Dalteparin and Sunitinib Malate as First-Line Therapy in Treating Patients With Kidney Cancer That is Metastatic or Cannot Be Removed by Surgery

Phase I Study of Dalteparin, A Low Molecular Weight Heparin (LMWH), in Combination With Sunitinib (SU11248), an Oral, Selective Multi-targeted Tyrosine Kinase Inhibitor, as First Line Treatment, in Patients With Metastatic Renal Cell Carcinoma

This phase I trial studies the side effects and best dose of dalteparin when given together with sunitinib malate in treating patients with kidney cancer that has spread to other parts of the body or cannot be removed by surgery. Anticoagulants, such as dalteparin, help prevent blood clots and have been shown to increase survival in patients with cancer. Anticoagulants may also prevent the formation of new blood vessels. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by inhibiting new blood vessels and blocking blood flow to the tumor. Giving dalteparin together with sunitinib malate may starve tumors and kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Renal Cell Carcinoma; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer; Clear Cell Sarcoma of the Kidney
• Intervention / Treatment: Other: Pharmacological Study; Drug: Sunitinib Malate; Drug: Dalteparin

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the recommended dosing for the combination of sunitinib (sunitinib malate) and dalteparin in patients with metastatic renal cell carcinoma.

II. To evaluate safety and tolerability for the combination of sunitinib and dalteparin in patients with metastatic renal cell carcinoma.

III. To determine early signs of clinical activity of the combination of sunitinib and dalteparin in patients with metastatic renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To determine the clinical response rate of sunitinib and dalteparin in patients with metastatic renal cell carcinoma.

II. To determine time-to-progression (TTP) and overall survival amongst patients with metastatic renal cell carcinoma receiving sunitinib and dalteparin.

III. To determine the effect of sunitinib alone and dalteparin alone compared to the combination of dalteparin plus sunitinib on plasma coagulation parameters.

IV. To determine the effect of sunitinib alone and dalteparin alone compared to the combination of dalteparin plus sunitinib on angiogenesis parameters in blood.

OUTLINE: This is a dose-escalation study of dalteparin.

Patients receive sunitinib malate orally (PO) once daily (QD) in weeks 1-4 and dalteparin subcutaneously (SC) QD in week 6 during course 1. In all subsequent courses, patients receive sunitinib malate PO QD in weeks 1-4 and dalteparin SC QD in weeks 1-6. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 3 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • Amsterdam, Netherlands, 1007 MB
    • Academ Zienkenhuis Bij De University
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

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 must have histologically confirmed renal cell carcinoma that is metastatic or unresectable
• Renal carcinoma patients with predominant clear-cell histology are eligible; papillary renal cell carcinoma, oncocytoma, collecting duct tumors and transitional cell carcinoma are NOT eligible
• No prior systemic treatments for metastatic disease are permitted, including antiangiogenic therapy, immunotherapy, chemotherapy and investigational therapy
• Prior palliative radiation to metastatic lesion(s) is permitted, provided there is at least one measurable and/or evaluable lesion(s) that has not been irradiated
• Radiation therapy must be completed > 4 weeks prior to registration
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as >= 20 mm with conventional techniques or as approximately >= 10 mm with spiral computed tomography (CT) scan (Response Evaluation Criteria in Solid Tumors [RECIST] 1.0 criteria)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Leukocytes > 3,000/mm^3
• Absolute neutrophil count > 1,500/mm^3
• Platelets > 100,000/mm^3
• Total bilirubin < 1.5 x laboratory upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x laboratory ULN
• Creatinine < 1.5 x laboratory ULN
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5
• Urine protein < 1+; if > 1+, 24 hour urine protein should be obtained and should be < 1000 mg
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
• Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Except for Dalteparin that will be administered as a study drug, the patients should not take any other anticoagulants or antiplatelet agents during the study, including but not limited to nonsteroidal anti-inflammatory drugs (NSAID) (any dose of aspirin), warfarin or other anticoagulants

Exclusion Criteria:

