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To determine the maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of PF-03446962 administered in patients with advanced solid tumors.

PF-03446962

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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.

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

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

AUC (0-28) = Area under the plasma concentration versus time curve from time zero (pre-dose) to Day 28 (0-28).

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

CL is a quantitative measure of the rate at which a drug substance is removed from the body. As per planned analysis, CL was summarized if at least 3 participants had reportable value.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. As per planned analysis, t1/2 was summarized if at least 3 participants had reportable value.

HAHA concentration was analyzed in blood samples for the evaluation of immunogenicity of PF-03446962. HAHA concentration was reported for samples above lower limit of quantification (\>=4.32).

Plasma concentrations of soluble proteins (Ang-2, BMP-9, C-C motif) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

Plasma concentrations of soluble proteins (CD106, CD54 and Endoglin) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

Plasma concentrations of soluble proteins (PLGF, TGFB1, VEGF-A) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

Plasma concentrations of soluble proteins (VEGF-C, VEGF-d, VEGFR1) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

Plasma concentrations of soluble proteins (VEGFR2, VEGFR3) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

Circulating endothelial cells (CECs) are noninvasive marker of vascular damage, remodeling, and dysfunction. Blood samples for the assessment of CECs and circulating CEPs were collected to analyze effects of therapy on the number, viability/apoptotic state, and/or target activity/expression in CECs. Circulating Cells were classified as CEPs if cluster differentiation 133 positive cells (CD133+) were detected.

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).

RP2D was defined as the lower dose level to MTD based on the safety profile.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

All participants who received PF-03446962 intravenous infusion (0.5 milligram/kilogram \[mg/kg\], 1 mg/kg, 2 mg, 3 mg/kg, 4.5 mg/kg, 6.75 mg/kg, 10 mg/kg, 15 mg/kg, 7 mg/kg), on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression or unacceptable toxicity.

Age, Continuous

Sex: Female, Male

Safety population included all enrolled participants who received at least one dose of study drug.

Results for tumor vascular function adopting dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was not reported as per change in planned analysis.

Pfizer ClinicalTrials.gov Call Center

All participants who received PF-03446962 intravenous infusion (0.5 milligram/kilogram \[mg/kg\], 1 mg/kg, 2 mg, 3 mg/kg, 4.5 mg/kg, 6.75 mg/kg, 10 mg/kg, 15 mg/kg), on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression or unacceptable toxicity.

The MTD analysis set included all participants who were enrolled in the dose escalation part of the study and received at least 1 dose of study drug.

Maximum Tolerated Dose (MTD): Part 1

Recommended Phase 2 Dose (RP2D): Part 1

All causalities

Treatment-related

PF-03446962 0.5 milligram per kilogram (mg/kg) intravenous infusion over 1 hour (hr) on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 0.5 mg/kg: Part 1

PF-03446962 1 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 1 mg/kg

PF-03446962 2 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 2 mg/kg : Part 1

PF-03446962 3 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 3 mg/kg: Part 1

PF-03446962 4.5 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 4.5 mg/kg: Part 1

PF-03446962 6.75 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 6.75 mg/kg: Part 1

PF-03446962 10 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 10 mg/kg: Part 1

PF-03446962 15 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 15 mg/kg: Part 1

PF-03446962 7 mg/kg intravenous infusion over 1 hr on Day 1 of cycle 1 (28 days) and on Day 1 of subsequent cycles (14 days) until disease progression, withdrawal by participant or unacceptable toxicity.

PF-03446962 7 mg/kg: Part 2

Number of Participants With Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

PF-03446962 1 mg/kg: Part 1

Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Severity: Part 1 and Part 2

Non-Serious Adverse Events

Serious Adverse Events

Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Seriousness: Part 1 and Part 2

Data for timing was reported in individual participant listing for every adverse event (AE) and mentioned for description of narrative of Serious AEs but was not statistically summarized for analysis on the entire safety population, as planned.

Time to Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2

Hemoglobin

Lymphocytes abs

Neutrophils abs

Platelets

White blood cells

Alanine Aminotransferase

Alkaline Phosphatase

Amylase

Aspartate Aminotransferase

Bilirubin

Creatinine

Hypercalcemia

Hyperglycemia

Hyperkalemia

Hypernatremia

Hypoalbuminemia

Hypocalcemia

Hypokalemia

Hyponatremia

Hypophosphatemia

Lipase

Hypoglycemia

Number of Participants With Laboratory Abnormalities: Part 1 and Part 2

Response-evaluable set included all participants who received at least 1 dose of study drug with an adequate baseline tumor assessment.

