Asian Phase I Study Of PF-03446962

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01337050
First received: April 6, 2011
Last updated: October 6, 2015
Last verified: October 2015
  Purpose
This is an Asian Phase 1, multi center, open label, single arm study of PF 03446962 with dose escalation and designed to define the Maximum Tolerated Dose [MTD] and the Recommended Phase 2 Dose [RP2D].

Condition Intervention Phase
Neoplasms
Drug: PF-03446962
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: A Phase I Pharmacokinetic And Pharmacodynamic Study Of Pf-03446962 In Asian Patient With Advanced Solid Tumors

Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: Baseline up to Week 6 ] [ Designated as safety issue: Yes ]
    The MTD was defined as the highest dose of PF-03446962 associated with the occurrence of Dose Limiting Toxicities (DLTs) in at most 1 of 6 participants with the next higher dose having at least 2/3 or 2/6 participants experiencing DLTs (that is (i.e.) Maximum Administrated Dose). DLT is defined if the participants meets the following criteria during the first 6 weeks of treatment, possibly attributable to PF-03446962. Neutropenia grade 4 (less than [< ])500/cubic millimeter [mm^ 3]) lasting for greater than equal to (>=) 8 days; Febrile Neutropenia >= Grade 3; Neutropenic Infection >= Grade 3; Grade 4 thrombocytopenia (<25,000/mm^3); Grade 3 thrombocytopenia (<50,000/mm^3) with active bleeding; Grade 3 or higher non-hematological toxicity.

  • Recommended Phase-2 Dose (RP2D) [ Time Frame: Baseline up to 28 days after last dose of study medication ] [ Designated as safety issue: Yes ]
    RP2D was determined by a comprehensive assessments based on all the safety data, efficacy data, pharmacokinetics profile and biomarker data using blood and tumor samples.


Secondary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last dose ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. Treatment-emergent 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 pre-treatment state. AEs included both SAEs and non-serious adverse events (non-SAEs).

  • Number of Participants With Treatment Emergent Adverse Events (AEs) Based on Severity [ Time Frame: Baseline up to 28 days after last dose ] [ Designated as safety issue: Yes ]
    Adverse event (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 1 (Mild Adverse Event), Grade 2 (Moderate Adverse Event), Grade 3 (Severe Adverse Event), Grade 4 (Life- Threatening or Disabling Adverse Event), Grade 5 (Death Related to Adverse Event).

  • Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last dose ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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. AEs included both SAEs and non-serious adverse events (non-SAEs). Relatedness to study drug was assessed based on investigator's discretion.

  • Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to 28 days after last dose ] [ Designated as safety issue: Yes ]
    Laboratory abnormalities were segregated into hematology, chemistry, coagulation and urinalysis test. It had been graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (Life-threatening). Participants with abnormality of any of these grades are reported.

  • Maximum Observed Serum Concentration (Cmax) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
  • Minimum Observed Serum Trough Concentration (Cmin) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to 28 Days [AUC (0-28)] [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
    AUC (0-28)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-28).

  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) for drug.

  • Systemic Clearance (CL) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
    CL is a quantitative measure of the rate at which a drug substance is removed from the body.

  • Volume of Distribution (Vd) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
    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.

  • Plasma Decay Half-Life (t1/2) [ Time Frame: 0 (pre dose), 0.5, 1 (right before the end of infusion), 1.5, 2, 5, 8, 24 hours after the start of infusion of the first dose on Day 1; Day 3, 5, 8, 11, 15, 22 of Cycle 1 ] [ Designated as safety issue: No ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

  • Soluble Proteins Level [ Time Frame: Baseline, Day 1, 0 hour (H), 6 H Cycle 1 Day 1, Day 22 of Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3 and end of treatment (up to cycle 30) ] [ Designated as safety issue: No ]
    Soluble proteins related to Activin Receptor-Like Kinase 1 (ALK-1) signaling and angiogenesis signaling including Vascular adhesion molecule (VAM), Monocyte chemotactic protein 1 (MCP-1), Angiopoietin 2, Tear intercellular adhesive molecule 1 (ICAM-1), Soluble intracellular adhesion molecule 1 (SIAM-1), Soluble vascular adhesion molecule 1 (SVAM-1), Vascular endothelial growth factor A (VEGF-A), Vascular endothelial growth factor C (VEGF-C), Vascular endothelial growth factor D (VEGF-D), Soluble vascular endothelial growth factor- Receptor 1 (REC 1) (SVEGF-REC 1), Soluble vascular endothelial growth factor- REC 2 (SVEGF-REC 2), Soluble vascular endothelial growth factor- REC 3 (SVEGF-REC 3), Bone morphogenetic protein-9 (BMP-9), Endoglin, Transforming growth factor- beta 1 (TGF- Beta 1), Placental growth factor (PGF) was evaluated.

