| 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 | | (Blood cancer) certain blood cells multiply abnormally in the bone marrow, impair the production of other blood cells and produce proteins that cumulate in other organs impairing their functioning. | |
| 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 | 16.0 | | 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 | | Evaluate the safety of the combination of pomalidomide (POM) and low dose dexamethasone(LD-DEX) in a large cohort of subjects with refractory MM or relapsed and refractory MM. | |
| E.2.2 | Secondary objectives of the trial | | -Analyze the population pharmacokinetics of POM and assess POM exposure response relationships in subjects with refractory MM or relapsed and refractory
MM administered POM and LD-DEX.
-Evaluate efficacy of the combination of POM and LD-DEX in subjects with refractory MM or relapsed and refractory MM.
-Evaluate the relationship between cytogenetic profiles and the combination of POM and LD-DEX in terms of response and outcome. | |
| 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 document (ICD).
2. The subject must understand and voluntarily sign an ICD prior to any study related assessments/procedures being conducted.
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 ≥ 0.5 g/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. A new treatment line is always started after progressive disease.
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.
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 lenalidomide-containing regimen in one of the following ways:
- Documented PD during or within 60 days of completing last treatment with lenalidomide, regardless of the response achieved, or
- In case of prior response (≥ partial response - PR) to lenalidomide and PD>60 days, subjects must have relapsed within 6 months after the last dose of treatment with lenalidomide-containing regimens.
●All subjects must have failed treatment with the last bortezomib-containing regimen in one of the following ways:
- Documented PD during or within 60 days of completing treatment with bortezomib, regardless of the response achieved, or
- In case of prior response (≥ PR) to bortezomib and PD > 60 days, subjects must have relapsed within 6 months after the last dose of treatment with bortezomib-containing regimens
Or for non-progressive subjects:
- Subjects who have less than MR response and have developed intolerance/toxicity after a minimum of two cycles of a bortezomib-containing regimen. Toxicity such as > grade 2 peripheral neuropathy or ≥ grade 2 painful neuropathy. Peripheral neuropathy must resolve to grade 1 prior to study entry.
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 4 consecutive cycles of an alkylator based therapy; or
● Progression on treatment with an alkylator; provided that the subject received at least 2 cycles of an alkylator-containing therapy.
9. ECOG performance status score of 0, 1, or 2.
10. Females of childbearing potential (FCBP) must agree to utilize two reliable forms of contraception simultaneously or practice complete abstinence 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.
11. Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation.
12. 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.
13. Males must also agree to refrain from donating semen or sperm while on POM and for 28 days after discontinuation from this study treatment.
14. All subjects must agree to refrain from donating blood while on study therapy and for 28 days after discontinuation from this study treatment.
15. All subjects must agree not to share medication. | |
| E.4 | Principal exclusion criteria | | The presence of any of the following will exclude a subject from study enrollment:
1. Any of the following laboratory abnormalities:
-Absolute neutrophil count < 800/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. Platelet transfusion is not allowed within the previous 3 days before screening.
-Creatinine Clearance < 45 mL/min according to Cockcroft-Gault formula. If
creatinine clearance calculated from the 24-hour urine sample is ≥ 45 mL/min,
subject will qualify for the study.
-Corrected serum calcium > 14 mg/dL (> 3.5 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 > 2.0 mg/dL (34.2 μmol/L); or > 3.0 x ULN for subjects with hereditary benign hyperbilirubinemia.
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 histological finding of prostate cancer (TNM stage of T1a or T1b).
3. Previous therapy with POM.
4. Hypersensitivity to thalidomide, lenalidomide, or DEX (this includes ≥ Grade 3 rash during prior thalidomide or lenalidomide therapy).
5. Peripheral neuropathy ≥ Grade 2.
6. 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 dependent on such treatment.
7. Subjects who are planning for or who are eligible for stem cell transplant.
8. 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.
9. Subjects who received any of the following within the last 14 days of initiation of study treatment:
-Major surgery (kyphoplasty is not considered major surgery)
-Use of any anti-myeloma drug therapy.
10. Use of any investigational agents within 28 days or five half-lives (whichever is longer) of treatment, unless approved by the Sponsor.
11. Incidence of gastrointestinal disease that may significantly alter the absorption of POM.
12. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
13. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the ICD or participating in the study.
14. Pregnant or breastfeeding females.
15. Known human immunodeficiency virus (HIV) positivity, active infectious hepatitis A, B or C or chronic hepatitis B or C. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Adverse events (type, frequency, seriousness,severity, relationship to POM and/or DEX and outcomes), including second primary malignancies (SPM). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | -AEs: After signing ICD and until 28 days after discontinuation from treatment.
-SPM: Every 3 months after signing ICD and up to 5 years after last subject enrollment or longer if clinically indicated. | |
| E.5.2 | Secondary end point(s) | | 1)POM exposure.
2)POM population pharmacokinetics and exposure-response.
3)Overall response rate (ORR), Time to response, Duration of response (DoR), Progression-free survival (PFS), Time to progression (TTP), Overall survival (OS).
4)Analysis of cytogenetic profiles. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | 1)Day 1 (± 1) of every cycle,Treatment Discontinuation
2)Day 15 (± 2) Cycles 1-6 only, Day 1 (± 1) of every cycle
3)Response, including PD, will be assessed at Day 1 of each cycle and at the treatment discontinuation visit. Survival status will be assessed during the follow up period, every 3 months (84 ± 14 days) for up to 5 years after last subject enrollment. The final statistical analyses will be performed when all subjects have completed/discontinued the study including the follow-up phase.
4)At diagnosis, at study entry and at time of relapse. | |
| 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 | 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.2.4 | 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 | 117 |
| 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 | | Belgium | | Denmark | | Estonia | | Finland | | France | | Germany | | Greece | | Ireland | | Israel | | Italy | | Netherlands | | Norway | | Poland | | Portugal | | Slovakia | | Slovenia | | Spain | | Sweden | | Switzerland | | Turkey | | United Kingdom | |
| 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 | | Study consists of: Screening, Treatment and Follow-up (FU). Screening period may be up to 28 days prior to start of study treatment. Treatment phase continues until documented progressive disease, discontinuation of study drug for any reason/as long as subjects benefit from therapy according to the opinion of the responsible study Investigator and discussed with the Sponsor. FU phase will start and continue for up to 5 years from the last subject enrolled or longer if clinically indicated. | |
| 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 | 1 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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