| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The treatment of multiple myeloma (MM) patients who have received at least 2 prior therapies, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to the most recent therapy. |
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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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 2:
• To determine the efficacy of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone as treatment for patients with relapsed-and-refractory MM as assessed by overall response rate. |
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| E.2.2 | Secondary objectives of the trial |
Phase 1b and Phase 2:
• To evaluate the safety of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone as treatment for patients with relapsed-and-refractory MM.
Phase 1b:
• To assess the pharmacokinetics (PK) of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory MM.
• To assess the PK of pomalidomide administered in combination with ACY-1215 and low-dose dexamethasone in patients with relapsed-and-refractory MM.
• To assess the pharmacodynamics of ACY-1215 administered in combination with pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory MM. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting the following criteria are to be enrolled in the study:
1. Must be able to understand and voluntarily sign an ICF.
2. Must be ≥ 18 years of age at the time of signing the ICF.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of MM and have relapsed-and-refractory disease. Patients must have received at least 2 lines of prior therapies. Patients must have relapsed after having achieved at least SD for at least one cycle of treatment to at least one prior regimen and then developed PD. Patients must also have documented evidence of PD during or within 60 days (measured from the end of the last cycle) of completing treatment with the last anti-myeloma drug regimen used just prior to study entry (refractory disease).
5. Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen).
6. Must not be a candidate for autologous stem cell transplant (ASCT), has declined the option of ASCT, or has relapsed after prior ASCT.
7. Must have measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours). Nonsecretory myeloma and serum free light chain (SFLC)-only myeloma are excluded.
8. Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
9. FCBP must have a negative serum or urine pregnancy test (must be serum for study participants in Canada), as described in Appendix 9.3 for the POMALYST REMS™ program (in the United States [US]) and Appendix 9.4 for the RevAid® program (in Canada). FCBP and males must either commit to continued abstinence from heterosexual intercourse or must abide by birth control requirements as described in Appendix 9.3 for the POMALYST REMS™ program (in US) and Appendix 9.4 for the RevAid® program (in Canada). The European Pomalidomide Pregnancy Prevention Risk Management Plans are described in Appendix 9.5.
10. Must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study.
11. Must agree not to share study medication with another person.
12. Must be able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulated, with an international normalized ratio (INR) of 2 to 3.
13. Must be registered into the mandatory POMALYST REMS™ program, and be willing and able to comply with the requirements of the POMALYST REMS™ program (or RevAid® for study participants in Canada). |
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from enrollment in the study:
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the ICF, including nonsecretory myeloma or SFLC-only myeloma.
2. Any serious concurrent medical conditions, laboratory abnormality, or psychiatric illness that might make the patient non-evaluable, put the patient’s safety at risk, or prevent the patient from following the study requirements.
3. Pregnant or lactating females.
4. Prior therapy with histone deacetylase (HDAC) inhibitor or pomalidomide.
5. Any of the following laboratory abnormalities:
• ANC < 1,000/μL (hematopoietic growth factors will not be permitted during screening in the Phase 1 or Phase 2 segments of the study or in Cycle 1 of the Phase 1b segment of the study) in either segment of the study.
• Platelet count < 75,000/μL for patients in whom < 50% of bone marrow nucleated cells are plasma cells, and < 50,000/μL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells.
• Hemoglobin < 8g/dL (< 4.9 mmol/L; prior red blood cell [RBC] transfusion is permitted).
• Creatinine clearance < 45 mL/min according to Cockcroft-Gault formula. If creatinine clearance calculated from the 24-hour urine sample is ≥ 45 mL/min, patient will qualify for the study.
• Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST), or serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) > 3.0 × ULN.
• Serum total bilirubin > 2.0 mg/dL
6. Prior history of malignancies, other than MM, unless the patient has been free of the disease for ≥ 3 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)
7. Corrected QT interval using Fridericia’s formula (QTcF) value > 480 msec at screening; family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy at screening; previous history of drug-induced QTc prolongation or the need for treatment with medications known or suspected of producing prolonged QTc intervals on electrocardiogram (ECG).
8. Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) and known or suspected active hepatitis C virus (HCV) infection.
9. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such as Steven Johnson Syndrome). Hypersensitivity, such as rash, that can be medically managed is allowable.
10. Peripheral neuropathy ≥ Grade 2 despite supportive therapy.
11. Radiotherapy or systemic therapy (standard or an investigational or biologic anticancer agent) within 14 days of initiation of study drug treatment.
12. Current enrollment in another clinical study involving treatment and/or is receiving an investigational agent for any reason
13. Inability or unwillingness to comply with birth control requirements or any of the POMALYST REMS™ or RevAid® (region-specific), per Appendix 9.3 and Appendix 9.4, respectively, or to the European Pomalidomide Pregnancy Prevention Risk Management Plans, per Appendix 9.5. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2:
• Objective response to treatment as assessed by site Investigators using the International Myeloma Working Group (IMWG) Uniform Response criteria. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be conducted when there are 30 evaluable patients; final analysis is planned after all enrolled patients either complete 6 cycles of study treatment, at treatment discontinuation, or withdraw early from the study. |
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| E.5.2 | Secondary end point(s) |
Efficacy:
Phase 1b and Phase 2:
• Time to response (TTR).
• Duration of response (DOR).
• Time to progression (TTP).
• Progression-free survival (PFS).
• Objective response to treatment as blindly assessed by the Central Adjudication Committee using IMWG criteria and dates of PD.
Safety:
Phase 1b and Phase 2:
• Safety (type, frequency, and severity of adverse events [AEs] and relationship of AEs to study drug) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be conducted when there are 30 evaluable patients; final analysis is planned after all enrolled patients either complete 6 cycles of study treatment, at treatment discontinuation, or withdraw early from the study. |
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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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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