A Safety, Tolerability, And Pharmacokinetic Trial With CVX-241 In Patients With Advanced Solid Tumors

This study has been terminated.
(See termination reason in detailed description.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01004822
First received: October 28, 2009
Last updated: June 4, 2015
Last verified: June 2015
  Purpose

The purpose of this study is to determine if CVX-241 (PF-05057459) is safe and tolerable when given as weekly infusions to adult patients with advanced solid tumors.


Condition Intervention Phase
Advanced Solid Tumors
Drug: CVX-241
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Open-label, Dose-escalation, Safety, Pharmacokinetic, And Pharmacodynamic Study Of Cvx-241, A Selective Angiopoietin-2 And Vascular Endothelial Growth Factor Binding, Anti-angiogenic Covx-body, In Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: Stage 1: Baseline up to Day 28 (end of cycle 1) ] [ Designated as safety issue: Yes ]
    MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT). DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

  • Recommended Phase 2 Dose (RP2D) [ Time Frame: Stage 1: Baseline up to Day 28 (end of cycle 1) ] [ Designated as safety issue: Yes ]
    RP2D was the highest dose where 0 of 3 or less than (<2) out of 6 participants experience a DLT. DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).


Secondary Outcome Measures:
  • Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Stage 1: Baseline up to Week 4 ] [ Designated as safety issue: Yes ]
    DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last dose of study medication (last dose = up to Cycle 39) ] [ 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. 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 are 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. AEs included SAEs and non-SAEs that occurred during the study.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] [ Time Frame: Pre-dose, 1, 2, 4, 6 hours post dose at Day 1 of cycle 1 ] [ Designated as safety issue: No ]
    AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞)u for unbound drug. It is obtained from AUC (0 - t)u plus AUC (t - ∞)u for unbound drug. Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 22 of cycle 1 ] [ Designated as safety issue: No ]
    Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

  • Minimum Observed Plasma Trough Concentration (Cmin) [ Time Frame: Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 22 of cycle 1 ] [ Designated as safety issue: No ]
  • Systemic Clearance (CL) [ Time Frame: Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 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. Due to premature termination of the study, only certain exposure-related noncompartmental PK parameters were calculated.

  • Plasma Decay Half-Life (t1/2) [ Time Frame: Pre-dose, 1, 2, 4, 6 hours post dose at Day 1 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. Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

  • Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentrations [ Time Frame: Cycle 1/Day 1, Cycle 1/Day 5, Cycle 1/Day 8, Cycle 1/Day 15, Cycle 1/Day 22, Cycle 2/Day 1 ] [ Designated as safety issue: No ]
    VEGF family consists of five glycoproteins known as VEGF-A, -B, -C, and -D, and placental growth factor (PlGF), which bind to three structurally similar receptor tyrosine kinases VEGFR1, VEGFR2, and VEGFR3. The different ligands have distinctive binding specificities for each of the receptors. In response to ligand binding, the VEGFRs activate distinct downstream signalling pathways. VEGFR2 is expressed in the vasculature and is the key mediator of VEGF-induced angiogenesis.

  • Change From Baseline in Serum Angiopoietin-2 (Ang2) Concentrations [ Time Frame: Cycle 1/Day 1, Cycle 1/Day 5, Cycle 1/Day 8, Cycle 1/Day 15, Cycle 1/Day 22, Cycle 2/Day 1 ] [ Designated as safety issue: No ]
    Angiopoietin-2 (Ang2) and a related protein, angiopoietin-1 (Ang1) are ligands of the endothelial cell receptor Tie-2, a receptor tyrosine kinase, and are known to mediate the angiogenesis process together with VEGF and other angiogenic regulators. Ang1 stimulates the phosporylation of Tie-2, recruits pericytes to newly formed blood vessels, and promotes their maturation. Ang2 competes with Ang1 for binding of Tie-2, promotes the dissociation of pericytes, and results in unstable blood vessels. In the presence of VEGF and other angiogenic factors, endothelial cells in these unstable vessels proliferate and migrate to form new blood vessels.

