Safety of SGI-1776, A PIM Kinase Inhibitor in Refractory Prostate Cancer and Relapsed/Refractory Non Hodgkin's Lymphoma

Safety Study to Determine the Maximum Tolerated Dose, Pharmacokinetics and Pharmacodynamics of SGI-1776, a PIM Kinase Inhibitor, in Subjects With Hormone and Docetaxel Refractory Prostate Cancer and Relapsed/Refractory Non Hodgkin's Lymphoma

Patients with hormone and docetaxel refractory prostate cancer or relapsed/refractory non-Hodgkin's lymphoma for which no available standard therapy or therapy which may provide clinical benefit is available will be enrolled. Primary objectives: estimate the maximum tolerated dose and dose-limiting toxicities. Secondary objectives: Response rate, pharmacokinetic and pharmacodynamic profiles, Prostate Specific Antigen response and renal elimination.

General

Inclusion Criteria:

1. Read, understand and sign the IRB- or IEC-approved ICF confirming his or her willingness to participate in this trial.
2. At least 18 years old.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
4. Adequate bone marrow function; normal renal and hepatic function, normal cardiac function.
5. Normal cardiac function in the opinion of the investigator and supported by LVEF 50% or greater on the screening echocardiogram (or MUGA), no significant abnormalities on the screening ECG (eg, left bundle branch block, III degree AV block, acute myocardial infarction, Wolff-Parkinson-White syndrome or QTc interval ≥ 450 msec) and no history of additional risk factors for torsades de pointes (eg, heart failure, hypokalemia or family history of Long QT Syndrome).

Exclusion Criteria:

1. Active secondary malignancy or history of other malignancy within the last two years except non-melanoma skin cancers or cervical carcinoma in situ.
2. History of significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure and/or myocardial infarction or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
3. Received any anticancer agent(s) within the past 3 weeks, including investigational agents, chemotherapy (6 weeks for nitrosoureas or mitomycin), immunotherapy, biologic or marketed or investigational tyrosine kinase inhibitors.
4. Received prior radiation therapy within the past 4 weeks or received irradiation of ≥ 25% of their bone marrow reserve.
5. Any serious, uncontrolled active infection that requires systemic treatment or known infection with HIV, HCV or HBV.
6. Symptomatic CNS metastases or lesions for which treatment is required.

Prostate Cancer

Inclusion Criteria:

1. Males with histologically confirmed adenocarcinoma of the prostate, which is now metastatic (e.g., any T, any N, M1a-c)based on bone scan, CT scan, or MRI scan. Demonstrated evidence of progressive disease despite androgen deprivation (androgen ablation or surgical castration), anti-androgen withdrawal and progression of disease after docetaxel-based therapy.

2. Demonstrated evidence of progressive disease despite androgen deprivation (androgen ablation or surgical castration), anti-androgen withdrawal and progression of disease after docetaxel-based therapy.

   • Greater than 25% increase in 3 consecutive tests (PSA 1 < PSA 2 < PSA 3), each PSA value separated by at least 1 week

3. Serum testosterone level ≤ 50 ng/dL post orchiectomy or while maintained on continuous or intermittent medical androgen suppression with a LHRH agonist or antagonist.

4. At least 4 weeks since prior flutamide, megestrol, ketoconazole, aminoglutethimide; and at least 6 weeks since prior bicalutamide or nilutamide.

5. Systemic corticosteroids discontinued within two weeks of dosing, except low dose regimens which may continue if unchanged

6. Strontium-89 or Samarium-153 must have been completed at least 8 weeks prior to the first dose of therapy and recovered from all treatment-related toxicities.

Exclusion Criteria:

1. Must not be receiving concurrent anti-androgen hormonal therapy for hormone refractory prostate cancer.

Non-Hodgkin's Lymphoma

Inclusion Criteria:

1. Histologically proven relapsed or refractory non-Hodgkin's lymphoma subjects for which there is no available standard therapy or therapy which may provide clinical benefit.
2. Measurable disease (at least 1 lesion ≥ 1.5 cm).

Exclusion Criteria:

1. Bulky disease by CT, defined as any single mass >10 cm in its greatest diameter.
2. Systemic corticosteroids within 2 weeks, except low dose regimens which may continue if unchanged.
3. Received any radiopharmaceutical therapy within the past six weeks.