Clinical Study of Oral IGF-1R Inhibitor in Subjects With Advanced Refractory Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open Label Multicentre Phase 1 Study of Oral IGF-1R Inhibitor PL225B in Subjects With Advanced Refractory Solid Tumors.

Conditions
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Advanced Refractory Solid Tumors

Intervention / Treatment
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* Drug: PL225B


Participation Criteria
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Eligibility Criteria
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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: Absolute neutrophil count ≥ 1500/cmm Platelets ≥ 100,000/cmm Total bilirubinwithin normal limits of the institution 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PL225B<br>Patients will receive study drug on a daily basis until disease progression or unacceptable toxicity in sequential cohorts following accelerated titration design. | Drug: PL225B<br>* Patients 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. This 21 day administration will define a treatment cycle. Patients may receive consecutive treatment cycles until evidence of disease progression, intolerance of therapy, or withdrawal from the protocol as specified.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | 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). | End of Cycle 1 (i.e. 21 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subject with adverse events | The toxic effects of the drug would be assessed from adverse events, vital signs and by clinically significant changes in the laboratory evaluations. | Until disease progression or unacceptable toxicity (expected to be 4-6 months) | 
| Pharmacokinetic profile(Cmax,Tmax and AUC) | The following PK parameters will be calculated: Cmax (peak plasma concentration), Tmax (time to peak plasma concentration), AUC0-t (area under the plasma concentration curve from time zero to time of last quantifiable concentration), AUC0-12, AUC0-inf (area under the plasma concentration curve from time zero extrapolated to infinity), percent AUC extrapolated, kel (elimination rate constant), t1/2 (elimination half-life), CL/F (oral clearance), Vz/F (oral apparent volume of distribution) and Racc (accumulation ratio). | Until disease progression or unacceptable toxicity (expected to be 4-6 months) | 
| Activity of PL225B based on selected biomarkers | Plasma samples will be used for analysis of circulating exploratory biomarkers which are likely to change in response to PL225B administration. | Until disease progression or unacceptable toxicity (expected to be 4-6 months) | 
| Objective response | Evaluation of Response: Clinical responses will be presented patient wise for different dose levels. | Until disease progression or unacceptable toxicity (expected to be 4-6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Refractory Solid Tumors