| 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 marrow 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 | 19.1 |
| 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 |
| The primary objective of the study is to determine the efficacy of daratumumab (DARA) plus durvalumab (DURVA) in subjects with relapsed and refractory multiple myeloma (RRMM) who have progressed on a current treatment regimen containing DARA. |
|
| E.2.2 | Secondary objectives of the trial |
Determine the safety of DARA plus DURVA in subjects with RRMM who have progressed while on a current treatment regimen containing DARA.
Evaluate additional measures of efficacy of DARA plus DURVA in subjects with RRMM who have progressed on a current treatment regimen containing DARA.
Evaluate the pharmacokinetics (PK) of DARA plus DURVA in subjects with RRMM who have progressed on a current treatment regimen containing DARA.
|
|
| 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 a immunomodulatory agent their disease must be refractory to the most recent immunomodulatory agent containing regimen.
2. All subjects must have failed DARA either as a single agent or in combination on last MM therapy. Failure is defined as PD on DARA either as a single agent or in combination.
3. 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
4. Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2 or less.
6. Subject’s toxicities resulting from previous therapy (including peripheral neuropathy) have resolved or stabilized to ≤ Grade 1.
7. Subject is at least 18 years of age at the time of signing the informed consent form (ICF).
8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
10. Females of childbearing potential (FCBP) must:
a. Have 2 negative pregnancy tests as verified by the investigator prior to starting study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
i. Negative serum pregnancy test at screening
ii. Negative serum or urine pregnancy test (investigator’s discretion) within 72 hours prior to starting study treatment (Cycle 1, Day 1), and before beginning each subsequent cycle of treatment, and after end of study treatment.
Note: Pregnancy testing does not need to be repeated prior to Cycle 1 if the serum pregnancy test for screening was performed within 72 hours of the first dose of study treatment.
b. Either practice true abstinence 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 (eg, oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; true abstinence; or vasectomized partner), 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. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of DARA or DURVA, whichever is later.
d. Refrain from egg cell donation for at least 90 days after the final dose of DURVA or DARA, whichever is later.
11. 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, or cancer vaccines
2. Subject has received ASCT within 12 weeks before the date of randomization.
3. History of organ or allogeneic stem cell transplantation
4. Subject received any of the following within the last 14 days of initiating study treatment:
a. Plasmapheresis
b. Major surgery
c. Radiation therapy other than local therapy for myeloma associated bone lesions
d. Use of any systemic anti-myeloma drug therapy (except for DARA either alone or in combination with other agents given with it)
5. Subject received prior treatment with a monoclonal antibody within 5 half-lives of initiating study treatment, other than DARA.
6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for cancer treatment.
7. Subject has any of the following laboratory abnormalities:
a. 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 (calculated using the Cockcroft-Gault formula or directly calculated from the 24-hour urine collection method)
e. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
f. AST or ALT > 2.5 × ULN
g. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome
8. Subject has clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS MM
9. Subject has known COPD with a FEV1 50% of predicted normal. Note that forced expiratory testing (FEV1)is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is < 50% of predicted normal.
10. Subject has known moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
11. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or amyloidosis
12. Subject has nonsecretory MM
13. Subject has known allergy or hypersensitivity to study drug formulations
14. 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 (eg, following Hashimoto’s disease) stable on hormone replacement.
c. Psoriasis not requiring systemic treatment.
15. Subject has history of primary immunodeficiency
16. Subject is positive for HIV-1, chronic or active hepatitis B or active hepatitis A or C.
17. Subject has received live, attenuated vaccine within 30 days prior to the first dose of DURVA.
18. 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, topical, inhaled, or local steroid injections (eg, intra-articular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent.
c. Steroids as premedication for hypersensitivity reactions (eg, infusion-related reactions, computed tomography [CT] scan premedication).
19. Subject has any one of the following:
a. Clinically significant abnormal ECG finding at screening
b. Congestive heart failure (NYHA Class III or IV)
c. Myocardial infarction within 12 months prior to starting study treatment
d. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
20. 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 (T1a or T1b using the TNM clinical staging system) or prostate cancer that is curative
21. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) - Tumor response (partial response [PR] or better), and the rate of progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR will be assessed throughout the study.
|
|
| E.5.2 | Secondary end point(s) |
Safety - Type, frequency, seriousness and severity of adverse events (AEs), and relationship of AEs to study treatment
Time-to-response (TTR) - Time from treatment initiation to the first documentation of response (PR or greater)
Duration of response (DOR) - Time from the first documentation of response (PR or greater) to the first documentation of PD or death, whichever is earlier, based on the investigator assessments according to the IMWG Uniform Response Criteria
Progression-free survival (PFS) - Time from treatment initiation to the first documentation of PD or death from any cause during study, whichever occurs earlier
Overall survival (OS) - Time from treatment initiation to death due to any cause
Pharmacokinetic (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 |
Safety, TTR, DOR, PFS and OS will be assessed throughout the study.
DURVA PK sample time points Part 1 Stage 1:
• C1D2: pre dose (-30 to -5 mins prior to dose), end of infusion (EOI) (+5 mins),
• C1D8: 144 hrs post C1D2 dose (± 1 hr)
• C1D15: 312 hrs post C1D2 dose (± 1 hr),
• C1D22: 480 hours post C1D2 dose (± 1 hr).
• Predose on C2D1, C4D1, C6D1, C10D1, and C14D1.
DARA PK time points Part 1 Stage 1:
· C1D1: predose (-30 to -5 mins prior to dose), and EOI (+5 mins)
· C1D8: predose (-30 to -5 mins prior to dose), and EOI (+5 mins)
· C1D15: predose (-30 to -5 mins prior to dose), and EOI (+5 mins)
· C1D22: predose (-30 to -5 mins prior to dose), and EOI (+5 mins)
· 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 | 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 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 |
| Austria |
| Canada |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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 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 pre specified 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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