E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cutaneous T-Cell Lymphoma (CTCL), Mycosis Fungoides (MF) Subtype |
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E.1.1.1 | Medical condition in easily understood language |
A cancer of the lymphatic system that affects the skin |
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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 | 22.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028483 |
E.1.2 | Term | Mycosis fungoides |
E.1.2 | System Organ Class | 100000004864 |
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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 trial is to evaluate the efficacy of cobomarsen in subjects with MF. |
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E.2.2 | Secondary objectives of the trial |
• Investigate the safety and tolerability of cobomarsen in subjects with MF. • Characterize the population pharmacokinetics (PK) of cobomarsen in subjects with MF. • During the crossover portion of the study: - Evaluate the efficacy, safety and tolerability of cobomarsen in subjects with MF who have shown disease progression following treatment with vorinostat. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Must provide written informed consent (signed and dated) and any authorizations required by law and be able to comply with all study requirements. • Males or females, ≥ 18 years of age at the time of informed consent. • Biopsy-proven CTCL, MF subtype. • Clinical stage IB, II, or III, with staging based on Screening assessments. • Minimum mSWAT score of 10 at Screening. • Receipt of at least one prior therapy for CTCL (per the National Comprehensive Cancer Network [NCCN] guidelines for generalized skin involvement; e.g., topical, phototherapy, Total Skin Electron Beam Therapy [TSEBT] or systemic therapy). • Subjects of childbearing potential must agree to use highly effective methods of contraception as defined in the protocol.
Additional Criteria for Crossover Period: • Must have participated in the comparator arm of the randomized period and completed the randomized period (confirmed disease progression in skin). Subjects who discontinued from the randomized period of SOLAR for any reason other than confirmed skin disease progression on the comparator arm are not eligible. |
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E.4 | Principal exclusion criteria |
• Previous enrollment in a cobomarsen study. • Prior therapy with vorinostat or other HDAC inhibitors, or contraindication to an HDAC inhibitor. • Sézary syndrome or mycosis fungoides with B2 involvement. • Current evidence of large cell transformation (LCT), defined as > 25% of the lymphocytes at least 4 × the size of normal lymphocytes. Current evidence refers to LCT diagnosis from biopsy performed within 4 months prior to randomization. Subjects with a history of LCT but with a negative current biopsy (within 4 months) are eligible, provided there is no clinical indication for chemotherapy. • Evidence of enlarged peripheral or central lymph node(s) > 1.5 cm in the long diameter or > 1.0 cm in the short diameter by radiographical imaging at Screening. A subject with one or more enlarged lymph node(s) may be allowed, provided that a representative lymph node has been confirmed (via biopsy or positron emission tomography [PET] scan) to be N0-N2 or SUV ≤ 5 within the 3 months prior to Day 1, and there has not been an appearance of new abnormal lymph nodes since the biopsy or PET scan. Subjects with uncharacterized enlarged lymph nodes (i.e. not confirmed by biopsy or PET scan) will not be allowed. • Any palpable peripheral node, regardless of size, that on physical examination is firm, irregular, clustered, or fixed, unless histologically confirmed to be non-malignant. • Evidence of visceral involvement related to MF at Screening. • Receipt of any the following treatments: - Macrolide or tetracycline antibiotics within 28 days prior to Screening; - More than 3 short courses (≤ 7 days) of prednisone equivalent > 10 mg per day within 8 weeks prior to Screening; however, a stable regimen of systemic prednisone equivalent to ≤ 10 mg per day (or steroid equivalent) is permitted; - Total skin electron beam therapy or radiotherapy within 4 weeks prior to Screening; - Investigational small molecule drug within 5 half-lives prior to Screening; - Investigational biologic drug within 5 half-lives prior to Screening; - Phototherapy within 4 weeks prior to Screening; - Antibody-directed or immunoglobulin-based immune therapy or other monoclonal antibody therapies within 8 weeks prior to Screening; - Previous chronic (more than 20 days total) high potency topical corticosteroid use within 4 weeks of Screening. Stable doses of low to medium potency topical corticosteroids are allowed; - Previous chronic (more than 20 days total) use of topical MF treatments (not listed in the bullets above) within 4 weeks prior to Screening; - Previous systemic MF treatments (not listed in the bullets above) within 4 weeks prior to Screening; - Previous treatment with an oligonucleotide. - Patients on chronic prophylactic (for prevention, more than 20 days per month) nonsteroidal antipruritic medications within 4 weeks of screening are excluded. Patients on symptomatic (for current symptoms) stable nonsteroidal antipruritic medications (dose and frequency remain the same for at least 1 month prior to screening) for symptomatic pruritus are allowed. • Clinically significant liver disease within 1 year prior to Screening. • Positivity for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or Hepatitis C at the time of Screening, • Clinically significant anemia, neutropenia or thrombocytopenia at Screening. • Previous or concurrent malignancy with the following exceptions: - Adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior to study entry), - In situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to the study, - Or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry. • History of long QT syndrome and/or a history of persistent hypokalemia. • Lactating or pregnant. • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure, as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment. • History of stroke or intracranial hemorrhage within 6 months prior to enrollment. • Clinically significant abnormalities which, in the opinion of the Investigator, would make subject unsuitable for inclusion in the study. • History of intolerance, or adverse or allergic reactions to oligonucleotide products and/or phosphate buffer solutions.
