clinical study of oral igf-1r inhibitor in subjects with advanced refractory solid tumors

Conditions: Advanced Refractory Solid Tumors

Summary: clinical study of oral igf-1r inhibitor pl225b in subjects with advanced refractory solid tumors. the primary objective is to determine the maximum tolerated dose and dose limiting toxicity (ies) of oral igf-1r inhibitor pl225b in subjects with advanced refractory solid tumors.

an open label multicentre phase 1 study of oral igf-1r inhibitor pl225b in subjects with advanced refractory solid tumors. this is a dose-finding trial using the modified accelerated titration design with 3 new subjects per cohort and 100% dose increments in the accelerated phase followed by standard phase with 40% dose increments.subjects will receive study drug on a daily basis for twenty-one (21) days according to the dose and schedule specified for a particular cohort of therapy. toxicity profile of the drug will be assessed during cycle 1 of subject treatment in each cohort for determination of maximum tolerated dose (mtd) according to the schedule given below.

Eligibility criteria:
inclusion criteria: * subjects having histologically and/or cytologically confirmed non-haematological malignancy that is metastatic or unresectable and for which standard curative or palliative treatment does not exist or is no longer effective * subjects should have measurable or evaluable disease * subjects of either sex, of all races and ethnic groups, and ≥18 years of age * ecog (eastern cooperative oncology group) performance status 0-1 * subjects with life expectancy of at least 4 months * subjects with fasting plasma glucose ≤ 125 mg/dl and hba1c \< 6.5 % at screening subjects with fasting plasma glucose ≤150 mg/dl and hba1c ≤ 7.0 % at screening for the diabetes expansion cohort. * for the diabetes expansion cohort - subjects with known history of type 2 diabetes mellitus that are well-controlled on a stable dose of oral anti-diabetic agents such as metformin and/or sulfonylureas for 4 weeks prior to screening. * subjects must have normal organ and marrow function as defined below: 1. absolute neutrophil count ≥ 1500/cmm 2. platelets ≥ 100,000/cmm 3. total bilirubinwithin normal limits of the institution 4. ast/alt ≤ 2.5 x institutional upper limit of normal (uln) or ≤ 5 x institutional upper limit of normal (uln) in the presence of liver metastases 5. creatinine ≤ 1.5 x institutional upper limit of normal (uln) * subjects willing for repeat oral dosing and follow-up, including pharmacokinetic sampling * women of childbearing potential and men willing to agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the duration of study participation and for at least 4 weeks after withdrawal from the study, unless they are surgically sterilised * ability to understand and the willingness to provide a written informed consent document exclusion criteria * subjects who have received any prior chemotherapy, radiotherapy, biologic/targeted anti-cancer therapy or surgery within 4 weeks (6 weeks for monoclonal antibodies, radioactive monoclonal antibodies or any radio- or toxin- immunoconjugates) before the first study drug administration and have not recovered (to aes \< grade 2) from the toxic effects from any prior therapy * subjects having received any other investigational agents within 4 weeks prior to the first study drug administration and have not recovered completely (to aes \< grade 2) from the side effects of the earlier investigational agent * subjects with documented history of diabetes mellitus except for the diabetes expansion cohort * for the diabetes expansion cohort - subjects who have type 1 diabetes mellitus, maturity onset diabetes of the young, hyperglycemia due to reasons other than type 2 diabetes mellitus. * for the diabetes expansion cohort - subjects who currently require insulin, thiazolidinediones, dual proliferator-activated receptors (ppar) agonists, glucagon-like peptide (glp-1) analogues, dipeptidyl peptidase (dpp-iv) inhibitors or have received the same in the 4 weeks prior to screening. * subjects with known complications of diabetes like diabetic nephropathy or diabetic retinopathy * subjects with known brain metastases * subjects with gastrointestinal abnormalities including inability to take oral medication, malabsorption or other conditions like chronic inflammatory bowel disease that may affect absorption. * subjects with a history of myocardial infarction or uncontrolled cardiac dysfunction during the previous 6 months * subjects with baseline qtc interval \>470 msec at screening * subjects on warfarin. prophylactic anticoagulation with low molecular weight heparin is allowed * subjects with history of anaphylaxis or angioedema, bronchial asthma, peptic ulcer and clinically significant food or drug allergy * subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * women who are pregnant or nursing * subjects with known seropositivity to human immunodeficiency virus (hiv), positive for hepatitis b, positive for hepatitis c (antigen positive), or known hepatic cirrhosis

Keywords: advanced refractory solid tumors