Due to the rapid response & the rapid rebound seen in some patients after being off treatment only a few days, all patients are offered forodesine administration 7 days a week. If required, an equivalent oral dose can be given up to 2 days per cycle. The 2-week rest periods between cycles 4 and 5 during the Initial Treatment Period and Long Term Follow up Period have been deleted. Concurrent dexamethasone therapy on Days 1-4 is no longer required. This has been changed to a rescue medication for blast crisis given according to the Investigator’s discretion. The duration of therapy for the initial treatment period has changed from 4 cycles of treatment administered over a 6-week period to 4 weeks of continuous daily treatment. Bone marrow evaluations have been changed to the 4 week and 8 week time points to better correlate with the new dosing schedule. The Long Term Follow-Up Period is termed an Extended Treatment Period, includes an additional 4 weeks of treatment and is limited to subjects whose disease has not progressed at the end the first 4 weeks of treatment. Patients can receive further treatment by compassionate use. The response criteria in this study have been modified to follow the standard leukemia guidelines for response, including bone marrow results, evaluation of extramedullary disease and normalization of other peripheral blood components. The introduction has been updated to include new information from phase 1 and 2 clinical studies. The criteria for dose modifications have been revised to include dose modifications for possibly related grade 3 (non-hematologic) or grade 4 (hematologic and non-hematologic) AEs. The dose modification guidelines have been revised to include an initial dose reduction rather than a break in therapy for these toxicities.

Clarification that the patient population allowed in this study, B-ALL patients, includes all disease subtypes under the newer terminology of precursor B-lymphoblastic leukemia/lymphoma, according to WHO guidelines for classification of leukemias. Addition of CD4+CD25+ to the panel of lymphocyte subpopulations analyzed for the study (as an optional assessment). Change study drug information, oral dose calculation, and number of capsules administered to reflect 100-mg final formulation. Clarify that adverse event and severe adverse event reporting (AE and SAE) begins after the patient has signed the informed consent document, rather than after administration of the first dose of study medication. Modification of Concomitant and Supportive Therapy section to state that patients with a CMV reactivation may be treated with empiric anti-CMV therapy, according to the Institution’s standard of care Clarification of the processing and shipping guidelines for blood samples collected for PNP and ex-vivo sensitivity analyses.

The dosing regimen has been redefined to include 5 days of intravenous study drug administration followed by 2 days but no more than 4 days of nontreatment. This change was necessary in an effort to obtain a more homogeneous study population for analysis. The intravenous dose has been changed from 135 mg/m2 to 80 mg/m2, since doses above 40 mg/m2 bid (total daily dose of 80 mg/m2) have not been shown to provide increases in the pharmacodynamic marker (dGuo) measured in previous studies. Guidelines for bone-marrow evaluation were clarified to include a second evaluation (i.e., “overread”) by a central laboratory. Guidelines for continuing forodesine treatment past the Initial Treatment Period were clarified so that only patients showing sufficient clinical activity would continue treatment in the Extended Treatment Period. This is based on data showing that all patients who have responded to forodesine treatment in previous studies have shown evidence of clinical activity within 2-4 weeks of treatment. Response criteria were updated to include guidelines for assessing response in patients with lymphoblastic lymphoma. The interim analysis was deleted and study-stopping criteria were added instead, for patient safety. Eligibility criteria were modified to exclude patients from the study who may be hypersensitive or intolerant to study drug components. Definition of acceptable birth control to be used during the study was added for clarification. Dose-modification guidelines were revised to reflect the 80-mg/m2 dose. Sections regarding study drug information were updated to reflect new information and correct or clarify existing information. Revisions were made to the number of sites needed for the study.

Clarification of items in the statistical section of the protocol regarding the stopping rules for the study and the basis for the sample size calculation.