Percentage of Participants With Objective Response: Part 1 and Part 2

Response-evaluable set included all participants who started Cycle 1 with an adequate baseline tumor assessment.

Percentage of Participants With Disease Control: Part 2

Safety population included all participants who received at least one dose of study drug.

Time To Progression (TTP): Part 2

Pharmacokinetic analysis set included all participants who received at least one dose of study drug and who had complete sampling for pharmacokinetic profiles for PF-03446962.

Maximum Observed Serum Concentration (Cmax): Part 1 and Part 2

Cycle 2 Day 1 (n=3, 2, 6, 3, 4, 5, 5, 2, 15)

Cycle 3 Day 1 (n=3, 2, 4, 3, 1, 4, 3, 1, 13)

Cycle 4 Day 1 (n=2, 2, 2, 3, 1, 4, 3, 1, 12)

Cycle 5 Day 1 (n= 1, 0, 2, 3, 1, 3, 3, 1, 12)

Cycle 6 Day 1 (n=0, 2, 2, 1, 1, 1, 1, 0, 7)

Cycle 7 Day 1 (n=0, 0, 2, 1, 1, 3, 1, 0, 7)

Cycle 8 Day 1 (n=0, 0, 2, 1, 1, 2, 1, 0, 5)

Cycle 9 Day 1 (n=0, 0, 2, 1, 1, 2, 1, 0, 4)

Cycle 10 Day 1 (n=0, 0, 1, 1, 1, 2, 1, 0, 3)

Cycle 11 Day 1 (n=0, 0, 0, 1, 1, 2, 1, 0, 3)

Cycle 12 Day 1 (n=0, 0, 0, 0, 1, 2, 1, 0, 2)

Pharmacokinetic analysis set included all participants who received at least one dose of study drug and who had complete sampling for pharmacokinetic profiles for PF-03446962. Here "N" (Number of participants analyzed) signifies those who were evaluable for the measure and "n" signifies those participants who were evaluable at specific time-point.

Minimum Observed Serum Trough Concentration (Cmin): Part 1 and Part 2

Pharmacokinetic analysis set included all participants who received at least one dose of study drug and who had complete sampling for pharmacokinetic profiles for PF-03446962. Here "N" (Number of participants analyzed) signifies those who were evaluable for the measure.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-03446962: Part 1 and Part 2

Area Under the Curve From Time Zero to Day 28 [AUC (0-28)]: Part 1 and Part 2

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): Part 1 and Part 2

Systemic Clearance(CL): Part 1 and Part 2

Volume of Distribution: Part 1 and Part 2

Plasma Decay Half-Life (t1/2): Part 1 and Part 2

Statistical Data was not statistically summarized as majority of participants had concentration below the limit of quantification.

Human Anti - Human Antibody (HAHA) Concentration: Part 1 and Part 2

Baseline: Ang-2 (n=5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: Ang-2 (n=4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: Ang-2 (n=4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: Ang-2 (n=3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: Ang-2 (n=3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: Ang-2 (n=5, 5, 2, 3, 4, 4, 5, 5, 17)

Baseline: BMP-9 (n=5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: BMP-9 (n=4, 3, 6, 2, 4, 7, 7, 6, 23)

C1D22: BMP-9 (n=4, 5, 6, 2, 4, 5, 7, 5, 19)

C2D1: BMP-9 (n=3, 2, 6, 2, 4, 4, 5, 2, 20)

C3D1: BMP-9 (n=2, 2, 4, 2, 1, 3, 3, 1, 12)

EOT: BMP-9 (n=5, 5, 2, 2, 4, 4, 5, 5, 17)

Baseline: CCL2 (n=5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: CCL2 (n=4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: CCL2 (n=4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: CCL2 (n=3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: CCL2 (n=3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: CCL2 (n=5, 5, 2, 3, 4, 4, 5, 5, 17)

Soluble protein biomarker analysis set included all participants who received at least one dose of study drug with a baseline (pre-dose C1D1) or screening biomarker result, and at least one on-treatment biomarker result for at least one biomarker. "n" signifies those participants who were evaluable at specific time-point.

