Sorafenib, Gemcitabine, and Capecitabine in Treating Patients With Unresectable and/or Metastatic Kidney Cancer

A Phase I/II Trial of BAY 43-9006 Plus Gemcitabine and Capecitabine in the Treatment of Patients With Advanced Renal Cell Carcinoma

This phase I/II trial is studying the side effects and best dose of sorafenib, gemcitabine, and capecitabine and to see how well they work in treating patients with unresectable and/or metastatic kidney cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with gemcitabine and capecitabine may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7
• Intervention / Treatment: Drug: Gemcitabine Hydrochloride; Drug: Capecitabine; Drug: Sorafenib Tosylate

Detailed Description

OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of sorafenib administered in combination with gemictabine and capecitabine in patients with advanced renal cell carcinoma.

II. Determine the objective response rate for sorafenib in combination with gemictabine and capecitabine in patients with advanced renal cell carcinoma.

III. Determine the duration of overall survival and progression free survival in these patients.

OUTLINE: This is a multicenter, non-randomized, phase I dose-escalation study followed by a phase II study.

PHASE I: Patients receive sorafenib* orally (PO) twice daily (BID) on days 1-21, gemcitabine intravenously (IV) over 30 minutes on days 1 and 8, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for at least 3 courses in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of sorafenib, gemcitabine, and capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

Note: *Patients who complete at least 3 courses of treatment with objective response or stable disease but are deemed poor candidates for continued chemotherapy may continue treatment with sorafenib

PHASE II: Patients receive sorafenib 200mg orally twice a day on days 1-21, gemcitabine 750 mg/m2 intravenously on days 1 & 8, and capecitabine 415 mg/m2 orally twice a day on days 1-14 of each 21 day cycle, as in phase I at the MTD determined in phase I.

After completion of study treatment patients are followed periodically.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • New York, New York, United States, 10065
      • Weill Medical College of Cornell University
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone

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 or cytologically confirmed renal cell carcinoma that is unresectable and/or metastatic; patients with collecting duct carcinoma, oncocytomas, or transitional cell carcinoma are not eligible; patients with sarcomatoid renal cell carcinoma are eligible, but those with pure sarcomas are not; histologic documentation of metastatic disease is not required; clinical confirmation, but not pathologic staging, of metastatic disease is required
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
• Patients may have received one prior immunotherapy based regimen (i.e. interleukin-2 or interferon alpha) ending >= 4 weeks prior to enrollment
• Patients may have received up to 2 prior regimens containing mitogen-activated protein kinases (MAPK), vascular endothelial growth factor (VEGF) pathway inhibitors (e.g. sunitinib or bevacizumab) and/or mammalian target of rapamycin (mTOR) inhibitor (e.g. temsirolimus) ending >= 4 weeks prior to enrollment
• Life expectancy of more than 3 months
• Eastern Cooperative Oncology Group (ECOG) =< 2 OR Karnofsky >= 60%
• Leukocytes >= 3000/uL
• Absolute neutrophil count >= 1,500/uL
• Platelet count >= 100,000/uL
• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x IULN
• Creatinine =< 1.5 x IULN OR creatinine clearance >= 60 mL/min/1.73m^2 for patients with creatinine levels above institutional normal
• The effects of sorafenib on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because raf kinase inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men 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

Exclusion Criteria:

• Patients may not have received prior chemotherapy; if patients have had prior definitive or other surgery, prior radiation therapy, they must have fully recovered from the effects of therapy with at least 4 weeks recovery time; for patients who have had a surgical biopsy only, they must have simply recovered
• Patients may not be receiving any other investigational agents
• Patients with known active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; previously treated brain metastases are allowed if they show no evidence of progression on CT or magnetic resonance imaging (MRI) at least 8 weeks after completion of surgery and/or radiotherapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib, gemcitabine and capecitabine
• No concurrent megestrol is permitted; no megestrol therapy within 4 weeks prior to protocol treatment is allowed; no concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, phenobarbitol or carbamazepine), rifampin, or St. John's wort
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary disease including asthma, chronic bronchitis, emphysema with requirements for chronic oxygen use or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because sorafenib is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with sorafenib, breastfeeding should be discontinued if the mother is treated with sorafenib; the potential risks may apply to other agents used in this study
• Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with sorafenib, gemcitabine, or capecitabine administered during the study; appropriate studies will be undertaken in patients receiving combination ant-retroviral therapy when indicated
• Any swallowing dysfunction leading to difficulty taking the investigational therapy or capecitabine
• Prior treatment with sorafenib
• Patients with any history or evidence of a bleeding diathesis
• Patients on therapeutic anticoagulation with coumarins (e.g. warfarin); prophylactic coumarin-based anticoagulation (i.e. low dose warfarin) for venous or arterial access devices is allowed provided that the requirements for prothrombin time (PT), international normalization ratio (INR) and/or partial thromboplastin time (PTT) are met; prophylactic or therapeutic low molecular weight heparin is allowed; patients with known brain metastases are excluded (even if treated and stable) if they are also on therapeutic doses of anticoagulation
• Patients with known dihydropyrimidine dehydrogenase deficiency

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: Sorafenib + Gemcitabine + Capecitabine; Patients receive sorafenib* PO BID on days 1-21, gemcitabine IV over 30 minutes on days 1 and 8, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for at least 3 courses in the absence of unacceptable toxicity or disease progression.	Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; LY-188011; LY188011; Drug: Capecitabine; Given PO; Other Names: Xeloda; Ro 09-1978/000; Drug: Sorafenib Tosylate; Given PO; Other Names: BAY 54-9085; Nexavar; BAY 43-9006 Tosylate; sorafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response for BAY 43-9006 in Combination With Gemcitabine and Capecitabine Evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST)	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR	Up to 9 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Number of Months of Progression Free Survival (PFS)	PFS will be measured from the time of the patient's initial best response (PR or CR) until documented progression.	From the time of the patient's initial best response (PR or CR) until documented progression, assessed up to 9 years
Number of Participants Who Survived (Overall Survival)	Overall survival (OS) is defined as the time from start of treatment to death from any cause.	Up to 9 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Scott Tagawa, Montefiore Medical Center - Moses Campus

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2005
• Primary Completion (Actual): March 14, 2017
• Study Completion (Actual): March 14, 2017

Study Registration Dates

• First Submitted: July 19, 2005
• First Submitted That Met QC Criteria: July 19, 2005
• First Posted (Estimate): July 21, 2005

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: March 17, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Sorafenib; Capecitabine
• Other Study ID Numbers: NCI-2009-00108 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA013330 (U.S. NIH Grant/Contract); N01CM62204 (U.S. NIH Grant/Contract); CDR0000434851; 0501007709 (Other Identifier: Montefiore Medical Center - Moses Campus); 6981 (Other Identifier: CTEP)