Clinical Study of Oral IGF-1R Inhibitor in Subjects With Advanced Refractory Solid Tumors
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PL225B Patients will receive study drug on a daily basis until disease progression or unacceptable toxicity in sequential cohorts following accelerated titration design. |
Drug: PL225B
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.
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose [End of Cycle 1 (i.e. 21 Days)]
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).
Secondary Outcome Measures
- Number of subject with adverse events [Until disease progression or unacceptable toxicity (expected to be 4-6 months)]
The toxic effects of the drug would be assessed from adverse events, vital signs and by clinically significant changes in the laboratory evaluations.
- Pharmacokinetic profile(Cmax,Tmax and AUC) [Until disease progression or unacceptable toxicity (expected to be 4-6 months)]
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).
- Activity of PL225B based on selected biomarkers [Until disease progression or unacceptable toxicity (expected to be 4-6 months)]
Plasma samples will be used for analysis of circulating exploratory biomarkers which are likely to change in response to PL225B administration.
- Objective response [Until disease progression or unacceptable toxicity (expected to be 4-6 months)]
Evaluation of Response: Clinical responses will be presented patient wise for different dose levels.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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
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Subjects should have measurable or evaluable disease
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Subjects of either sex, of all races and ethnic groups, and ≥18 years of age
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ECOG (Eastern Cooperative Oncology Group) performance status 0-1
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Subjects with life expectancy of at least 4 months
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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.
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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.
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Subjects must have normal organ and marrow function as defined below:
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Absolute neutrophil count ≥ 1500/cmm
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Platelets ≥ 100,000/cmm
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Total bilirubinwithin normal limits of the institution
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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
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Creatinine ≤ 1.5 X institutional upper limit of normal (ULN)
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Subjects willing for repeat oral dosing and follow-up, including pharmacokinetic sampling
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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
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Ability to understand and the willingness to provide a written informed consent document
Exclusion Criteria
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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
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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
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Subjects with documented history of diabetes mellitus except for the Diabetes Expansion Cohort
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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.
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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.
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Subjects with known complications of diabetes like diabetic nephropathy or diabetic retinopathy
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Subjects with known brain metastases
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Subjects with gastrointestinal abnormalities including inability to take oral medication, malabsorption or other conditions like chronic inflammatory bowel disease that may affect absorption.
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Subjects with a history of myocardial infarction or uncontrolled cardiac dysfunction during the previous 6 months
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Subjects with baseline QTc interval >470 msec at screening
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Subjects on warfarin. Prophylactic anticoagulation with low molecular weight heparin is allowed
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Subjects with history of anaphylaxis or angioedema, bronchial asthma, peptic ulcer and clinically significant food or drug allergy
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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
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Women who are pregnant or nursing
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Subjects with known seropositivity to human immunodeficiency virus (HIV), positive for Hepatitis B, positive for Hepatitis C (antigen positive), or known hepatic cirrhosis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | USC Norris Comprehensive Cancer Center | Los Angeles | California | United States | 90033 |
| 2 | Central India Cancer Research Institute | Nagpur | Maharashtra | India | 440010 |
| 3 | Curie Manavata Cancer Centre | Nashik | Maharashtra | India | 422004 |
| 4 | Ruby Hall Clinic | Pune | Maharashtra | India | 411001 |
| 5 | Meenakshi Mission Hospital and Research Centre | Madurai | Tamil Nadu | India | 625107 |
Sponsors and Collaborators
- Piramal Enterprises Limited
Investigators
- Principal Investigator: Dr Anthony El-Khoueiry, MD, University of Southern California
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PL225B/71/11