| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 compare progression-free survival (PFS) in patients with multiple myeloma relapsed after 1 to 3 prior therapies treated with either carfilzomib plus dexamethasone (Cd) or bortezomib (Velcade®) plus dexamethasone (Vd). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following between the treatment groups:
- Overall Survival (OS)
- Overall Response Rate (ORR) [defined as the proportion of best
overall response of stringent Complete Response (sCR), Complete
Response (CR), Very Good Partial Response (VGPR), and Partial
Response (PR)]
- Duration of Response (DOR)
- Neuropathy Events (defined from Grade 2 or higher peripheral
neuropathy)
- Safety and Tolerability - Assess changes from baseline in LVEF, RV function, and pulmonary artery pressure in a subset of patients from both treatment groups |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic sub-study:
Blood samples will be collected from approximately 100 patients in the Cd arm for measurement of plasma carfilzomib concentrations and subsequent estimation of a number of pharmacokinetic parameters.
Pharmacodynamics and Biomarkers sub-study:
Pharmacodynamics in the form of proteasome inhibition will be measured in whole blood and isolated peripheral blood mononuclear cells collected from at least 15 patients per treatment arm. Analysis of biomarkers predictive of response to proteasome inhibitors will also be performed on these samples, as will genomic and proteomic analyses in an attempt to determine biomarkers that predict for response metrics and safety signals.
ECHO sub-study:
A transthoracic ECHO to assess LVEF, RV function, right ventricular size, right ventricular wall thickness, and pulmonary artery pressure will be obtained on all patients at baseline prior to the start of therapy. A subset of patients from both arms (a minimum of 100 patients and a maximum of 300 patients total; 50 to 150 patients per treatment arm) will be assessed for LVEF, RV function, right ventricular size, right ventricular wall thickness, and pulmonary artery pressure every 12 weeks and at end of treatment. A clinical adjudication committee composed of 2 to 3 cardiologists who will review all echocardiographic data in conjunction with available clinical (e.g., signs or symptoms of
CHF, cardiac ischemia, conduction abnormalities) and diagnostic
correlates (e.g., results of stress test, ECG, cardiac angiogram, cardiac catheterization) from substudy patients who exhibit incidental changes in LVEF, RV function or pulmonary artery pressure in order to assess their clinical relevance.
For patients who present acutely with signs or symptoms of CHF,
cardiac ischemia or conduction abnormalities an ECG and ECHO
should be performed. As part of the evaluation, additional diagnostic tests such as a stress test, chest x-ray and CT angiogram could be performed. For patients who present with a clinically significant pulmonary adverse event such as dyspnea or hypoxia, the time course of onset and resolution of the event must be recorded and oximetry and/or blood gases measurements as well as response to oxygen supplementation. Consultation with a pulmonary specialist should occur when clinically appropriate. Any patient with emergent cardiac and/or pulmonary toxicities will have the cardiopulmonary adverse event eCRF completed.
Minimal Residual Disease (MRD) testing:
A bone marrow aspirate will be collected in patients who consent to the optional MRD assessment by flow cytometry, at the time of CR, sCR, or VGPR, and in consenting patients with previously established CR or sCR, and will be analyzed for the presence of MRD. The MRD analysis will only be performed in countries that meet local tissue sample transportation requirements. |
|
| E.3 | Principal inclusion criteria |
1.Multiple myeloma with relapsing or progressing disease at study entry.
2.Patients must have evaluable multiple myeloma with, at least one of the following (assessed within 21 days prior to randomization):
•Serum M-protein ≥ 0.5 g/dL, or
•Urine M-protein ≥ 200 mg/24 hour, or
•In patients without detectable serum or urine M-protein, serum free light chain (FLC) > 100 mg/L (involved light chain) and an abnormal serum kappa/lambda ratio, or
•For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL).
3.Patients must have documented at least PR to at least 1 line of prior therapy. PR documentation can be based on Investigator assessment.
4. Received at least 1, but no more than 3 prior treatment regimens or lines of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/ maintenance therapy will be considered as one line of therapy).
5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to prior Velcade therapy, was not removed from Velcade therapy due to toxicity, and will have at least a 6 month Velcade treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month Velcade treatment-free interval).
6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity, and had at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib treatment-free interval). The exception to this are patients randomized or previously randomized in any other Onyx-Sponsored Ph 3
trial
7.Males and females ≥ 18 years of age.
8. ECOG Performance Status of 0 to 2.
9. Adequate hepatic function within 21 days prior to randomization, with bilirubin < 1.5 times the ULN, and AST and ALT < 3 times the ULN.
10. LVEF ≥ 40%.
11. ANC ≥ 1000/mm3 within 21 days prior to randomization. Screening ANC should be independent of growth factor support for ≥ 1 week.
12. Hemoglobin ≥ 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic stimulating factors and RBC transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.
13. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma
involvement in the bone marrow is > 50%) within 21 days prior to randomization. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the screening
platelet count.
14. Calculated or measured CrCl of ≥ 15 mL/min within 21 days prior to randomization. Calculation should be based on standard formula such as the Cockcroft and Gault: [(140 – Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female.
15. Written informed consent in accordance with federal, local, and institutional guidelines.
16. Female patients of childbearing potential (FCBP) must have a
negative serum pregnancy test within 21 days prior to randomization and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if
required per local regulations). FCBP is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
17. Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP. |
|
| E.4 | Principal exclusion criteria |
1. Multiple myeloma of IgM subtype.
2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to randomization.
3. POEMS syndrome.
4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 109/L.
5. Waldenstrom’s Macroglobulinemia.
6. Patients with known amyloidosis.
7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to randomization.
8. Patients randomized or previously randomized in any other Onyx-sponsored Phase 3 trial.
9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e., prior radiation must have been to less than 30% of the bone marrow).
10. Immunotherapy within 21 days prior to randomization.
11. Major surgery (except kyphoplasty) within 28 days prior to randomization.
12. Active congestive heart failure (NYHA Class III to IV; refer to Appendix H), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to randomization.
13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to randomization.
14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B SAg or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed).
15. Patients with known cirrhosis.
16. Second malignancy within the past 3 years except:
- adequately treated basal cell or squamous cell skin cancer
- carcinoma in situ of the cervix
- prostate cancer Gleason score ≤ 6 with stable prostatespecific antigen (PSA) over 12 months
- breast carcinoma in situ with full surgical resection
- treated medullary or papillary thyroid cancer
17. Patients with myelodysplastic syndrome.
18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to randomization.
19. Female patients who are pregnant or lactating.
20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.
22. Patients with contraindication to dexamethasone.
23. Contraindication to any of the required concomitant drugs or supportive treatments,including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
24. Ongoing graft-vs-host disease.
25. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
26. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS by Independent Review Committee (IRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Study is expected to have required number of PFS events approximately 8 months after enrollment is complete |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
•Overall survival
•Overall Response Rate (defined as the proportion of best overall response of sCR, CR, VGPR, and PR)
•Duration of Response
•Neuropathy Events (defined from Grade 2 or higher peripheral neuropathy)
•Safety and Tolerability:
Change from baseline in LVEF, RV function, and pulmonary artery pressure in a subset of patients from both treatment
groups |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary end points are to be evaluated at the time of the final OS analysis when the required number of events have been reached, estimated at approximately 78 months after the enrollment start.
|
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 84 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Taiwan |
| Ukraine |
| 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
|
| End of the study defined as when the final OS analysis takes place |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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