| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To determine whether the addition of selinexor to cyclophosphamide and prednisolone may lead to an increased progression free survival compared to historic cyclophosphamide and prednisolone data.
• The use of a cyclophosphamide and prednisolone calibration arm has been incorporated to assess whether the efficacy estimates observed within the study are representative of the participant population from which the historic control data was specified.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To assess the safety and toxicity profile
• To estimate progression-free survival
• To estimate the proportion of patients with each maximum response category
• To estimate time to maximum response
• To estimate duration of maximum response
• To assess compliance to therapy
The exploratory endpoints are:
• To process (including CD138 selection) and biobank bone marrow and peripheral blood tissue for future analysis.
For the treatment switch phase of the trial (from CP to SCP after progression on CP):
• To estimate second progression-free survival (PFS2)
• To evaluate the clinical activity of SCP with regard to additional secondary endpoints
• To determine the safety and toxicity profile of SCP
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to give informed consent and willing to follow study protocol assessments
2. Aged 18 years or over
3. Participants with confirmed myeloma based on International Myeloma Working Group (IMWG) criteria Rajkumar et al. (2014)
4. Measurable disease with at least one of the following:
- Paraprotein ≥5g/L
- Serum free light chains ≥100mg/L with abnormal ratio for light chain only myeloma
- Bence Jones protein ≥200mg/L
5. Participants with relapsed or relapsed refractory myeloma who have received ≥ 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide, and now require further treatment
6. Patients for which cyclophosphamide and prednisone alone would be a suitable treatment
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
8. Female participants of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative urine pregnancy test at screening. Male participants must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment
9. Required laboratory values within 14 days prior to randomisation:
- Platelet count ≥50x109/L. Platelet count of 30-50 is acceptable if bone marrow aspirate or trephine shows tumour replacement of >50%. Platelet support is permitted within 14 days prior to randomisation, although platelet transfusions to help participants meet eligibility criteria are not allowed within 72 hours prior to the blood sample to confirm protocol eligibility
- Absolute neutrophil count ≥1.0 x 109/L. Growth factor support is not permitted within 14 days prior to randomisation
- Haemoglobin ≥ 90 g/L. Blood support is permitted
- Alanine transaminase (ALT) and / or aspartate transaminase (AST) ≤3 x upper limit of normal
- Creatinine clearance ≥ 30 ml/min (using Cockcroft Gault formula)
- Bilirubin ≤1.5 x upper limit of normal
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| E.4 | Principal exclusion criteria |
Participants meeting any of the following exclusion criteria are not eligible to take part in this trial:
1. The following participants will be excluded:
- those with non-measurable disease
- those with a solitary bone or solitary extramedullary plasmacytoma
- plasma cell leukaemia
2. Participants with a history of malignancy (other than myeloma) within 5 years before the date of randomisation (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator, with concurrence with the Chief Investigator, is considered cured with minimal risk of recurrence within 5 years)
3. Participants with a known or underlying uncontrolled concurrent illness that, in the investigator’s opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study, including, but not limited to the following:
- acute or chronic graft versus host disease,
- uncontrolled hypertension,
- symptomatic congestive heart failure,
- unstable angina pectoris,
- myocardial infarction within past 6 months,
- uncontrolled cardiac arrhythmia,
- active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis
Ocular herpes simplex
- psychiatric or social conditions that may interfere with participant compliance,
- uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral
- or any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study
4. Participants who have previously received Selinexor.
5. Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment. (NB: Prednisone up to a dose of 175 mg per week may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease are also permitted).
6. Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures or conditions that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s)
7. Female participants who are lactating or have a positive pregnancy test at screening
8. Known allergy or intolerance to any of the study medications, their analogues, or excipients in the various formulations of any agent
9. Major surgery within 14 days prior to randomisation
10. Radiotherapy within 7 days prior to randomisation for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation
11. Chemotherapy or immunotherapy or any other anticancer therapy within 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1 (except steroids in the doses outlined above)
12. Myeloma involving the Central Nervous System
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival at 6 months – this will be calculated as proportion of participants alive and progression free at 6 months post-randomisation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
This will be evaluated after all patients have been followed up for 6 months or have progressed on the first phase of treatment (whichever comes first).
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| E.5.2 | Secondary end point(s) |
The secondary outcome measures are:
• Safety and toxicity
• Progression-free survival
• Maximum response
• Time to maximum response
• Duration of response
• Compliance to therapy
The exploratory outcome measures are:
Molecular biomarker analyses can be performed to correlate molecular markers, including mutational, gene expression, and epigenetic features, to outcomes on the selinexor/ cyclophosphamide/ prednisone treatment arm.
For the treatment switch phase of the trial (from CP to SCP after progression on CP):
• Second progression-free survival (PFS2)
• Safety and toxicity
• Progression-free survival from treatment switch
• Maximum response
• Time to maximum response
• Duration of response
• Compliance to therapy
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All of the secondary endpoints will be evaluated once the final participant has been followed up for 6 months or has progressed (whichever comes first).
Further analyses relating to the treatment switch phase of the trial will take place after all patients have been followed up for at least 6 months or have progressed (whichever is sooner). |
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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 | Yes |
| 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 | No |
| 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 | 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 | No |
| 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 the trial is defined as the last participant's last data item. |
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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 | 3 |
| 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 | 3 |
| 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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