  • Number of Anti Drug Antibody Samples With Positive Anti-CVX-241 Antibodies [ Time Frame: Day 1 pre-dose of each cycle up to last dose of study medication (last dose = up to Cycle 39) ] [ Designated as safety issue: No ]
    Results were summarized for overall study population as per planned analysis.

  • Objective Response Rate - Percentage of Participants With Objective Response [ Time Frame: Every 8 weeks from start of treatment until last dose of study medication (last dose = up to Cycle 39) ] [ Designated as safety issue: No ]
    Percentage of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short aixs was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease was defined as not qualifying for CR, PR, and Progressive Disease.

  • Participants WithTumor Response of CA-125 Epithelial Ovarian Cancer (EOC)/ Primary Peritoneal Cancer (PPC) [ Time Frame: Stage 2 every cycle ] [ Designated as safety issue: No ]
    Participants with epithelial ovarian cancer or primary peritoneal cancer having CA-125 levels greater than 2x the upper limit of normal, 2 weeks prior to starting therapy were evaluated for CA-125 response and response is defined as a 50% decrease in CA-125 from a pre-treatment sample. The response was confirmed and maintained for at least 28 days. CA-125 response was calculated as intervening samples and the 28-day confirmatory sample must be less than or equal to (within assay variability of 10%) the previous sample Progression or recurrence based on serum CA-125 is defined according to the participants baseline levels.

  • Participants With Reduction in Tumor Vascular Permeability: Blood Flow and Blood Volume as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) [ Time Frame: Stage 2 predose up to end of study ] [ Designated as safety issue: No ]
    DCE-MRI is a non-invasive method that provides a functional assessment of microvasculature. The technique can measure changes in vascular permeability, extracellular, and extravascular and vascular volumes. Based on its ability to detect vascular changes, DCE-MRI has recently been evaluated as a biomarker of drug efficacy in clinical trials of angiogenesis inhibitors. Assessment of DCE-MRI started at the 3.0 mg/kg dose cohort.


Enrollment: 31
Study Start Date: March 2010
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Active Drug
Weekly infusions of CVX-241 at specified doses
Drug: CVX-241
0.3 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
1 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
3 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
6 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
12 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
15 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
18 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459
Drug: CVX-241
25 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.
Other Name: PF-05057459

Detailed Description:

The study was prematurely discontinued on 14 September 2011 due to no significant pharmacological effects (safety/PD/efficacy) through 25 mg/kg cohort, the T1/2 based on VEGF binding was shorter than expected and the current and/or higher doses were not considered feasible for further development. There were no safety concerns associated with the decision to terminate the program/study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed solid tumors unresponsive to current therapy or for which there is no standard therapy.
  • Stage 2 only: Histologically or cytologically documented EOC or PPC with < or equal to 3 previous anti-cancer therapies, but at least 1 prior platinum containing regimen.
  • Adequate coagulation, liver, and renal function.
  • Candidate for Dynamic Contrast-Enhanced Magnetic Resonance Imaging [DCE-MRI] evaluation
  • Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1

Exclusion Criteria:

  • History of clinically significant toxicity to Vascular Endothelial Growth Factor [VEGF] inhibition.
  • Evidence of bleeding problems.
  • Uncontrolled hypertension.
  • Patients with primary brain cancer and/or non-small cell lung cancer of squamous cell histology
  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: NCT01004822

Locations
United States, Arizona
Premiere Oncology of Arizona
Scottsdale, Arizona, United States, 85258
United States, California
Premiere Oncology, A Medical Corporation
Santa Monica,, California, United States, 90404
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01004822     History of Changes
Other Study ID Numbers: B1561001, CVX-241-101
Study First Received: October 28, 2009
Results First Received: May 11, 2015
Last Updated: June 4, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Treatment Non-Randomized Single Group Assignment Safety Study Neoplasms Carcinoma Cancer Malignancy

ClinicalTrials.gov processed this record on July 01, 2015