at Screening.
16. Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies:
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. Incidental histological findings of prostate cancer such as T1a or T1b using the Tumor/Node/Metastasis (TNM) classification of malignant tumors or prostate cancer that is curative
17. Uncontrolled active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose.
18. Known infection with human immunodeficiency virus (HIV). Testing is not required for eligibility.
19. Known active infection with hepatitis B (surface antigen); or infection with hepatitis C in absence of sustained virologic response. Testing is not mandatory for eligibility, unless required by local regulations.
20. Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment.
21. Currently pregnant or breastfeeding, or who intends to become pregnant during the participation in the study.
22. Any known or underlying medical, psychiatric condition, and/or social situations that, in the opinion of the investigator, would limit compliance with study requirements
23. Hypersensitivity to any of the treatments.
24. Have received vaccine containing live virus within 4 weeks prior to first dose of study treatment. (Note: Non oncology vaccines containing live virus for prevention of infectious diseases are prohibited during the study and for 3 months after the last dose of study treatment; inactivated seasonal influenza vaccines or Covid-19 vaccines are permitted on study without restriction.)
25. For participants who may receive a regimen containing iberdomide, concurrent administration of prohibited concomitant drugs: strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including grapefruit, St. John’s Wort, or related products within 14 days of initiating study treatment.
26. Unable or unwilling to undergo protocol-required thromboembolism prophylaxis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Incidence of dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), serious adverse events (SAEs), changes in vital signs, electrocardiograms (ECGs), and laboratory tests according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE).
- Incidence of TEAEs, SAEs, changes in vital signs, ECGs, and laboratory tests, according to NCI CTCAE.
- Overall response rate (stringent Complete Response [sCR] + Complete Response [CR] + Very Good Partial Response [VGPR] + Partial Response [PR]), assessed according to the International Myeloma Working Group (IMWG) Uniform Response Criteria (Kumar et al., 2016). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Table 8: Schedule of Assessment – Part 1
Table 9: Schedule of PK/PD sampling timepoints – Part 1
Table 10: Schedule of Assessment Part 2 — Expansion
Table 11: Schedule of PK/PD sampling timepoints – Part 2 |
|
| E.5.2 | Secondary end point(s) |
- Overall response (stringent Complete Response [sCR] + Complete Response [CR] + Very Good Partial Response [VGPR] + Partial Response [PR]) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria
- Progression-free survival (PFS), duration of response (DoR) and time to response (TTR) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria
- Summary measures of PK parameters of EOS-448, and incidence of anti-drug antibodies (ADA) to EOS-448 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Table 8: Schedule of Assessment – Part 1
Table 9: Schedule of PK/PD sampling timepoints – Part 1
Table 10: Schedule of Assessment Part 2 — Expansion
Table 11: Schedule of PK/PD sampling timepoints – Part 2 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/II study to evaluate the safety profile, antitumor activity PK and PD profiles of EOS-448 |
|
| 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.8.3 |
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 | 6 |
| 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 |
| United States |
| France |
| Belgium |
|
| 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
|
| End of study visit will be defined as the last safety follow-up visit/call or the last assessment/phone call during the long-term follow-up whichever occurs last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
Print
