A First In Patient, Study Of Investigational Drug PF-03446962 In Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and effectiveness of PF-03446962 when given as a single agent. Tumors require new blood vessels to support their ability to grow and to spread (metastasize). New treatments aimed at preventing these blood vessels have the ability to improve the clinical management of cancer.

Official Title
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A Phase 1 Pharmacokinetic And Pharmacodynamic Study Of Pf-03446962 In Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: PF-03446962


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced measurable or non-measurable solid tumors Adequate bone marrow function Adequate liver function Adequate renal function Be able and willing to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures Exclusion Criteria: Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of first dose of study medication Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, hemoptysis or melena in the past 6 months Any of the following within the 12 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack, or pulmonary embolus; or any other active thromboembolic event QTc prolongation defined as QTc >450 msec Patients with known brain metastasis Patients with peritoneal carcinosis at risk of bleeding Major surgical procedure within 4 weeks of treatment Pregnancy or breastfeeding

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: PF-03446962<br>* To determine the maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of PF-03446962 administered in patients with advanced solid tumors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD): Part 1 | MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT and at least 2 out of 3/6 participants in the next higher dose. DLT was defined as any of the following events occurring during the first 42 days of study drug: any grade greater than or equal to 3 hematologic and non-hematologic toxicity, all non-disease-related adverse events (AEs). | Baseline up to 42 days after the start of each increased treatment dose | 
| Recommended Phase 2 Dose (RP2D): Part 1 | RP2D was defined as the lower dose level to MTD based on the safety profile. | Baseline up to 42 days after the start of each increased treatment dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2 | An all causality AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Treatment-related AEs was any untoward medical occurrence in participant that was attributed to study drug. Treatment-emergent events were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Cycle 1 of Day 1 up to 28 days after the last dose of treatment | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Severity: Part 1 and Part 2 | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity; Grade 0 (no change from normal); grade 1 (mild AE which did not cause any significant problem, no dose adjustment required); grade 2 (moderate AE which caused problem that did not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event); grade 3 (severe AE which caused problem that interfered significantly with usual activities or the clinical status, study drug stopped due to adverse event); grade 4 (life threatening AE) and grade 5 (death). Treatment-emergent events were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Cycle 1 of Day 1 up to 28 days after the last dose of treatment | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Seriousness: Part 1 and Part 2 | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Seriousness of an AE was assessed as serious adverse event (SAE) and non-serious adverse event (non-SAE). An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Non-SAE included all AE minus SAE. Treatment-emergent events were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Cycle 1 of Day 1 up to 28 days after the last dose of treatment | 
| Time to Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2 | Total time from onset of adverse event till the event is resolved. Treatment-emergent events were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Cycle 1 of Day 1 up to 28 days after the last dose of treatment | 
| Number of Participants With Laboratory Abnormalities: Part 1 and Part 2 | Laboratory tests included hematology (hemoglobin, lymphocytes absolute [abs], neutrophils abs, platelets, white blood cells) and chemistry (alanine aminotransferase, alkaline phosphatase, amylase, aspartate aminotransferase, bilirubin, creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, lipase). Assays were based on National Cancer Institute [NCI] Common Terminology Criteria for AE (CTCAE) grading scale for AEs (grade 1 [mild AE: did not cause any significant problem, no dose adjustment required]; grade 2 [moderate AE: caused problem that did not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event]; grade 3 [severe AE: caused problem that interfered significantly with usual activities or the clinical status, study drug stopped due to adverse event] and grade 4 [life threatening AE]). Overall data of the 4 grades is reported. | Cycle 1 of Day 1 up to 28 days after the last dose of treatment | 
| Percentage of Participants With Objective Response: Part 1 and Part 2 | Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR defined as disappearance of all target lesions and non-target lesions. PR defined as >=30 % decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non-target lesions. | Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 | 
| Percentage of Participants With Disease Control: Part 2 | Participants who achieved either a confirmed complete Response or confirmed partial response or a Stable disease lasting at least 12 weeks from the first dose was defined as achieving disease control. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR: disappearance of all target lesions and non-target lesions. PR: >=30 % decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD and stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as a reference the smallest sum of the LD according to RECIST associated to non-progressive disease response for non-target lesions. Percentage of participants achieving disease control was calculated out of the participants participating in the exploratory phase. | Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 | 
| Time To Progression (TTP): Part 2 | Time in months from start of treatment to first documentation of objective tumor progression. TTP was calculated as (first event date or last known progression-free date minus the date of treatment plus 1) divided by 30.44. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST). PD: >=20% increase in the sum of the LD of the target lesions taking as a reference the smallest sum of the LD or the appearance of one or more new lesions and as unequivocal progression of existing non-target lesions, or the appearance of >=1 new lesions. TTP was calculated out of the participants participating in the exploratory phase. | Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 | 
| Volume of Distribution: Part 1 and Part 2 | 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 blood concentration of a drug. As per planned analysis, volume of distribution was summarized if at least 3 participants had reportable value. | 0 hr (pre-dose),0.5,1,1.5,2,5,10,24 hr post-dose on Day (D) 1,3,5,8,11,15,22 of Cycle (C) 1, 0 hr,1 hr post-dose on Day 1 of subsequent cycles up to cycle 12, 28 days after last dose for dose (up to 3 months after last dose for >=2 mg/kg arms) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors Transforming Growth Factor Beta Activin Receptor-like Kinase 1