Soluble Protein Biomarker [Angiopoietin-2 (Ang-2), Bone Morphogenetic Protein-9 (BMP-9), Chemokine (C-C Motif) Ligand 2 (CCL2)]: Part 1 and Part 2

Baseline: CD106 (n= 5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: CD106 (n= 4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: CD106 (n= 4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: CD106 (n= 3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: CD106 (n= 3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: CD106 (n= 5, 5, 2, 3, 4, 4, 5, 5, 17)

Baseline: CD54 (n= 5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: CD54 (n= 4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: CD54 (n= 4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: CD54 (n= 3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: CD54 (n= 3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: CD54 (n= 5, 5, 2, 3, 4, 4, 5, 5, 17)

Baseline: Endoglin (n= 5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: Endoglin (n= 4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: Endoglin (n= 4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: Endoglin (n= 3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: Endoglin (n= 3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: Endoglin (n= 5, 5, 2, 3, 4, 4, 5, 5, 17)

Soluble Protein Biomarker [Cluster of Differentiation 106 (CD106), Cluster of Differentiation 54 (CD54), Endoglin]: Part 1 and Part 2

Baseline: PLGF (n=4, 3, 5, 3, 2, 7, 6, 5, 21)

C1D16H: PLGF (n=4, 3, 5, 3, 2, 7, 6, 5, 22)

C1D22: PLGF (n=4, 5, 6, 2, 3, 6, 6, 4, 18)

C2D1: PLGF (n=3, 2, 6, 1, 3, 4, 3, 2, 18)

C3D1: PLGF (n=3, 2, 3, 1, 1, 4, 2, 1, 10)

EOT: PLGF (n=5, 4, 2, 2, 2, 3, 2, 4, 14)

Baseline: TGFb1 (n=5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: TGFb1 (n=4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: TGFb1 (n=4, 5, 6, 3, 4, 6, 7, 5, 20)

C2D1: TGFb1 (n=3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: TGFb1 (n=3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: TGFb1 (n=5, 5, 2, 3, 4, 4, 5, 5, 17)

Baseline: VEGF-A (n=4, 5, 6, 3, 3, 8, 7, 6, 24)

C1D16H: VEGF-A (n=4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: VEGF-A (n=4, 5, 6, 3, 4, 6, 7, 4, 20)

C2D1: VEGF-A (n=3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: VEGF-A (n=3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: VEGF-A (n=5, 5, 2, 3, 4, 4, 5, 5, 17)

Soluble Protein Biomarker [Placental Growth Factor (PLGF), Transforming Growth Beta 1 (TGFB1), Vascular Endothelial Growth Factor A (VEGF-A)]: Part 1 and Part 2

Baseline: VEGF-C (n= 3, 1, 3, 2, 2, 4, 4, 4, 15)

C1D16H: VEGF-C (n= 2, 2, 4, 2, 2, 5, 5, 4, 13)

C1D22: VEGF-C (n= 3, 5, 4, 2, 2, 4, 4, 4, 12)

C2D1: VEGF-C (n= 2, 1, 2, 1, 2, 4, 4, 1, 11)

C3D1: VEGF-C (n= 2, 1, 2, 0, 1, 3, 1, 0, 8)

EOT: VEGF-C (n= 5, 4, 0, 1, 2, 3, 4, 5, 10)

Baseline: VEGF-d (n= 5, 5, 6, 3, 4, 8, 7, 6, 24)

C1D16H: VEGF-d (n= 4, 3, 6, 3, 4, 8, 7, 6, 24)

C1D22: VEGF-d (n= 4, 5, 6, 3, 4, 6, 7, 5, 19)

C2D1: VEGF-d (n= 3, 2, 6, 3, 4, 5, 5, 2, 20)

C3D1: VEGF-d (n= 3, 2, 4, 3, 1, 4, 3, 1, 12)

EOT: VEGF-d (n= 5, 5, 2, 3, 4, 4, 5, 5, 17)

Baseline: VEGFR1 (n= 5, 5, 6, 3, 4, 7, 7, 6, 23)

C1D16H: VEGFR1 (n= 4, 3, 6, 3, 4, 8, 6, 6, 23)

C1D22: VEGFR1 (n= 4, 5, 6, 3, 3, 5, 7, 4, 20)

Soluble Protein Biomarker [Vascular Endothelial Growth Factor C (VEGF-C), Vascular Endothelial Growth Factor-d (VEGF-d), Vascular Endothelial Growth Factor Receptor Type 1 (VEGFR1)]: Part 1 and Part 2

Spots Global Cancer Trial Database for A First In Patient, Study Of Investigational Drug PF-03446962 In Patients With Advanced Solid Tumors

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