Tinzaparin in Treating Patients With Metastatic Kidney Cancer That Cannot Be Removed By Surgery

A Phase I/II Trial of Tinzaparin (Innohep), a Low Molecular Weight Heparin (LMWH) for Treatment of Advanced Renal Cell Carcinoma

RATIONALE: Tinzaparin may stop the growth of kidney cancer by blocking blood flow to the tumor.

PURPOSE: This phase I/II trial is studying the side effects of tinzaparin and to see how well it works in treating patients with metastatic kidney cancer that cannot be removed by surgery.

Study Overview

• Status: Unknown
• Conditions: Kidney Cancer
• Intervention / Treatment: Drug: tinzaparin sodium

Detailed Description

OBJECTIVES:

Primary

• Determine the effect of tinzaparin sodium on fibrin formation (prothrombin fragment F1.2), thrombin generation (thrombin-antithrombin complexes), and fibrinolysis (D-Dimer) from baseline to 2 weeks and at nadir or disease progression in patients with unresectable metastatic renal cell carcinoma (RCC).

Secondary

• Determine the effect of tinzaparin sodium treatment on circulating angiogenesis markers, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
• Determine the proportion of patients developing venous thromboembolism and hemorrhage.
• Determine the tolerability of tinzaparin sodium treatment for up to 6 months in these patients.
• Establish the feasibility of undertaking a multicenter renal cell carcinoma trial with specialized coagulation test collection, shipping, and processing.
• Obtain more accurate and specific mean, median, and variability in biomarker data in advanced RCC patients treated with tinzaparin sodium for purposes of planning larger future trials.
• Estimate the progression-free survival at 4 months in patients treated with tinzaparin sodium.
• Correlate progression-free survival with changes in markers of coagulation activation or angiogenesis.
• Correlate the anticoagulant activity of tinzaparin sodium (anti-Xa activity) with change in coagulation markers, angiogenesis markers, and progression-free survival.

OUTLINE: This is an open-label, pilot, multicenter study.

Patients receive a treatment dose of tinzaparin sodium subcutaneously (SC) once daily for 14 days followed by a prophylactic dose of tinzaparin sodium SC once daily for up to 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05405-0110
      • Vermont Cancer Center at University of Vermont

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed renal cell carcinoma of clear cell histology

  • Tumors of mixed histology eligible if ≥ 50% of tumor has clear cell histology
  • No nonclear cell histologies, collecting duct tumors, oncocytomas, or transitional cell tumors

• Metastatic and unresectable disease that is clinically extending beyond the regional lymph nodes (histological confirmation not required)

  • Patients who are inoperable for their primary tumor representing the sole site of disease are ineligible
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 2 cm by conventional techniques OR ≥ 1 cm by spiral CT scan
• No known brain metastases

PATIENT CHARACTERISTICS:

• Expected survival > 2 months
• CALGB (ECOG/ZUBROD) performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Hemoglobin ≥ 10 g/dL
• Platelet count ≥ 100,000/mm^3
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN
• INR ≤ 1.5 times control value
• PTT < 1.5 times control value
• Negative pregnancy test
• Fertile patients must use effective contraception
• Patients must be able to receive subcutaneous injections at home
• No other primary malignancy in the past 5 years other than basal cell carcinoma or carcinoma in situ of the cervix that has been curatively treated and is associated with a less than 30% risk of relapse in the next 5 years
• No signs or symptoms of bleeding within 4 the past weeks
• No known bleeding diathesis or high risk for bleeding due to any condition, including trauma within the past 4 weeks, active current bleeding, or hemorrhagic stroke or intraocular bleeding within the past 6 months
• No active thromboembolism highly likely to require anticoagulation during the study period
• No known or suspected history of type II heparin-induced thrombocytopenia
• No allergy or hypersensitivity to heparin, tinzaparin sodium, pork products, sulfite, or benzyl alcohol
• No uncontrolled severe intercurrent illness, including ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• No uncontrolled arterial hypertension, history of gastrointestinal ulceration, and/or bleeding in the past 4 weeks
• No diabetic retinopathy or history of retinal hemorrhage
• Not pregnant or nursing
• HIV-positive patients are allowed

PRIOR CONCURRENT THERAPY:

• No treatment with anticoagulation lasting > 1 month in the past 6 months
• No anticoagulation, including treatment with a low molecular weight heparin, at any time within the past month
• More than 4 weeks since prior surgery, radiation therapy, immunotherapy, or chemotherapy
• Recovered from prior therapy
• No other concurrent investigational agents

• No other concurrent anticoagulation therapy, including oral anticoagulants, thrombolytic agents, or any form of heparin

  • Concurrent antiplatelet agents allowed
• No spinal or epidural puncture, anesthesia, or post-operative indwelling epidural catheters within the past 48 hours
• No other concurrent anticancer agents or therapies
• No concurrent sex hormones except for postmenopausal hormone replacement
• No concurrent chemotherapy or immunotherapy
• No concurrent palliative radiotherapy
• Concurrent urgent use of corticosteroids allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Blood markers or coagulation as measured by plasma prothrombin F1.2, thrombin-antithrombin complexes, and D-dimers at 2 weeks, 2 months and 6 months

Secondary Outcome Measures

Outcome Measure
Blood markers of angiogenesis as measured by serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) at 2 weeks, 2 months, and 6 months
Venous thromboembolism as measured by clinical evaluation at 6 months
Progression free survival as measured by clinical evaluation at 4 months

Collaborators and Investigators

• Sponsor: University of Vermont
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Deborah L. Ornstein, MD, Yale University

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Anticipated): February 1, 2007

Study Registration Dates

• First Submitted: February 16, 2006
• First Submitted That Met QC Criteria: February 16, 2006
• First Posted (Estimate): February 17, 2006

Study Record Updates

• Last Update Posted (Estimate): November 6, 2013
• Last Update Submitted That Met QC Criteria: November 5, 2013
• Last Verified: February 1, 2007

More Information

Terms related to this study

• Keywords: stage IV renal cell cancer; recurrent renal cell cancer; clear cell renal cell carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: CDR0000459794; VCC-0403; VCC-05-040