E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary cutaneous T-cell lymphomas (CTCLs) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028508 |
E.1.2 | Term | Mycosis fungoides/Sezary syndrome |
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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 is to determine the objective response rate to treatment with oral forodesine in subjects with cutaneous manifestations of CTCL, stages IIb, III and IVa. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
1. To assess the safety and tolerability of daily administration of oral forodesine in this population; 2. To determine the time to objective response in subjects with CTCL having cutaneous manifestations of the disease; 3. To determine the duration of objective response in subjects with CTCL having cutaneous manifestations of the disease; 4. To determine the loss of objective response; 5. To determine the objective response rate of extracutaneous manifestations of CTCL (lymph node enlargement, Sezary cells in peripheral blood). 6. To determine the time to objective response and duration of objective response of extracutaneous manifestations of CTCL in subjects who have extracutaneous manifestations of disease; and, 7. To determine subjects' assessments of treatment-related changes in health related quality of life (HRQoL). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title - same as main protocol title. Sub-study of 30 persons for Pk analysis on Day 1 and Day 14. |
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E.3 | Principal inclusion criteria |
1. Males or non-pregnant females aged ≥18 years; 2. Histologically confirmed diagnosis of CTCL, including mycosis fungoides and/or sezary syndrome; 3. Subjects with CTCL stages IB, IIA, IIB, III or IVA who have persistent, progressive, or recurrent disease during or following treatment with at least three forms of systemic therapy, one of which must have been bexarotene, unless treatment with oral bexarotene was not tolerated or was medically contraindicated; 4. Anticipated life expectancy > 6 months; 5. Performance status of 0, 1, or 2 by ECOG; 6. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of study treatment ; 7. Females of child bearing potential and sexually active males, if indicated, must be willing and able to use method(s) of contraception that are adequate to prevent or minimize the risk of pregnancy for the duration of the study; and, 8. Written informed consent to participate in the study.
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E.4 | Principal exclusion criteria |
CTCL-related Exclusion Criteria
1. Proven or suspected extracutaneous visceral CTCL involvement (M1) (CTCL stage IVB) (note: presence of lymphadenopathy is permitted); 2. Previous treatment with forodesine; 3. ECOG performance status >2; 4. Concomitant use of any anti-cancer therapy or immune modifier; 5. Concomitant use of any investigational agent or device; 6. Concurrent treatment with any other anti-CTCL therapy, or radiation therapy. Topical corticosteroids (except classes 1 and 2 which are prohibited) or low dose oral corticosteroids (≤10 mg/day prednisone or equivalent) will not be excluded, but if used, must be a stable dose and schedule during the four weeks immediately prior to study entry; 7. Use of previous therapies for CTCL within the timeframes specified below: a. Phototherapy in the previous 30 days; b. Electron beam therapy, photopheresis, systemic anticancer therapy, interferon therapy, or other investigational therapy in the previous 30 days; c. Oral retinoid (including bexarotene) in the previous 30 days; d. Alemtuzumab (Campath) or other monoclonal antibody within the previous 30 days e. Vorinostat or other HDAC inhibitor within previous 30 days f. Any investigational therapy within the previous 30 days;
Hepatic/Renal/Metaboli Exclusion Criteria
8. ALT or AST >3 times ULN or alkaline phosphatase >2 times ULN; 9. Calculated creatine clearance ≤50mL/min or serum creatine ≥1.8mg/dL; 10. Serum potassium <3.3mg/dL or >5.5mg/dL; 11. Evidence of clinically significant (uncontrolled) hypo- or hyperthyroidism;
Cardiovascular Exclusion Criteria
12. Recent (in past 6 months) medically significant cardiac event (i.e., myocardial infarction, cardiac surgery); 13. Presence of congestive heart failure (NYHA class IV) or angina (NYHA class IV) or presence of a medically significant dysrhythmia; 14. Presence of any of the following ECG findings: a. Congenital long QT syndrome; b. QTc interval >480 msec (Bazett’s correction); 15. Presence of uncontrolled hypertension manifested by systolic blood pressure ≥160mmHg and or diastolic blood pressure ≥90mmHg;
Hematologic Exclusion Criteria
16. Hemoglobin <9.0gm/dL (intermittent red blood cell transfusions permitted); 17. Absolute neutrophil count <1500cells/mm^3; 18. Platelet count <75,000/mm^3; 19. Requirement for neutrophil or platelet growth factor therapy or administration of such therapy in the previous 30 days; 20. CD4 count <200/mm^3
Infection-Related Exclusion Criteria
21. Documented current active infection with HIV, Hepatitis B, Hepatitis C and/or CMV; 22. Presence of uncontrolled bacterial or viral infection (subject may be receiving chronic antimicrobial therapy); or, 23. History of culture-documented bacteremia in the previous 2 weeks.
General Exclusion Criteria
24. Recent (i.e., in past 2 weeks) change in doses or regimens of medications used for any chronic non-oncologic condition for reasons of worsening of the chronic illness (change in doses of chronic medications associated with improvement in a chronic illness are not exclusionary); 25. Presence of any acute or chronic non-oncologic disease which, in the opinion of the investigator, is medically uncontrolled; 26. coexistent second malignancy or history of prior malignancy within 5 years [excluding basal cell or squamous cell carcinoma of skin and cervical neoplasia (carcinoma in situ) that has been treated curatively]. Surgically resected nonmelanomatous skin cancer (non-CTCL) with no evidence of recurrence in 6 months is permitted; and, 27. Any significant medical or psychiatric condition that in the opinion of the investigator, might prevent the subject from complying with all required study procedures.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point is an assessment of objective response (OR) for each patient, defined as either complete cutaneous response (CR) or partial cutaneous response (PR), in subjects with CTCL Stages IIB, III, or IVA. Cutaneous response will be determined by use of a modified severity weighted assessment tool (mSWAT). Objective response will be defined as either no evidence of clinical disease or a marked improvement that is ≥50% decrease in mSWAT score compared to Baseline. Confirmation of objective response will be required by a second assessment after at least 28 days. At the time of confirmation of OR, CT scans (neck, chest, abdomen and pelvis) should be performed to confirm the absence of progression of any pre-existing lymph node disease involvement. Cutaneous disease manifestations will be documented by serial standardised body photgraphy and skin assessment worksheets. |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 | Information not present in EudraCT |
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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The end of the trial will be after the last enrolled patient has been treated for 6 months. Access to forodesine will continue to be provided for those patients who are deriving benefit and who are not adversely affected by side effects. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |