| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bone marrow |
|
| 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 |
|
| 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 |
| Determine the recommended dose of durvalumab in combination with LEN +/- dex in subjects with NDMM. |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate the safety and preliminary efficacy of durvalumab in combination with LEN +/- dex in subjects with NDMM
- Evaluate the pharmacokinetics of durvalumab and LEN with and without dex in subjects with NDMM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4. Subject must have documented diagnosis with previously untreated (for cohort C, the induction and consolidation treatment along with the first ASCT are allowed), symptomatic multiple myeloma (MM) as defined in the protocol
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
6. 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 subject practices true abstinence from heterosexual contact.
b. She must either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and be source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study treatment, during the study therapy (including dose interruptions), and for 90 days after discontinuation of study treatment.
c. Refrain from egg cell and blood donation for 90 days after the final dose of durvalumab.
7. Male subjects must :
a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 90 days following study treatment discontinuation, even if he has undergone a successful vasectomy.
b. Refrain from sperm and blood donation for at least 90 days after the final dose of durvalumab
8. For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the following high risk factors:
a. Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or del(17p); and / or 1q amplification; and / or t(14:16);or
b. ISS Stage III; or
c. Serum LDH > 2 x ULN
9. For Cohort B subject must be ≥ 65 years of age at the time of signing the informed consent form (ICF) and transplant non-eligible (TNE); excluding the subjects who meet the Cohort A criteria
10. For Cohort C subject must be after first autologous stem cell transplantation (ASCT) for NDMM and meet the following criteria:
a. Have a post-transplant response as PR or better at the time of enrollment to this study;
b. Have one of the following high risk factors at the time of NDMM diagnosis:
- Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and/ or del(17p); and / or 1q amplification; and / or t(14; 16); or
- ISS stage III; or
- Serum LDH > 2 x ULN;
c. MRD positive (defined as more than 1 malignant cell in 10^5 cells) measured by ClonoSIGHT™ NGS assay of a BMA sample) at the time of enrollment to this study; BMA sample collected at the time of multiple myeloma diagnosis, prior to induction therapy available for central MRD assessment by ClonoSIGHT™ NGS assay |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of Cycle 1 Day 1], for Cohort C, the induction and consolidation treatment along with the first ASCT are allowed)
2. Any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000/μL
b. Untransfused platelet count < 75,000 cells/μL
c. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) > 2.5 × upper limit of normal (ULN)
d. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome
e. Corrected serum calcium >13.5 mg/dL (> 3.4 mmol/L)
3. Renal failure requiring hemodialysis or peritoneal dialysis
4. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, subject with unstable cardiac disease as defined by: cardiac events such as myocardial infarction (MI) within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment
5. Peripheral neuropathy ≥ Grade 2
6. Primary AL (immunoglobulin light-chain) amyloidosis and myeloma complicated by amyloidosis
7. Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive 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 histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
8. Subjects is positive for human immunodeficiency virus (HIV); chronic or active hepatitis B or active hepatitis A, or C
9. Subject had prior exposure to immunotherapy, including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 monoclonal antibody or inhibitor, cell-based therapies, or cancer vaccines
10. Subjects had history of organ or allogeneic stem cell transplantation
11. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma, or plasma cell leukemia
12. Known or suspected hypersensitivity to the excipients contained in the formulation of durvalumab, lenalidomide, or dexamethasone
13. Major surgery (as defined by the investigator) within the 28 days prior to the first dose of study treatment
14. Received prior treatment (for any reason)with a monoclonal antibody within 5 half-lives of initiating study treatment
15. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
16. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of study treatment. Exceptions to this criterion are detailed in the protocol
17. Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment. Exceptions to this criterion are detailed in the protocol
18. History of primary immunodeficiency
19. Subject has incidence of gastrointestinal disease that may significantly alter the absorption of LEN
20. Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab
21. Unable or unwilling to undergo protocol required thromboembolism prophylaxis(for Cohort C, this will be only for the subjects who have a history of VTE)
22. Females who are pregnant, nursing or breastfeeding, or intend to become pregnant during the participation to the study
23. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
24. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
25. Any condition that confounds the ability to interpret data from the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Review safety (including dose-limiting toxicities [DLTs]), and if applicable, PK/Pd, and/or biomarker, and/or preliminary efficacy data by Dose Review Team (DRT) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: 28 (+3) days after the EOT visit and 90 (+3) days after the last dose of durvalumab
Efficacy: Day 1 of each cycle, and at End of Treatment
The PK sampling time points will be as follows:
- C1D1: preinfusion (-30 to -5 minutes prior to dose), end of infusion (EOI) (± 5 minutes), 4 hours (± 1 hour), 168 hours (C1D8) (± 2 hour), 336 hours (C1D15) (± 2 hour) and 504 hours (C1D22) (± 2 hour) after administration of durvalumab
- C2D1: preinfusion (-30 to -5 minutes prior to dose), EOI (± 5 minutes), 4 hours (± 1 hour), and 336 hours (C2D15) (± 2 hour) after administration of durvalumab
- C4D1, C6D1, C10D1, and C14D1: preinfusion (-30 to -5 minutes prior to dose)
Biomarkers will be assessed at different time points, as applicable. |
|
| E.5.2 | Secondary end point(s) |
Safety - Type, frequency, seriousness and severity of adverse events (AEs) (included second primary malignancies), and relationship of AEs to study treatment
Overall Response Rate (ORR) (for Cohorts A and B) - Tumor response, including progressive disease, based on the investigator assessments according to the International Myeloma Working Group (IMWG) Uniform Response Criteria
Response Improvement Rate (RIR) (for Cohort C) - Response improved from the assessment at the Cycle 1 Day 1 (C1D1); (Pre-autologous stem cell transplantation [ASCT] diseases measurement will be used as baseline for response assessment)
Time to Response (TTR) (for Cohorts A and B) - Time from C1D1to the first documentation of response
Duration of response (DOR) (for Cohorts A and B) - Time from the first response (partial response [PR] or better) to the first documentation of disease progression or death, whichever is earlier, based on the investigator assessments according to the IMWG Uniform Response Criteria
Pharmacokinetic - Typical serum/plasma PK parameters for durvalumab and lenalidomide, such as maximum observed concentration (Cmax), area under the concentration-time curve (AUC), time to maximum concentration (Tmax), terminal elimination half-life (t1/2), clearance (CL/F), and volume of distribution (Vz/F)
Immunogenicity - Frequency of development of anti-drug antibodies and neutralization
Progression-Free Survival (PFS) - Time from C1D1 to the first documentation of disease progression (based on the investigator assessments according to the IMWG Uniform Response Criteria) or death from any cause during study, whichever occurs earlier
Overall Survival (OS) - Time from C1D1 to death due to any cause |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: 28 (+3) days after the EOT visit and 90 (+3) days after the last dose of durvalumab
Efficacy: Day 1 of each cycle, and at End of Treatment
The PK sampling time points will be as follows:
- C1D1: preinfusion (-30 to -5 minutes prior to dose), end of infusion (EOI) (± 5 minutes), 4 hours (± 1 hour), 168 hours (C1D8) (± 2 hour), 336 hours (C1D15) (± 2 hour) and 504 hours (C1D22) (± 2 hour) after administration of durvalumab
- C2D1: preinfusion (-30 to -5 minutes prior to dose), EOI (± 5 minutes), 4 hours (± 1 hour), and 336 hours (C2D15) (± 2 hour) after administration of durvalumab
- C4D1, C6D1, C10D1, and C14D1: preinfusion (-30 to -5 minutes prior to dose)
Biomarkers will be assessed at different time points, as applicable. |
|
| 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 | Yes |
| 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) | 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 |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| durvalumab in combination with lenalidomide with and without dexamethasone |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 17 |
| 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 |
| Canada |
| Denmark |
| Finland |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Spain |
| United States |
|
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for the primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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