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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00557856
Recruitment Status : Completed
First Posted : November 14, 2007
Results First Posted : August 13, 2015
Last Update Posted : October 19, 2015
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: PF-03446962 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Pharmacokinetic And Pharmacodynamic Study Of Pf-03446962 In Patients With Advanced Solid Tumors
Study Start Date : November 2007
Actual Primary Completion Date : March 2013
Actual Study Completion Date : March 2013
Arms and Interventions
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Arm Intervention/treatment
Experimental: 1 Drug: PF-03446962
To determine the maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of PF-03446962 administered in patients with advanced solid tumors.


Outcome Measures
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Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD): Part 1 [ Time Frame: Baseline up to 42 days after the start of each increased treatment dose ]
    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).

  2. Recommended Phase 2 Dose (RP2D): Part 1 [ Time Frame: Baseline up to 42 days after the start of each increased treatment dose ]
    RP2D was defined as the lower dose level to MTD based on the safety profile.


Secondary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2 [ Time Frame: Cycle 1 of Day 1 up to 28 days after the last dose of treatment ]
    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.

  2. Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Severity: Part 1 and Part 2 [ Time Frame: Cycle 1 of Day 1 up to 28 days after the last dose of treatment ]
    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.

  3. Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Seriousness: Part 1 and Part 2 [ Time Frame: Cycle 1 of Day 1 up to 28 days after the last dose of treatment ]
    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.

  4. Time to Treatment-Emergent Adverse Events (AEs): Part 1 and Part 2 [ Time Frame: Cycle 1 of Day 1 up to 28 days after the last dose of treatment ]
    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.

  5. Number of Participants With Laboratory Abnormalities: Part 1 and Part 2 [ Time Frame: Cycle 1 of Day 1 up to 28 days after the last dose of treatment ]
    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.

  6. Percentage of Participants With Objective Response: Part 1 and Part 2 [ Time Frame: Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 ]
    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.

  7. Percentage of Participants With Disease Control: Part 2 [ Time Frame: Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 ]
    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.

  8. Time To Progression (TTP): Part 2 [ Time Frame: Baseline then 6 weeks after Cycle 1 of Day1 thereafter every 6 weeks up to Day 490 ]
    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.

  9. Volume of Distribution: Part 1 and Part 2 [ Time Frame: 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) ]
    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.


Other Outcome Measures:
  1. Maximum Observed Serum Concentration (Cmax): Part 1 and Part 2 [ Time Frame: 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) ]
  2. Minimum Observed Serum Trough Concentration (Cmin): Part 1 and Part 2 [ Time Frame: 0 hr (pre dose), 1 hr post-dose C1D1, 0 hr,1 hr post-dose on Day 1 of subsequent cycles up to C12 ]
  3. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-03446962: Part 1 and Part 2 [ Time Frame: 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) ]
  4. Area Under the Curve From Time Zero to Day 28 [AUC (0-28)]: Part 1 and Part 2 [ Time Frame: 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) ]
    AUC (0-28) = Area under the plasma concentration versus time curve from time zero (pre-dose) to Day 28 (0-28).

  5. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): Part 1 and Part 2 [ Time Frame: 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) ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

  6. Systemic Clearance(CL): Part 1 and Part 2 [ Time Frame: 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) ]
    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.

  7. Plasma Decay Half-Life (t1/2): Part 1 and Part 2 [ Time Frame: 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) ]
    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.

  8. Human Anti - Human Antibody (HAHA) Concentration: Part 1 and Part 2 [ Time Frame: Baseline up to 3 months after last dose ]
    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).

  9. 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 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    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.

  10. Soluble Protein Biomarker [Cluster of Differentiation 106 (CD106), Cluster of Differentiation 54 (CD54), Endoglin]: Part 1 and Part 2 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    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.

  11. Soluble Protein Biomarker [Placental Growth Factor (PLGF), Transforming Growth Beta 1 (TGFB1), Vascular Endothelial Growth Factor A (VEGF-A)]: Part 1 and Part 2 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    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.

  12. 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 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    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.

  13. Soluble Protein Biomarker [Vascular Endothelial Growth Factor Receptor Type 2 (VEGFR2), Vascular Endothelial Growth Factor Receptor Type 3 (VEGFR3)]: Part 1 and Part 2 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    Plasma concentrations of soluble proteins (VEGFR2, VEGFR3) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.

  14. Circulating Endothelial Cells (CEC)and Circulating Endothelial Progenitors (CEP): Part 1 and Part 2 [ Time Frame: Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490) ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00557856


Locations
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United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, South Carolina
Medical University of South Carolina, Hollings Cancer Center
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37212-3505
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Italy
S.C Diagnostica Radiologica 2
Milano, Italy, 20133
S.C. Chirurgia Generale Indirizzo Oncologico 1 (epato-gastro-pancreatica)
Milano, Italy, 20133
S.C. Medicina Oncologica I, Fondazione IRCCS Istituto Nazionale Tumori
Milano, Italy, 20133
Dipartimento di Medicina
Milano, Italy, 20141
UO di Oncologia ed Ematologia, Istituto Clinico Humanitas-Humanitas Cancer Center
Rozzano (MI), Italy, 20089
Korea, Republic of
Seoul National University Hospital / Department of Internal Medicine
Seoul, Korea, Republic of, 110-744
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00557856    
Other Study ID Numbers: A8471001
2007-001422-27 ( EudraCT Number )
First Posted: November 14, 2007    Key Record Dates
Results First Posted: August 13, 2015
Last Update Posted: October 19, 2015
Last Verified: September 2015
Keywords provided by Pfizer:
Solid Tumors Transforming Growth Factor Beta Activin Receptor-like Kinase 1
Additional relevant MeSH terms:
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Neoplasms