| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and Refractory Multiple Myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether the addition of cyclophosphamide to pomalidomide and dexamethasone (CPD) improves progression-free survival in patients with relapsed refractory myeloma (RRMM) in the UK, compared to pomalidomide and dexamethasone (Pd) alone. |
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| E.2.2 | Secondary objectives of the trial |
To compare the safety profiles of CPD and Pd
To further assess the activity of CPD vs. Pd in relation to response, MRD, and overall survival.
To evaluate the efficacy of pomalidomide in RRMM in the UK.
To generate a tissue repository from RRMM.
To identify clinical biomarkers of mechanism of action, and response or resistance to, pomalidomide and dexamethasone combination therapy (+/- cyclophosphamide) in a group of RRMM patients.
To specifically study the role of clinical factors associated with outcome to treatment with pomalidomide and dexamethasone, +/- cyclophosphamide.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Diagnosed with symptomatic multiple myeloma (according to IMWG 2014 criteria) and have measurable disease
•Participants must require therapy for relapsed and/or refractory disease
•Participants must have received ≥ 2 treatment lines of anti-myeloma therapy (induction therapy followed by ASCT and consolidation/maintenance will be considered as one line).
•Participants must have received prior treatment with both lenalidomide and a proteasome inhibitor, either as single agents or in combination regimens
•All participants must have failed treatment with either lenalidomide and a proteasome inhibitor in one of the following ways:
1) Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or a proteasome inhibitor; or
2) In case of prior response [≥ partial response (PR)] to lenalidomide or a proteasome inhibitor, participants must have relapsed within 6 months after stopping treatment with lenalidomide and/or a proteasome inhibitor-containing regimens; or
3) Participants who have not had a ≥ minimal response (MR) despite receiving at least 4 cycles of treatment or who have developed intolerance/toxicity after a minimum of two cycles of lenalidomide- and/or a proteasome inhibitor-containing regimen
•Patients must have received adequate prior alkylator therapy in one of the following ways
a.As part of a stem cell transplant; or
b.A minimum of 4 consecutive cycles of an alkylator based therapy; or
c.Progression on treatment with an alkylator; provided that the participant received at least 2 cycles of an alkylator-containing therapy.
•Life expectancy of at least 3 months
•Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
•Required laboratory values within 14 days of day 1 of treatment:
oAbsolute neutrophil count ≥ 1.0 x109 /L (growth factor support is permitted)
oPlatelet count ≥ 30 x 109/L (platelet transfusion is permitted)
oCreatinine clearance > 30 mL/min (using Cockcroft Gault formula)
oCorrected serum calcium ≤ 3.5 mmol/L
oHaemoglobin ≥ 8 g/dL (blood transfusion support is permitted)
oAspartate aminotransferase (AST) or Alanine aminotransferase (ALT) < 3 times Upper Limit of Normal (ULN)
oSerum total bilirubin < 17µmol/l
•Participants must consent to provide the bone marrow samples specified at screening and throughout the trial, in order to enter the trial. Confirmation of receipt of the sample from the lab must be received before treatment commences.
•Able to give informed consent and willing to follow trial protocol
•Aged over 18 or over
•Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe.
•Females must agree to abstain from breastfeeding during trial participation and 28 days after trial drug discontinuation
•Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during any dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy
• Males must also agree to refrain from donating semen or sperm while on pomalidomide, including during any dose interruptions and for 28 days after discontinuation from this trial
•All participants must agree to refrain from donation blood while on trial drug, including during dose interruptions and for 28 days after discontinuation from this trial
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| E.4 | Principal exclusion criteria |
•Previous therapy with pomalidomide
•Hypersensitivity to thalidomide, lenalidomide, cyclophosphamide or dexamethasone
•Participants with non-secretory multiple myeloma
•Peripheral neuropathy ≥ Grade 3
•Participants who have received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant
• Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment (or 5 half-lives, whichever is longer). A pulse of dexamethasone may be given up to 14 days before the start of protocol treatment Bisphosphonates for bone disease and radiotherapy for palliative intent are permitted.
•Participants with any of the following
a. Uncontrolled congestive heart failure
b.Myocardial infarction within 12 months prior to starting trial treatment
c. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.
•Participants with gastrointestinal disease that may significantly alter absorption of pomalidomide
•Participants with a history of other malignancies within 5 years before the date of study entry (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that is considered cured with minimal risk of recurrence within 5 years).
• Participants unable or unwilling to undergo antithrombotic prophylactic treatment
• Pregnant or breastfeeding females
• Participants known to be seropositive for HIV, or active infectious hepatitis A, B or C
•Participants for any reason unwilling or cannot consent to follow the Pomalidomide pregnancy prevention programme
•Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if they were to participate in the trial
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the proposed trial is progression free survival; defined by the date of randomisation to first documented evidence of disease progression or death. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and toxicity will be analysed based on reported SAE, SAR and SUSAR data collected during treatment and until the end of the trial. Adverse reactions will be collected until 28 days post the cessation of trial therapy. |
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| E.5.2 | Secondary end point(s) |
• Response to treatment (≥PR)
• Clinical benefit rate overall (≥SD)
• Maximum response overall
• Time to maximum response
• Duration of response
• Progression-free survival
• Overall survival
• Treatment compliance
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary enpoint analysis will be in accordance with the statistical analysis plan which will be finalised before any data is evaluated.
Response to treatment outcomes including;
• Response to treatment (≥PR)
• Clinical benefit rate overall (≥SD)
• Maximum response overall
• Time to maximum response
• Duration of response
• Progression-free survival
• Overall survival
• Treatment compliance
will be based upon data collected during treatment, at the end of treatment, and during follow-up.
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| 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 | 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) | 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 | 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 | 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) | Yes |
| 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 | 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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The end of trial will be defined as the last participants last data item.
Survival follow-up data will continue to be collected until final trial analysis, this will depend upon response to treatment and determination of disease progression. An End of Trial Notification will be submitted to the relevant authorities and ethics committees. |
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| 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 | 1 |
| 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 | 1 |
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