Additional Criteria for Crossover Period • Unresolved toxicities from prior vorinostat treatment, defined as having not resolved to CTCAE, version 5.0, grade 0 or 1. • Receipt of any CTCL systemic therapy after completion of the randomization period and prior to Day 1 for the crossover period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Evaluation: Proportion of subjects achieving an objective skin response (complete response [CR] or partial response [PR]) of at least 4 months duration (ORR4) using the Modified Severity Weighted Assessment Tool (mSWAT) scoring. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response criteria collected 4 weeks after 4 months of sustained response (PR or CR) in the skin, and every 12 weeks thereafter.
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E.5.2 | Secondary end point(s) |
Efficacy measures • Progression-free survival (PFS). • Complete response rate (CRR). • Time to progression (TTP). • Time to maximal effect in skin (mSWAT). • Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 28-days duration (ORRI). • Proportion of subjects achieving ≥ 50% improvement in mSWAT from baseline at 28 days and at 4 months. • Time to ≥ 50% improvement in mSWAT. • Duration of response in skin (no progression after achieving ≥ 50% improvement in mSWAT). • Change in pruritus medication utilization from baseline and incidence of pruritus medication utilization.
• During the crossover portion of the study: o Proportion of subjects achieving an objective skin response (complete response [CR] or partial response [PR]) of at least 4 months duration (ORR4) using the mSWAT scoring. o Progression-free survival (PFS). o Complete response rate (CRR). o Time to progression (TTP). o Time to maximal effect in skin (mSWAT). o Proportion of subjects achieving ≥ 50% improvement in mSWAT of at least 28-days duration (ORR1). o Proportion of subjects achieving ≥ 50% improvement in mSWAT from baseline at 28 days and at 4 months. o Time to ≥ 50% improvement in mSWAT. o Duration of response in skin (no progression after achieving ≥ 50% improvement in mSWAT). o Change in pruritus medication utilization from baseline and incidence of pruritus medication utilization.
Safety and Tolerability Evaluations: • Incidence and severity of clinically significant adverse events (AEs) (including grade 3 and 4 AEs, treatment-related AEs, serious adverse events [SAEs], and AEs requiring discontinuation), physical examination findings, changes in electrocardiograms (ECGs), changes in laboratory parameters and changes in vital signs. • Characterization of anti-drug antibody generation.
Pharmacokinetic Evaluation: • Population PK parameters. • During the crossover portion of the study: o Pharmacokinetic Cmax and trough concentration analysis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression free survival, time to progression, complete response rate: assessed throughout study Skindex-29, mSWAT: every 4 weeks to week 81, every 8 weeks thereafter Safety and tolerability: assessed throughout study PK: Days 1, 2, 3, 5, 8, 15, 29, every 4 weeks through week 81 and every 8 weeks thereafter. |
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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 | 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 | 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 | 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 | 9 |
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 |
Belgium |
Canada |
France |
Spain |
United Kingdom |
United States |
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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 | 3 |
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 | 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 | 0 |