A Dose Finding Study Of A New Medication, PF-00337210 That Will Possibly Decrease Blood Supply To Tumors

Study Overview
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Brief Summary
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This study will test a new cancer medication to determine if this medication will block blood supply to a tumor and decrease growth of a tumor. This study will also define the safety profile and define the safest dose of this new medication for people who have cancer.

Official Title
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Phase I, Open-Label, Multi-Center, Accelerated Dose Escalation Study Of The Anti-Angiogenesis Agent PF-00337210 In Patients With Advanced Solid Tumors

Conditions
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Neoplasm

Intervention / Treatment
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* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210
* Drug: PF-00337210


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced solid tumors un-responsive to currently available therapies or for which there is no standard therapy. At least 1 measurable disease site as defined by Response Evaluation Criterion in Solid Tumors [RECIST]. Adequate bone marrow, liver function and renal function as defined by protocol. Blood pressure Requirements During dose escalation - no evidence of pre-existing hypertension and no antihypertensive medications at baseline. During dose expansion - patient's whose hypertension is controlled by antihypertensive therapy. Exclusion Criteria: Chemotherapy, radiotherapy or any investigational therapy within 4 weeks of study entry Current use or anticipated need for drugs that are known CYP34 inhibitors or inducers. Patients with carcinomatous meningitis or un-treated brain metastases. Any acute cardiovascular incident within the past 12 months. Patients with active gastrointestinal bleeding or significant gastrointestinal abnormalities as defined by protocol Patients with no evidence of the following for 5 years: malignancy or metastatic disease of skin cancer (except melanoma), in situ cervical cancer or breast cancer or T1C prostate cancer.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Drug: PF-00337210<br>* 0.67mg Capsule Once Daily (Accelerated Dose Escalation) Continuous<br>|
| Experimental: Cohort 2<br> | Drug: PF-00337210<br>* 1mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 3<br> | Drug: PF-00337210<br>* 2mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 4<br> | Drug: PF-00337210<br>* 4mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 5<br> | Drug: PF-00337210<br>* 6mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 6<br> | Drug: PF-00337210<br>* 9mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 7<br> | Drug: PF-00337210<br>* 8mg Capsule Once Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 8<br> | Drug: PF-00337210<br>* 4mg Capsule Twice Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 9<br> | Drug: PF-00337210<br>* 6mg Capsule Twice Daily (Dose Escalation) Continuous<br>|
| Experimental: Cohort 10<br> | Drug: PF-00337210<br>* 6mg Capsule Twice Daily (Dose Expansion) Continuous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | DLTs included events occurring in Cycle 1: blood pressure of 180/110 millimeters of mercury (mmHg) or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or greater than (>) 160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia for greater than or equal to (>=) 7 days or >=Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree Celsius [degree C] or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. | Baseline up to Day 28 | 
| Maximum Tolerated Dose (MTD) | MTD: dose level at which no more than 1 of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or >160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia >=7 days or >= Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree C or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. | Day 28 | 
| Maximum Administered Dose (MAD) | MAD: dose level at which 2 or more out of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or >160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia >=7 days or >= Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree C or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. | Day 28 | 
| Recommended Phase-2 Dose (RP2D) | RP2D was determined based on the safety profile and pharmacodynamic findings. The twice daily dosing was preferred over once daily dosing for RP2D, as per investigator's discretion, due to more consistent changes in pharmacodynamic markers and greater clinical benefit observed in twice daily dosing. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hours(hrs) post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Apparent Volume of Distribution (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed. | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | 
| Number of Participants With Objective Response of Complete Response or Partial Response | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target and non-target lesions and no appearance of new lesions. Confirmed PR defined as at least 30 percent decrease in sum of the longest dimensions (LD) of the target lesions, taking as a reference the baseline sum LD, without progression of non-target lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response. | Baseline, every 8 weeks up to Cycle 25 (Week 100) | 
| Change From Baseline in Biomarkers at Day 1 of Each Cycle up to Cycle 25 | Biomarkers included soluble plasma proteins associated with angiogenesis (vascular endothelial growth factor [VEGF], soluble vascular endothelial growth factor-2 receptor [sVEGFR2], soluble vascular endothelial growth factor-3 receptor [sVEGFR3], soluble beta type platelet-derived growth factor [sPDGFR beta]) and tumor proliferation (soluble stem-cell factor receptor [sKIT]) | Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VGEF inhibitor, Anti angiogenesis, Advanced Solid Tumors