  • Number of Participants With Human Anti-Human Antibody (HAHA) [ Time Frame: Baseline, Post-dose (Day 1 of every Cycle up to 28 days after last dose) up to Cycle 30 ] [ Designated as safety issue: No ]
    HAHA analysis was performed using validated, sensitive and specific chemiluminescence enzyme-linked immunosorbent assay (ELISA) methodology.

  • Number of Participants With Best Overall Response (BOR) [ Time Frame: Baseline, thereafter every 6 weeks up to end of treatment (up to Cycle 30) ] [ Designated as safety issue: No ]
    Number of participants with best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST); Complete response (CR): disappearance of all lesions, Pathological lymph nodes' reduction in short axis (SA) to less than (<)10 millimeter (mm); Partial response (PR): greater than equal to (>=) 30% decrease in sum of longest dimensions (LD) of Target Lesions (TL) taking reference baseline sum LD; Progressive disease (PD):>=20% (>= 5 mm increase) increase sum of LD of TL taking as a reference smallest sum of LD recorded since treatment start, appearance of >=1 new lesions, unequivocal progression of existing non-TL, or appearance of >=1 new lesion; Stable disease (SD): insufficient shrinkage to qualify for PR, insufficient increase to qualify for PD taking reference smallest sum of the LD since treatment start. Confirmed response=that persist at least 4 weeks after initial documentation.

  • Number of Participants With Clinical Benefit Response (CBR) [ Time Frame: Baseline, thereafter every 6 weeks up to end of treatment (up to Cycle 30) ] [ Designated as safety issue: No ]
    Number of participant with clinical benefit response (CBR): CBR was defined as CR, PR, SD >12 weeks, SD<12weeks or PD according to RECIST criteria; Complete response (CR): disappearance of all lesions, Pathological lymph nodes' reduction in short axis (SA) to <10 mm; Partial response (PR): >=30% decrease in sum of longest dimensions (LD) of Target Lesions (TL) taking reference baseline sum LD; Progressive disease (PD):>=20% (>= 5 mm increase) increase sum of LD of TL taking as a reference smallest sum of LD recorded since treatment start, appearance of >=1 new lesions, unequivocal progression of existing non-TL, or appearance of >=1 new lesion; Stable disease (SD): insufficient shrinkage to qualify for PR, insufficient increase to qualify for PD taking reference smallest sum of the LD since treatment start.

  • Progression Free Survival (PFS) [ Time Frame: Baseline, thereafter every 6 weeks up to end of treatment (up to Cycle 30) ] [ Designated as safety issue: Yes ]
    PFS was defined as the time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Months) = (first event date minus randomization or the first dose date plus 1) divided by 30.44). PFS was calculated using the median, and 95% Confidence Intervals (CIs) and Progressive disease (PD):>=20% (>= 5 mm increase) increase sum of LD of TL taking as a reference smallest sum of LD recorded since treatment start, appearance of >=1 new lesions, unequivocal progression of existing non-TL, or appearance of >=1 new lesion.


Enrollment: 36
Study Start Date: July 2011
Study Completion Date: March 2014
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
PF-03446962
Drug: PF-03446962
PF 03446962 given by a 1 hour IV infusion. Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28 day observation period. Cycle 2 will start on Day 29. The dosing interval will be 14 days for Cycle 2 and subsequent cycles.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of stomach cancer
  • advanced/metastasis solid tumor refractory or intolerant to established therapy
  • adequate blood chemistry, blood counts and kidney/liver function
  • willing to participate to study requirements and sign an informed consent document

Exclusion Criteria:

  • Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of first dose of study medication
  • excessive toxicities related to prior therapies
  • pregnant or breastfeeding patients
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01337050

Locations
Japan
National Cancer Center Hospital East
Kashiwa, Chiba, Japan, 277-8577
Korea, Republic of
Seoul National University Hospital/Department of Internal Medicine
Seoul, Korea, Republic of, 110-744
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01337050     History of Changes
Other Study ID Numbers: A8471004 
Study First Received: April 6, 2011
Results First Received: July 16, 2015
Last Updated: October 6, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Hepatocellular Carcinoma
Advanced/Metastatic solid tumors

Additional relevant MeSH terms:
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 23, 2016