| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory Multiple Myeloma (MM) or relapsed and refractory MM. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Refractory Multiple Myeloma (MM) or relapsed and refractory MM. |
|
| 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 | 18.0 |
| 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 |
| The primary objective of the study is to compare the efficacy of POM + LD-DEX with that of HD-DEX in subjects with refractory MM or relapsed and refractory MM. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to compare the safety of POM + LD-DEX with that of HD-DEX in subjects with refractory MM or relapsed and refractory MM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be ≥ 18 years at the time of signing the informed consent form.
2. The subject must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted. The only exception is if a skeletal survey was performed within 60 days prior to the start of Cycle 1, a new survey will not be required.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Subjects must have documented diagnosis of multiple myeloma and have measurable disease (serum M-protein ≥0.5g/dL or urine M-protein ≥200 mg/24 hours)
5. Subjects must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy. Induction therapy followed by ASCT and consolidation/maintenance will be considered as one line.
6. Subjects must have either refractory or relapsed and refractory disease defined as documented disease progression during or within 60 days of completing their last myeloma therapy.
• Primary refractory: Subjects who have never achieved any response better than PD to any previous line of anti-myeloma therapy.
• Relapsed and refractory: Subjects who have relapsed after having achieved at least stable disease for at least two cycles of treatment to at least one prior regimen and then developed PD on or within 60 days of completing their last myeloma therapy.
7. All subjects must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib, either alone or in combination regimens as follows in criterion # 9.
8. Subjects must have received adequate prior alkylator therapy in one
of the following ways:
•As part of a stem cell transplant or
•a minimum of 6 consecutive cycles of an alkylator based therapy or
•progression on treatment with an alkylator, provided that the patient received at least 2 cycles of an alkylator-containing therapy.
9.All subjects must have failed both lenalidomide and bortezomib and medical records must be available that provide documentation of the following criteria for refractoriness that make the subject eligible for the study:
•All subjects must have failed treatment with the last lenalidomidecontaining
regimen in one of the following ways:
-Documented PD during or within 60 days of completing treatment with
lenalidomide, or
-In case of prior response (≥ PR) to lenalidomide, subjects must have relapsed within 6 months after stopping treatment with lenalidomidecontaining regimens
•All subjects must have failed treatment with the last bortezomibcontaining
regimen in one of the following ways:
-Documented PD during or within 60 days of completing treatment with
bortezomib, or
-In case of prior response (≥ PR) to bortezomib, subjects must have relapsed within 6 months after stopping treatment with bortezomibcontaining regimens, or
-Subjects who have not had a ≥ MR response and have developed intolerance/toxicity after a minimum of two cycles of a bortezomibcontaining
regimen. For example, a toxicity such as > grade 2 peripheral neuropathy or ≥ grade 2 painful neuropathy. Peripheral neuropathy must resolve to grade 1 prior to study entry.
10. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
11. Females of childbearing potential (FCBP) must agree to utilize two reliable forms of contraception simultaneously or practice complete abstinence (True abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]) from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe.
12. Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation.
13. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy.
14. Males must also agree to refrain from donating semen or sperm while on pomalidomide and for 28 days after discontinuation from this study treatment.
15. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
16. All subjects must agree not to share medication. |
|
| E.4 | Principal exclusion criteria |
1. Any of the following laboratory abnormalities:
• Absolute neutrophil count (ANC) < 1,000/µL
• Platelet count < 75,000/ µL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 30,000/ µL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells
• Creatinine Clearance < 45 mL/min according to Cockcroft-Gault formula
(See Appendix I). If creatinine clearance calculated from the 24-hour urine sample is ≥45mL/min, patient will qualify for the trial.
• Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L); or free ionized calcium > 6.5 mg/dL (> 1.6 mmol/L)
• Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted)
• Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)
• Serum total bilirubin > 2.0mg/dL (34.2μmol/L); or >3.0xULN for
subjects with hereditary benign hyperbilirubinaemia.
2. Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following:
• Basal or Squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix or breast
• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
3. Previous therapy with Pomalidomide.
4. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone. (This includes ≥ Grade 3 rash during prior thalidomide or lenalidomide therapy.)
5. Resistance to high-dose dexamethasone used in the last line of therapy: Defined as disease progression on or within 60 days of receiving the last dose of high-dose dexamethasone used in the last line of therapy, either as single agent or in combination. Subjects who progressed on low-dose dexamethasone will qualify for the trial.
6. Peripheral neuropathy ≥ Grade 2.
7. Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least 4 weeks prior to initiation of study treatment and are currently dependant on such treatment.
8. Subjects who are planning for or who are eligible for stem cell transplant.
9. Subjects with any one of the following:
• Congestive heart failure (NY Heart Association Class III or IV)
• Myocardial infarction within 12 months prior to starting study treatment
• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
10. Subjects who received any of the following within the last 14 days of initiation of study treatment:
• Plasmapheresis
• Major surgery (kyphoplasty is not considered major surgery)
• Radiation therapy
• Use of any anti-myeloma drug therapy
11. Use of any investigational agents within 28 days or 5 half lives (whichever is longer) of treatment, unless approved by the Sponsor.
12. Subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment. Subjects receiving corticosteroids (> 10 mg/day of prednisone or equivalent) within 3 weeks prior to enrollment.
13. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
14. Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide.
15. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment will not be eligible to participate in this study.
16. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the informed consent form.
17. Pregnant or breastfeeding females.
18. Known HIV positivity or active infectious hepatitis A, B or C. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary study endpoint is progression-free survival (PFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Safety (type, frequency, and severity of adverse events [AEs], and relationship of AEs to study drug or comparator)
• Overall survival (OS)
• Response (using the new International Myeloma Working Group Uniform [IMWG] response criteria)
• Objective Response (European Group for Blood and Marrow Transplantation [EBMT] criteria)
• Time to progression (TTP)
• Time to response
• Duration of response
• Clinical benefit responses (Time to increased hemoglobin value, time to improvement of bone pain, time to improvement of renal function, time to improvement of ECOG performance status)
• The European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) Module, the Cancer QoL Questionnaire for Patients with Cancer (EORTC QLQ-C30) Module, and the descriptive system of the EQ-5D |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Canada |
| Russian Federation |
| Switzerland |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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