• Patients may not be receiving any other investigational agents
• Patients with known central nervous system (CNS) metastases; patients should have a head CT/magnetic resonance imaging (MRI) within 4 weeks prior to treatment initiation; any imaging abnormality indicative of CNS metastases will exclude the patient from the study
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not eligible; patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy and are considered by their physician to be at less than 30% risk of relapse
• Patients with a large (> 2 cm) pulmonary lesion involving the trachea or one of the main bronchus and any endobronchial lesion
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dalteparin
• Evidence of bleeding diathesis within last 6 months
• Serious or non-healing wound, ulcer or bone fracture or active peptic ulceration
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last 6 months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within 6 months (thrombotic or hemorrhagic), hypertension (defined as blood pressure of > 160 mmHg systolic and/or > 90 mm Hg diastolic on medication), hemorrhagic retinopathy, history of peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with an ejection fraction < 50% by multi gated acquisition scan (MUGA) scan are not eligible
• Pregnant women are excluded from this study
• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to day 1 therapy

• Invasive procedures defined as:

  • Major surgical procedure, open biopsy, or significant traumatic injury within 6 weeks prior to day 1 therapy
  • Anticipation of need for major surgical procedures during the course of the study
  • Core biopsy within 7 days prior to start therapy

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: Treatment (sunitinib malate, dalteparin); Patients receive sunitinib malate PO QD in weeks 1-4 and dalteparin SC QD in week 6 during course 1. In all subsequent courses, patients receive sunitinib malate PO QD in weeks 1-4 and dalteparin SC QD in weeks 1-6. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.	Other: Pharmacological Study; Correlative studies; Drug: Sunitinib Malate; Given PO; Other Names: Sutent; SU011248; SU11248; sunitinib; Drug: Dalteparin; Given SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early signs of clinical activity of the combination of sunitinib malate and dalteparin		Up to 4 years
Incidence of toxicities for the combination of dalteparin and sunitinib malate	Toxicities will be summarized by tabulation. Summaries will be made across all types of toxicities and by grade and type.	Up to 4 weeks after last treatment
Recommended dosing for the combination of dalteparin and sunitinib malate	The maximally tolerated dose (MTD) will be the highest dose at which < 33% of patients (=< 2 out of 6 patients) suffer from dose limiting toxicities (DLTs) related to the combination treatment.	Up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response rate of dalteparin and sunitinib malate, determined as the proportion of treated patients who had partial or complete response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0		Up to 4 weeks after last treatment
Overall survival	Described in all patients using Kaplan-Meier curves.	Up to 4 years
TTP	Described in all patients using Kaplan-Meier curves.	Up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in angiogenesis parameters in blood	Each will be explored to determine if transformations (e.g. log or square-root) are necessary to achieve normality. For each of baseline and changes, exploratory plots (e.g. histograms, boxplots) will be created and means will be estimated along with 95% confidence intervals. Wilcoxon signed-rank tests will be used to determine whether or not the data shows evidence of changes from baseline.	Baseline to 4 weeks after last treatment
Changes in plasma coagulation parameters	Each will be explored to determine if transformations (e.g. log or square-root) are necessary to achieve normality. For each of baseline and changes, exploratory plots (e.g. histograms, boxplots) will be created and means will be estimated along with 95% confidence intervals. Wilcoxon signed-rank tests will be used to determine whether or not the data shows evidence of changes from baseline.	Baseline to 4 weeks after last treatment

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: Pfizer

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2010
• Primary Completion (Actual): October 14, 2015
• Study Completion (Actual): April 21, 2017

Study Registration Dates

• First Submitted: February 1, 2010
• First Submitted That Met QC Criteria: February 1, 2010
• First Posted (Estimate): February 3, 2010

Study Record Updates

• Last Update Posted (Actual): August 5, 2022
• Last Update Submitted That Met QC Criteria: August 3, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Neoplasms, Connective Tissue; Sarcoma; Carcinoma, Renal Cell; Carcinoma; Sarcoma, Clear Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Anticoagulants; Sunitinib; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: I 145508 (Other Identifier: Roswell Park Cancer Institute); NCI-2009-01694 (Registry Identifier: CTRP (Clinical Trial Reporting Program))