Trial of PTK787/ZK 222584 Plus Paclitaxel

Phase I Study of the Oral Vascular Endothelial Growth Factor Inhibitor PTK787/ZK 222584 in Combination With Paclitaxel in Patients With Advanced Solid Tumors.

PTK787/ZK 222584 is an inhibitor of VEGFR family tyrosine kinases. The primary objective of this study is to assess the safety of daily oral PTK787/ZK 222584 in combination with paclitaxel infused every 21 days. Secondary objectives include pharmacokinetic assessment of the impact of PTK787/ZK 222584 on paclitaxel metabolism and evaluation of tumor response to the investigational treatment.

Study Overview

• Status: Terminated
• Conditions: Metastatic Non-hematologic Malignancies
• Intervention / Treatment: Drug: PTK787/ZK 222584; Drug: paclitaxel

Detailed Description

• We are looking for the highest dose of Paclitaxel that can be given safely in combination with the highest safe dose of Vatalanib. Therefore, not all people will receive the same dose of the study drug.
• Small groups of people will be enrolled in steps on this trial. This first group will be given a certain dose of Paclitaxel and Vatalanib. If they have few or manageable side effects, the next small group of people enrolled will receive higher doses of the study drugs. This increase in doses will continue until the study doctors find the highest dose of the drugs that can be given without causing severe or unmanageable side effects.
• In this study, Vatalanib tablets are taken daily, and paclitaxel is given by three-hour intravenous infusion once every 21 days.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical 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:

• Patients with advanced solid tumors for whom there is no potentially curative treatment (surgery, radiation therapy or chemotherapy).
• Measurable or non-measurable disease
• Age ≥ 18 years old
• ECOG Performance Status 0 -1
• Laboratory values ≤ 14 days weeks prior to starting study treatment:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (≥ 1500/mm3)
• Platelets (PLT) ≥ 100 x 109/L (≥ 100,000/mm3)
• Hemoglobin (Hgb) ≥ 9 g/dL
• Serum creatinine ≤ 1.5 ULN
• Serum bilirubin ≤ 1.0 x ULN
• Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x ULN (≤ CTC grade 1).
• Negative for proteinuria based on dip stick reading OR, if documentation of +1 result for protein on dip stick reading, then total urinary protein ≤ 500 mg and measured creatinine clearance (CrCl) ≥ 50 mL/min from a 24-hour urine collection
• Women of child-bearing age must have a negative serum or urine test.
• Life expectancy ≥ 12 weeks
• Written informed consent obtained
• Resolution of toxicity from previous chemotherapy to ≤ Grade I.
• QTc interval ≤ 0.45 seconds (men) or ≤ 0.47 seconds (women).

Exclusion Criteria:

• Previous hypersensitivity reaction to taxanes or cremophor.
• History or presence of central nervous system (CNS) disease (i.e., primary brain tumor, malignant seizures, CNS metastases or carcinomatous meningitis).
• Prior chemotherapy ≤ 4 weeks prior to registration. Prior nitrosoureas or mitomycin C ≤ 6 weeks prior to registration.
• Prior biologic or immunotherapy ≤ 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities
• Prior radiotherapy ≤ 4 weeks prior to registration. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease
• Major surgery (i.e., laparotomy) ≤ 4 weeks prior to registration. Minor surgery ≤ 2 weeks prior to registration. Insertion of a vascular access device is not considered major or minor surgery in this regard. Patients must have recovered from all surgery-related toxicities
• Patients who have received investigational drugs ≤ 4 weeks prior to registration.
• Peripheral neuropathy with functional impairment ≥ CTC grade 2 neuropathy, regardless of causality.
• Pleural effusion or ascites that causes respiratory compromise (≥ CTC grade 2 dyspnea)
• Female patients who are pregnant or breast-feeding, or adults of reproductive potential who are not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Please refer to appendix for a list of examples of substrates of human liver microsomal P450 enzymes
• Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
• Uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen
• Unstable angina pectoris
• Symptomatic congestive heart failure
• Myocardial infarction ≤ 6 months prior to registration and/or randomization
• Serious uncontrolled cardiac arrhythmia
• Uncontrolled diabetes
• Active or uncontrolled infection
• Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
• Acute or chronic liver disease (eg., hepatitis, cirrhosis)
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PTK787/ZK 222584 (i.e., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow the tablets)
• Patients with confirmed diagnosis of human immunodeficiency virus (HIV) infection are excluded at the investigator's discretion if he/she feels that 1) a potential drug interaction between PTK787/ZK 222584, paclitaxel and any of the patient's anti-HIV medications could influence the efficacy of the anti-HIV medication, or 2) it may place the patient at risk due to the pharmacologic activity of PTK787/ZK 222584. Please refer to appendix for a list of examples of substrates of human liver microsomal P450 enzymes
• Patients who are taking therapeutic warfarin sodium (Coumadin) or similar oral anticoagulants that are metabolized by the cytochrome P450 system. Heparin products are allowed. Please refer to appendix for a list of examples of substrates of human liver microsomal P450 enzymes
• Patients unwilling to or unable to comply with the protocol
• Use of recombinant G-CSF products (Neupogen, Neulasta) within three weeks of registration. Chronic use of recombinant erythropoietin is permitted.

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: PTK787/ZK 222584	Drug: PTK787/ZK 222584; Taken in tablet form daily; Other Names: Vatalanib; Drug: paclitaxel; Given as a 3-hour infusion once every 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety of PTK787/ZK 222584 in combination with paclitaxel	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic effect of PTK787/ZK 222584 on paclitaxel metabolism. Clinical tumor response to study treatment.	2 years

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Massachusetts General Hospital; Beth Israel Deaconess Medical Center; Novartis Pharmaceuticals; Brigham and Women's Hospital
• Investigators: Principal Investigator: Pankaj Bhargava, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2006
• Primary Completion (Actual): May 29, 2008
• Study Completion (Actual): May 29, 2008

Study Registration Dates

• First Submitted: July 28, 2006
• First Submitted That Met QC Criteria: July 28, 2006
• First Posted (Estimate): July 31, 2006

Study Record Updates

• Last Update Posted (Actual): April 29, 2022
• Last Update Submitted That Met QC Criteria: April 25, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: pharmacokinetics; angiogenesis; taxane; Taxol; tyrosine kinase; Vatalanib
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Protein Kinase Inhibitors; Paclitaxel; Vatalanib
• Other Study ID Numbers: 05-046