| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Multiple Myeloma patients presenting with extramedullary disease
|
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 |
| To evaluate the Complete Response (CR) rate |
|
| E.2.2 | Secondary objectives of the trial |
The secondary Objectives are:
- To evaluate Duration of Response (DoR)
- To evaluate the Progression Free Survival (PFS)
- To evaluate the Overall Response Rate (ORR)
- To evaluate Time to next Therapy (TnT)
- To evaluate Overall Survival (OS)
- To assess the safety (adverse events) of DaraVCD treatment" |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Confirmed diagnosis of MM (IMWG consensus guidelines)
2. Newly diagnosed or relapsed (patients should have received a maximum of one line of prior therapy – see Appendix K) patients presenting with EMD of the skin, liver, lungs, central nervous system, lymph nodes or other tissues, but not solely paraskeletal plasmacytoma * detected by physical exam and confirmed (when required) by WBCT/MRI/PET-CT and/or biopsy**. Documentation of plasma cell infiltration is highly recommended unless it requires invasive surgical intervention such as intracerebral infiltration of plasmacytomas.
*Note: paraosseous plasmacytomas meet the eligibility criteria if plasma cell infiltration arising from the bone erodes bone cortex and expands into the adjacent soft tissues
**Note: An additional radiologic assessment at screening is not required to confirm EMD. Documentation in terms of physician’s/pathologist’s report and/or radiologic assessments performed within 42 days of C1D1 will suffice for the purposes of eligibility. All patients however will undergo a baseline radiologic assessment at C1D1 for response purposes.
3. Patients with one prior line of therapy must have:
achieved a response (PR or better based on investigator’s determination of response by the IMWG criteria) to at least one prior regimen.
documented evidence of PD based on Investigator’s determination of response as defined by the IMWG criteria on or after the last line of treatment.
4. Age ≥ 18 years
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Note: for patients with CNS involvement, an ECOG performance status >2 is also acceptable
6. Each patient must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
7. Patient must have measurable disease manifested by either monoclonal protein and/or light chain in the serum or urine
8. Reproductive Status
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test at screening. Females are not of childbearing potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy
Women must not be breastfeeding
WOCBP must agree to follow instructions for reliable methods of birth control. This includes one highly effective (< 1% failure rate per year) form of contraception (tubal ligation, intrauterine device [IUD], combined or progestogen only hormonal contraception associated with inhibition of ovulation [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks before the start of treatment, and continue for the duration of study treatment and for 3 months after cessation of daratumumab or 12 months after cessation of cyclophosphamide, whichever is longer.
Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for 3 months after cessation of daratumumab or 6 months after cessation of cyclophosphamide, whichever is longer.
Female patients must not donate eggs for up to 3 months after cessation of daratumumab or 12 months after cessation of cyclophosphamide, whichever is longer.
Male patients must not donate sperm for up to 3 months after cessation of daratumumab or 6 months after cessation of cyclophosphamide, whichever is longer.
Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described above. |
|
| E.4 | Principal exclusion criteria |
1. Solitary plasmacytoma
2. Presence of paraosseous plasmacytomas only. EXCEPTION: paraosseous plasmacytomas meet the eligibility criteria if plasma cell infiltration arising from the bone erodes bone cortex and expands into the adjacent soft tissues
3. Previous therapy with any anti-CD38 or anti-CS1 monoclonal antibody
4. Patients refractory to bortezomib based regimens (PD on or within 60 days of completion of bortezomib OR failure to achieve at least a minimal response [MR]) as the prior line of therapy
5. Patients who have Bortezomib or Daratumumab hypersensitivity
6. Patients who have active or chronic infections
7. Patients who have received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before Cycle 1 Day 1 (C1D1). The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1.
8. Previous ASCT within 12 weeks before C1D1.
9. Previous allogenic stem cell transplant (alloSCT) regardless of timing.
10. Patient has received radiotherapy within 14 days from C1D1. NOTE: Urgent localized radiotherapy for Spinal Cord Compression or Central Nervous System Involvement is allowed.
11. Patient has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and patients must be excluded if FEV1 <50% of predicted normal
12. Patient has known moderate or severe persistent asthma within the past 2 years (see) or currently has uncontrolled asthma of any classification. Note: Patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
13. Severe cardiovascular disease (arrhythmias [CTCAE Grade 3 or higher] requiring chronic treatment, congestive heart failure [New York Heart Association (NYHA) Class III – IV] or symptomatic ischemic heart disease);
14. Severe pulmonary dysfunction (CTCAE grade 3-4, see appendix D);
15. Severe neurological or psychiatric disease;
16. Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times the upper limit of normal [ULN]) unless related to hepatic involvement with MM.
Note: Patients with Gilbert Syndrome are not excluded provided that direct bilirubin is ≤2 x ULN.
17. Significant renal dysfunction (creatinine clearance <30 ml/min after rehydration) Note: refer to Appendix F for creatinine clearance calculation;
18. Significant bone marrow suppresion as evidenced by ANY of the below laboratory tests during screening:
Absolute neutrophil count ≤1.0 × 109/L;
Hemoglobin level ≤7.5 g/dL (≤4.65 mmol/L); transfusions are NOT allowed to reach this level
Platelet count ≤75 × 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and platelet count ≤50 × 109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells; transfusions are NOT allowed to reach this level
19. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, active systemic infection, uncontrolled hypertension, cancer, etc.) that is likely to interfere with the study procedures/results or which, in the opinion of the investigator, would constitute a hazard for participating in this study.
20. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
21. Any of the following:
Known active hepatitis A
Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Patients with resolved infection (ie, patients who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy).
22. Patient known to be HIV-positive;
23. Current participation in another clinical trial
24. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with CR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Duration of Response (DoR)
- Progression Free Survival (PFS)
- Overall Response Rate (ORR)
- Time to next Therapy (TnT)
- Overall Survival (OS)
- Safety (Adverse Events)" |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| 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 |
|
| 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
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| Last subject out, i.e. five years after enrollment of last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| 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 | 0 |
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