| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and refractory multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bone marrowof that has recurred or no longer responds to current treatment |
|
| 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 |
| To determine the safety and efficacy of DURVA and DARA in subjects with RRMM |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate additional measures of efficacy (time-to-response, duration of response, progressive-free survival) of DURVA and DARA in subjects with RRMM;
- Evaluate the pharmacokinetics (PK) of DURVA and DARA in subjects with RRMM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject received at least 3 prior anti-myeloma regimens including a PI and an immunomodulatory agent or is double-refractory to a PI and an immunomodulatory agent.
· Induction, bone marrow transplant with or without maintenance therapy is considered one regimen.
· Refractory is defined as disease that is nonresponsive on therapy, or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy.
· For subjects who received more than 1 regimen containing a PI their disease must be refractory to the most recent PI containing regimen.
· For subjects who received more than 1 regimen containing an immunomodulatory agent their disease must be refractory to the most recent immunomodulatory agent containing regimen.
2. Subject has measurable disease defined as:
a. M-protein (serum protein electrophoresis (sPEP) or urine protein electrophoresis (uPEP): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours) and/or
b. Light chain MM without measurable disease in the serum or the urine: serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
3. Subject achieved a response (MR or better) to at least 1 prior treatment regimen.
4. Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen.
5. Subject received an alkylating agent alone or in combination with other myeloma treatment.
6. Subject has an Eastern Cooperative Oncology Group performance-status score of 2 or less.
7. Subject’s toxicities resulting from previous therapy (including peripheral neuropathy) have resolved or stabilized to ≤ Grade 1.
8. Subject is at least 18 years of age at the time of signing the informed consent form (ICF).
9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
11. Females of childbearing potential (FCBP ) must:
a. Have 2 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. Either practice true abstinence2 from heterosexual contact (which must be reviewed on a monthly basis and 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 at least 90 days after discontinuation of study treatment.
c. Refrain from egg cell donation for at least 90 days after the final dose of DURVA or DARA, whichever is later.
12. Male subjects must:
a. Either 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 female of childbearing potential 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 donation for at least 90 days after the final dose of DURVA or DARA, whichever is later.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has had prior exposure to anti-CTLA-4, anti-PD-1, anti-PD-L1 mAbs, cell-based therapies, or cancer vaccines
2. Subject received DARA or other anti-CD38 antibodies therapies previously
3. Subject received any of the following within the last 14 days of initiating study treatment:
a. Plasmapheresis
b. Major surgery (as defined by the investigator)
c. Radiation therapy other than local therapy for myeloma associated bone lesions
d. Use of any systemic anti-myeloma drug therapy
4. Subject received prior treatment with a monoclonal antibody within 5 half-lives of initiating study treatment
5. Subject used any investigational agents within 28 days or 5 half-lives of initiating study treatment
6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for cancer treatment
7. History of organ or allogeneic stem cell transplantation
8. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks before the date of randomization
9. Subject has any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000/μL
b. Platelet count: < 75,000/μL (it is not permissible to transfuse a subject to reach this level)
c. Hemoglobin < 8 g/dL (< 4.9 mmol/L)(it is not permissible to transfuse a subject to reach this level)
d. Creatinine Clearance (CrCl) < 45 mL/min
e. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
f. Serum aspartate aminotransferase (AST) or alanine aminotransferase(ALT) > 2.5 × upper limit of normal (ULN)
g. Serum total bilirubin > 1.5 × upper limit of normal (ULN) or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome
10. Subject has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS MM
11. Subject has known COPD with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal
12. Subject has known moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification
13. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or amyloidosis
14. Subject has nonsecretory MM
15. Subject has known allergy or hypersensitivity to study drug formulations
16. Subject has active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
a. Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism stable on hormone replacement.
c. Psoriasis not requiring systemic treatment.
17. Subject has history of primary immunodeficiency
18. Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C
19. Subject has received live, attenuated vaccine within 30 days prior to the first dose of DURVA
20. Subject is currently using or has used immunosuppressive medication within 14 days prior to the first study dose of study treatment. The following are exceptions to this criterion:
a. Intranasal, inhaled, or local steroid injections
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
c. Steroids as premedication for hypersensitivity reactions
21. Subject has any one of the following:
a. Clinically significant abnormal ECG finding at screening
b. Congestive heart failure
c. Myocardial infarction within 12 months prior to starting study treatment
d. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
22. Subject has 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 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 histologic finding of prostate cancer or prostate cancer that is curative
23. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study
24. Subject has significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
25. Subject has a condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
26. Subject has a condition that confounds the ability to interpret data from the study
For subjects who will have POM+dex added to the D2 and enrolled into the PD3 cohort:
27. Subject has history of anaphylaxis or hypersensitivity to thalidomide, LEN, POM, or dex
28. Subject has history of rash ≥ Grade 3 during prior thalidomide, LEN, or POM therapy
29. Subject has known or suspected hypersensitivity to the excipients contained in the formulation of POM or dex.
30. Subject is a current smoker |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Overall response rate (ORR): tumor response, including progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria.
- Safety: type, frequency, seriousness and severity of adverse events (AEs), and relationship of AEs to study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall response rate: Tumor response, including PD, will be assessed by the investigators using the IMWG criteria. The ORR will be calculated as the percent of responders (count of subjects with at least a PR, divided by the number of subjects in the EE Population). The ORR together with the proportions in each response category based on the IMWG criteria will be tabulated by dose cohort and arm. A 95% confidence interval of the ORR of D2 for all subjects treated with the RP2D and an 80% confidence interval of the ORR of exploratory PD3cohort will be provided.
AEs: At screening and Continuously, until 90 days after last dose of DURVA or DARA, whichever is later |
|
| E.5.2 | Secondary end point(s) |
- Time-to-response (TTR): time from enrollment to the first documentation of response (Partial Response [PR] or greater).
- Duration of response (DOR): time from the first documentation of response (PR or greater) to the first documentation of PD.
- Progression-free survival (PFS): time from enrollment to the first documentation of PD or death from any cause during study, whichever occurs earlier.
PK parameters: Typical serum/plasma PK parameters for DURVA and DARA, 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- The PK sampling time points for DURVA in Phase 2 Stage 1 (including subjects enrolled in the D2 safety run-in phase) will be as follows:
• C1D2: predose (-30 to -5 minutes prior to dose), end of infusion (EOI) (+30 minutes),
•C1D8,
• C1D15,
• C1D22.
• Additional Durvalumab PK samples to be collected to match immunogenicity collections predose (-30 to -5 minutes prior to dose) on C2D1, C4D1, C6D1, C10D1, and C14D1 and EoT.
The PK sampling time points for DARA in Phase 2 Stage (including subjects enrolled in the D2 safety run-in phase) will be as follows:
• C1D1, C1D8, C1D15, C1D22: predose (-30 to -5 minutes prior to dose), and EOI (+30 minutes)
• EOT,
• 28 days after EOT,
• 90 days after last DARA or DURVA dose.
|
|
| 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) | 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 | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 3+3 design to confirm the tolerability for DURVA and DARA. Simon 2-stage design for Phase 2 portion |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| durvalumab in combination with datatumumab with and without pomalidomide + dexamethasone |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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