Forodesine in the Treatment of Cutaneous T-Cell Lymphoma

This is a Phase II, non-randomized, open-label, single-arm trial that will be conducted at up to 50 sites in North America, Europe and Australia. This study is designed to assess objective response (OR) \[complete response (CR) or partial response (PR)\] in subjects with cutaneous manifestations of CTCL with a requirement for maintenance of such objective response for at least 28 days in subjects with stage IIB, III, and IVA CTCL. Additionally, this study will evaluate the safety and tolerability of CTCL subjects Stages IB, IIA, IIB, III, or IVA treated with oral forodesine.


Eligibility Criteria:
Inclusion Criteria:

* Males or non-pregnant females aged ≥18 years;
* Histologically confirmed diagnosis of CTCL, including mycosis fungoides and/or Sezary syndrome, documentation of diagnosis by histologic examination should be available;
* Subjects with CTCL stages IB, IIA, IIB, III, or IVA at the screening visit (i.e. stage refers to stage at study entry) and 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 oral bexarotene, unless treatment with oral bexarotene was not tolerated or was medically contraindicated;
* Anticipated life expectancy greater than 6 months;
* Performance status of 0, 1, or 2 by Eastern Cooperative Oncology Group (ECOG) criteria;
* Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of study treatment;
* Females of childbearing 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;
* Written informed consent to participate in the study.

Exclusion Criteria:

* Proven or suspected extracutaneous visceral CTCL involvement (M1) (CTCL stage IVB) (note: presence of lymphadenopathy is permitted);
* Previous treatment with Forodesine;
* ECOG performance status \>2;
* Concomitant use of any anti-cancer therapy or immune modifier;
* Concomitant use of any investigational agent or device;
* Concurrent treatment with any other anti-CTCL therapy, or radiation therapy \[topical corticosteroids (classes 1 and 2 prohibited) or low dose oral corticosteroids (≤10 mg/day prednisone or equivalent) will not be excluded, but if used, must be a stable dose and schedule during the four weeks immediately prior to study entry\];
* Use of previous therapies for CTCL within the timeframes specified below:

  1. Phototherapy in the previous 30 days;
  2. Electron beam therapy, photopheresis, systemic anticancer therapy, interferon therapy, or other investigational therapy in the previous 30 days;
  3. Oral retinoid (including bexarotene) in the previous 30 days
  4. Alemtuzumab (Campath) or other monoclonal antibody within the previous 30 days
  5. Vorinostat or other HDAC inhibitor within previous 30 days
  6. Any investigational therapy within the previous 30 days;
* ALT or AST \>3 times ULN or alkaline phosphatase \>2 times ULN;
* Calculated creatinine clearance ≤50 mL/min or serum creatinine ≥1.8 mg/dL;
* Serum potassium \<3.3 mg/dL or \>5.5 mg/dL;
* Evidence of clinically significant (uncontrolled) hypo- or hyperthyroidism;
* Recent (in past 6 months) medically significant cardiac event (i.e., myocardial infarction, cardiac surgery);
* Presence of congestive heart failure (NYHA class IV) or angina (NYHA class IV) or presence of a medically significant dysrhythmia;
* Presence of any of the following ECG findings:

  1. Congenital long QT syndrome;
  2. QTc interval \>480 msec (Bazett's correction);
* Presence of uncontrolled hypertension manifested by systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥90 mmHg;
* Hemoglobin \<9.0 gm/dL (intermittent red blood cell transfusions permitted);
* Absolute neutrophil count \<1500 cells/mm3;
* Platelet count \<75,000/mm3;
* Requirement for neutrophil or platelet growth factor therapy or administration of such therapy in the previous 30 days;
* CD4 count \<200/mm3;
* Documented current active infection with HIV, Hepatitis B, Hepatitis C, and/or CMV;
* Presence of uncontrolled bacterial or viral infection (subject may be receiving chronic antimicrobial therapy); or,
* History of culture-documented bacteremia in the previous 2 weeks;
* 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);
* Presence of any acute or chronic non-oncologic disease which, in the opinion of the investigator, is medically uncontrolled;
* Coexistent second malignancy or history of prior malignancy within previous 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 previous 6 months is permitted; and,
* Any significant medical or psychiatric condition that, in the opinion of the investigator, might prevent the subject from complying with all required study procedures.