Dose Escalation Study to Assess the Safety and Tolerability of Genz-644282 in Patients With Solid Tumors

This is a Phase I, open-label, multicenter, dose-escalation study designed to assess the safety and tolerability of Genz-644282, administered as an IV infusion, to patients with advanced malignant solid tumors. Drug will be administered as a 60-minute IV infusion on days 1, 8, and 15 of the 28 day treatment cycle, or on days 1 and 8 of the 21 day treatment cycle.

Treatment with Genz-644282 will continue until disease progression or unacceptable toxicity is observed. Patients will be enrolled in escalating dose cohorts until the Maximum Tolerated Doses (MTDs) are established.

Safety will be evaluated throughout the study.

Inclusion criteria

• Signed written informed consent
• Patients enrolled in dose-escalation phase: Histologically or cytologically confirmed advanced malignant solid tumor for which no standard therapeutic option exists.
• For the disease indications evaluated in the expansion phase, the following criteria must be met:

• Have one of the following histologically or cytologically confirmed advanced malignant solid tumors for which no standard therapeutic option exists:

• Colorectal cancer (prior systemic regimen must have included ≥1 of the following: fluoropyrimidine or oxaliplatin);
• Squamous Non-small cell lung cancer or small cell lung cancer (prior systemic regimen must have included ≥1 of the following: cis-platinum or carbo platinum);
• Pancreatic cancer (prior systemic regimen must have included gemcitabine);
• Breast cancer (prior systemic regimen must have included ≥1 of the following: taxane, anthracycline, or fluoropyrimidine)
• Received no more than 4 prior systemic therapy regimens for their malignancy
• Experienced progression or intolerance to their immediate prior systemic therapy regimen.
• Evaluable or measurable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 12 weeks.
• Adequate organ and hematologic function.
• Prior chemotherapy, major surgery, or irradiation must have been completed at least 3 weeks prior to starting treatment with study drug, with the exception of mitomycin-C or nitrosoureas, which should be completed at least 6 weeks prior. Additionally, patients must have recovered to ≤ Grade 1 toxicities incurred as a result of the previous therapy, with the exception of nail dystrophy, alopecia, or local radiation therapy induced adverse events (e.g., impotence or incontinence). A patient who has received radiation to < 5% of their total bone marrow volume and who has had 2 weeks of rest may be considered for study entry after discussion with the Sponsor
• Hormone treatment must have been completed > 2 weeks prior to receiving study drug.
• Prostate cancer patients who are chemically castrated with hormonal therapy (e.g., luteinizing hormone-releasing hormone agonists) will be allowed to enter the study. However, doses and schedules of such treatments must be maintained throughout the trial and all major toxicities must have resolved to ≤ Grade 1 prior to study entry.
• Concomitant stable treatment with bisphosphonates is allowed, unless dose requires readjustments or discontinuation.
• Ability to comply with study procedures and follow-up examinations.
• Male and female patients must agree to use an effective barrier means of birth control (i.e., latex condom, diaphragm, cervical cap, etc.) throughout the entire duration of the study and for at least 3 months after last dose of study drug.
• Male patients must agree to not donate sperm throughout the study and for at least 3 months following the last dose of study drug.

Exclusion criteria

• Received previous treatment with or have a known hypersensitivity to Genz-644282 or to any of its components.
• Received radiotherapy to the only site of measurable disease, unless the tumor at this site continues to increase in size after the patient has completed radiotherapy treatment.
• Used any investigational agent, other than anti-cancer chemotherapy, during the 4 weeks prior to the first dose of Genz-644282.
• Have psychiatric disorder(s) that would interfere with consent, study participation, or follow up (with the possible exception of incompetence as defined by New Jersey for the purposes of participation in clinical trials in the state of New Jersey).
• Have uncontrolled congestive heart failure or angina, a history of myocardial infarction within 6 months prior to study enrollment, or a cardiac functional capacity Class III or IV, as defined by the New York Heart Association Classification.
• Have a resting QT with Bazett's correction (QTcB) interval of > 460 msec, calculated as the average of at least 2 of the longest QT intervals measured on 12-lead recordings made prior to dosing with Genz-644282.
• Have a systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement) despite appropriate antibiotics or other treatment.
• Have any other severe concurrent disease or a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo chemotherapy.
• A known diagnosis of human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS) or viral hepatitis B or C.
• Presence of ≥ Grade 2 peripheral neuropathy.
• Pregnant or lactating women, due to the unknown effects of Genz-644282 on the developing fetus or newborn infant.