E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Myeloma (MM), relapsed or relapsed-and-refractory |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
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 compare progression-free survival (PFS), in patients treated with PAN in combination with BTZ/Dex vs. patients treated with placebo in combination with BTZ/Dex |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary
•To compare OS (overall survival) Other Secondary
•To compare ORR (overall response rate) comprising CR, nCR and PR
•To compare nCR plus CR rate (near complete response plus + complete response)
•To compare MRR (minor response rate)
•To compare TTR (time to response)
•To compare TTP (time to progression)
•To assess duration of response (DOR; from first occurring PR or better)
•To assess safety of the combination therapy
•To assess health-related quality of life and symptoms of multiple
Myeloma |
|
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 |
Title:
Biomarker Companion Study
Biomarker companion study in the multicenter, randomized, double-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and
dexamethasone in patients with relapsed multiple myeloma
Version 00, release date 14-Sep-2009
Objective:
- To correlate baseline tumour cell molecular characteristics (such as chromosome
abnormalities, and protein markers such as HR23B) with response.
- To investigate molecular CR as defined in IMWG08 criteria by ASO-PCR in patients with CR. |
|
E.3 | Principal inclusion criteria |
1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions. All three of the following criteria must have been met:
a. Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine
b. Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma
c. Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)
2. Patient with 1 to 3 prior lines of therapy who require retreatment of myeloma (cf IMWG 2003 ) for one of the 2 conditions below:
a. Relapsed, defined by disease that recurred in a patient that responded under a prior therapy, by reaching a MR or better, and had not progressed under this therapy nor up to 60 days of last dose of this therapy. Patients priorly treated by BTZ may be eligible.
b. Relapsed-and-refractory to a therapy, provided that meets both conditions:
- patient has relapsed to at least one prior line
- and patient was refractory to another line (except BTZ), by either not reaching a MR, or progressed while under this therapy, or within 60 days of its last dose
3. Patient has measurable disease on M protein at study screening defined by at least one of the following measurements as per thresholds clarified in IMWG 2003 disease definitions (Kyle, et al 2003):
• Serum M-protein ≥ 1 g/dL (≥ 10 g/L)
• Urine M-protein ≥ 200 mg/24 h
4. Patients treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy
5. Patient’s age is ≥ 18 years at time of signing the informed consent
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2
7. Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before screen fail is concluded but supportive therapies are not to be administered within the week prior to screening tests for absolute neutrophil count or platelet counts)
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
b. Platelet count ≥ 100 x 109 /L
c. Serum potassium, magnesium, phosphorus, within normal limits (WNL) for institution
d. Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not higher than CTCAE grade 1 in case of elevated value
Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are < LLN:
e. AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
f. Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)
g. Serum creatinine levels ≤ 1.5 x ULN, or calculated creatinine clearance ≥ 60 ml/min
8. Patient has provided written informed consent prior to any screening procedures
9. Patient is able to swallow capsules
10. Patient must be able to adhere to the study visit schedule and other protocol requirements
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment
|
|
E.4 | Principal exclusion criteria |
1. Patients who have progressed under all prior lines of anti MM therapy (primary refractory)
2. Patients who have been refractory to prior BTZ (ie. did not achieve at least a MR, or have progressed under it or within 60 days of last dose)
3. Allogeneic stem cell transplant recipient presenting with graft versus host disease either active or requiring immunosuppression
4. Patient has shown intolerance to bortezomib or to dexamethasone or components of these drugs or has any contraindication to one or the other drug, following locally applicable prescribing information
5. Patient has grade ≥ 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination within 14 days before randomization
6. Patient received prior treatment with DAC inhibitors including panobinostat
7. Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment
8. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)
9. Patient has another primary malignancy < 3 years from first dose of study treatment
10. Patient who received:
a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex ≤ 3 weeks prior to start of study.
b. experimental therapy or biologic immunotherapy including monoclonal antibodies ≤ 4 weeks prior to start of study.
c. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior start of study.
11. Patient has not recovered from all therapy-related toxicities associated with above listed treatments to < grade 2 CTCAE.
12. Patient has undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to < grade 2 CTCAE
13. Patients with evidence of mucosal or internal bleeding
14. Patient has unresolved diarrhea ≥ CTCAE grade 2
15. Patient has impaired cardiac function, including any one of the following:
a. LVEF < LLN of institutional norm, as determined by ECHO or MUGA
b. obligate use of a permanent cardiac pacemaker
c. congenital long QT syndrome
d. history or presence of ventricular tachy-arrhythmias
e. resting bradycardia defined as < 50 beats per minute
f. QTcF > 450 msec on screening ECG
g. complete left bundle branch block (LBBB), bifascicular block
h. any clinically significant ST segment and/or T-wave abnormalities
i. presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria.
j. myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study drug
k. symptomatic congestive heart failure (New York Heart Association class III-IV)
l. other clinically significant heart disease and vascular disease (e.g. uncontrolled hypertension)
16. Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes, if such treatment cannot be discontinued or switched to a different medication prior to starting study drug
17. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
18. Patient has any other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause, uncontrolled thyroid dysfunction) that could cause unacceptable safety risks or compromise compliance with the protocol
19. Patient has a known history of HIV seropositivity or history of active/treated hepatitis B or C (a test for screening is not required)
20. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double method of contraception during the study and 3 months after the study evaluation completion treatment, of which one must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e. patient has had menses at any time in the preceding 12 consecutive months.
21. Patient is a male not willing to use a barrier method of contraception (a condom) during the study and for 3 months after the study evaluation completion treatment
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
PFS i.e. PD for patients not in CR or relapse for patients in CR (per
investigator assessment based on modified EBMT criteria) or death from any cause |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 3 weeks during treatment and then every 6 weeks after end of Treatment |
|
E.5.2 | Secondary end point(s) |
1. OS
2. ORR (comprising CR, nCR, and PR)
3. nCR +Cr
4. MRR
5. TTR
6. DOR
7. TTP
8. HRQoL and multiple myeloma symptoms as measured by: EORTC QLQC30, EORTC QLQ-MY20, and FACT/GOG-NTX
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. to 7.: every 3 weeks during treatment and then every 6 weeks after end of treatment
8.: at screening, day 1 of each cycle and study evaluation completion |
|
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 |
correlative biomarker analysis |
|
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 82 |
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 | Information not present in EudraCT |
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 |
Argentina |
Australia |
Brazil |
Canada |
China |
Egypt |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Lebanon |
Mexico |
Russian Federation |
Singapore |
South Africa |
Taiwan |
Thailand |
Turkey |
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
|
|
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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |