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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: PF-03446962

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20133
    • 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, 20141
    • Dipartimento di Medicina
  • Rozzano (MI), Italy, 20089
    • UO di Oncologia ed Ematologia, Istituto Clinico Humanitas-Humanitas Cancer Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital / Department of Internal Medicine
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, Hollings Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37212-3505
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Serum Concentration (Cmax): Part 1 and Part 2		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)
Minimum Observed Serum Trough Concentration (Cmin): Part 1 and Part 2		0 hr (pre dose), 1 hr post-dose C1D1, 0 hr,1 hr post-dose on Day 1 of subsequent cycles up to C12
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-03446962: Part 1 and Part 2		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 Curve From Time Zero to Day 28 [AUC (0-28)]: Part 1 and Part 2	AUC (0-28) = Area under the plasma concentration versus time curve from time zero (pre-dose) to Day 28 (0-28).	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 Curve From Time Zero to Last Quantifiable Concentration (AUClast): Part 1 and Part 2	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).	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)
Systemic Clearance(CL): Part 1 and Part 2	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.	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 (t1/2): Part 1 and Part 2	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.	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)
Human Anti - Human Antibody (HAHA) Concentration: Part 1 and Part 2	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).	Baseline up to 3 months after last dose
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	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.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)
Soluble Protein Biomarker [Cluster of Differentiation 106 (CD106), Cluster of Differentiation 54 (CD54), Endoglin]: Part 1 and Part 2	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.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)
Soluble Protein Biomarker [Placental Growth Factor (PLGF), Transforming Growth Beta 1 (TGFB1), Vascular Endothelial Growth Factor A (VEGF-A)]: Part 1 and Part 2	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.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)
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	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.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)
Soluble Protein Biomarker [Vascular Endothelial Growth Factor Receptor Type 2 (VEGFR2), Vascular Endothelial Growth Factor Receptor Type 3 (VEGFR3)]: Part 1 and Part 2	Plasma concentrations of soluble proteins (VEGFR2, VEGFR3) may be associated with tumor angiogenesis or tumor physiology and may correlate with efficacy or biological activity.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)
Circulating Endothelial Cells (CEC)and Circulating Endothelial Progenitors (CEP): Part 1 and Part 2	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.	Baseline (pre-dose of C1D1), C1D1 6 hours post dosing, C1D22, C2D1, C3D1 and end of treatment (Day 490)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Simonelli M, Zucali P, Santoro A, Thomas MB, de Braud FG, Borghaei H, Berlin J, Denlinger CS, Noberasco C, Rimassa L, Kim TY, English PA, Abbattista A, Gallo Stampino C, Carpentieri M, Williams JA. Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma. Ann Oncol. 2016 Sep;27(9):1782-7. doi: 10.1093/annonc/mdw240. Epub 2016 Jun 20.
• Goff LW, Cohen RB, Berlin JD, de Braud FG, Lyshchik A, Noberasco C, Bertolini F, Carpentieri M, Stampino CG, Abbattista A, Wang E, Borghaei H. A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors. Clin Cancer Res. 2016 May 1;22(9):2146-54. doi: 10.1158/1078-0432.CCR-15-1622. Epub 2015 Dec 11.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: November 12, 2007
• First Submitted That Met QC Criteria: November 12, 2007
• First Posted (Estimate): November 14, 2007

Study Record Updates

• Last Update Posted (Estimate): October 19, 2015
• Last Update Submitted That Met QC Criteria: September 27, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Solid Tumors Transforming Growth Factor Beta Activin Receptor-like Kinase 1
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: A8471001; 2007-001422-27 (EudraCT Number)