Sunitinib and Erlotinib in Treating Patients With Unresectable or Metastatic Kidney Cancer

A Dose Escalation Phase II Study of Sunitinib Plus Erlotinib in Advanced Renal Carcinoma

RATIONALE: Sunitinib and erlotinib may stop the growth of tumor cell by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving sunitinib together with erlotinib may kill more tumor cells.

PURPOSE: This phase II trial is studying the best dose of erlotinib when given together with sunitinib and to see how well they work in treating patients with unresectable or metastatic kidney cancer.

Study Overview

• Status: Completed
• Conditions: Kidney Cancer
• Intervention / Treatment: Drug: erlotinib hydrochloride; Drug: sunitinib malate; Procedure: biopsy

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of erlotinib hydrochloride when administered with sunitinib malate in patients with unresectable or metastatic renal cell carcinoma.
• Determine the 8-month progression-free survival of patients treated with this regimen.

Secondary

• Determine the safety of sunitinib malate and erlotinib hydrochloride in these patients.
• Determine the duration of response in these patients.
• Determine the proportion of patients whose best overall response is complete response, partial response, stable disease, or progressive disease.
• Determine the overall survival of patients treated with this regimen.
• Determine the maximum percent reduction in tumor measurement in patients treated with this regimen.
• Collect blood and tissue from these patients for future correlative studies.

OUTLINE: This is an open-label, multicenter, dose-escalation study of erlotinib hydrochloride.

Patients receive oral sunitinib malate once daily on days 1-28 and oral erlotinib hydrochloride once daily on days 1-42. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 33% of patients experience dose-limiting toxicity. Once the MTD is determined, patients are treated with erlotinib hydrochloride at the MTD and sunitinib malate.

Patients undergo blood and tumor specimen collection periodically during study for future correlative studies.

PROJECTED ACCRUAL: A total of 49 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Oregon
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
    • Portland, Oregon, United States, 97239-3098
      • OHSU Knight Cancer Institute
    • Salem, Oregon, United States, 97301
      • Salem Hospital

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

DISEASE CHARACTERISTICS:

• Histologically confirmed renal cell carcinoma with a component of clear cell or papillary carcinoma

  • Unresectable or metastatic disease (radiologically or clinically confirmed)
• Measurable disease (≥ 1 site)
• No known brain metastasis that has not been adequately treated with radiotherapy and/or surgery

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• No grade 3 hemorrhage within the past 4 weeks
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN (< 5 times ULN if due to underlying disease)
• No chronic liver disease (i.e., chronic active hepatitis or cirrhosis)
• Creatinine ≤ 1.5 times ULN

• None of the following cardiovascular conditions within the past 12 months:

  • Myocardial infarction
  • Severe/unstable angina
  • Coronary/peripheral artery bypass graft
  • Symptomatic congestive heart failure
  • Cerebrovascular accident or transient ischemic attack
  • Pulmonary embolism
  • Ongoing cardiac dysrhythmia ≥ grade 2
  • Atrial fibrillation of any grade
  • Prolongation of the corrected QT (QTc) interval to > 450 msec for males or to > 470 msec for females
• Left Ventricular Ejection Fraction (LVEF) normal by Multigated Acquisition (MUGA) or echocardiogram
• No hypertension uncontrolled with medical therapy
• No other active malignancy within the past 5 years except basal cell skin cancer or cervical carcinoma in situ
• No uncontrolled adrenal insufficiency
• No uncontrolled hypothyroidism
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection)
• No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs
• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 4 weeks since prior major surgery
• More than 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• More than 4 weeks since prior radiotherapy
• No prior radiotherapy to > 25% of the bone marrow
• More than 28 days since prior investigational agents
• No prior sunitinib malate
• No prior anti-epidermal growth factor receptor therapy (e.g., erlotinib hydrochloride, panitumumab, cetuximab, or gefitinib)

• No concurrent therapeutic warfarin

  • Low-dose oral warfarin ≤ 2 mg daily for deep vein thrombosis prophylaxis is allowed after the maximum tolerated dose of erlotinib hydrochloride is determined
• No concurrent Hypericum perforatum (St. John's wort)
• No concurrent chemotherapy or biologic therapy
• No other concurrent anticancer therapy
• No other concurrent investigational agents

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: Erlotinib and Sunitinib; Drug: erlotinib hydrochloride Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily; 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily;; 150 mg/day, continuous daily Drug: sunitinib malate Will be administered at 50 mg daily, 4 weeks on, 2 weeks off

Drug: erlotinib hydrochloride; Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily; 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily;; 150 mg/day, continuous daily; Drug: sunitinib malate; Will be administered at 50 mg daily, 4 weeks on, 2 weeks off; Procedure: biopsy; Paraffin block (or unstained slides) of the primary tumor and/or metastatic lesions (as available) and a plasma sample for future correlative studies will be collected. A paraffin block (or at least 10 unstained slides, each of 10 micromillimeter thickness) from the original paraffin-embedded biopsy material taken at the diagnosis will be stored at 4 degrees Celsius.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib.	The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of the patients.	Participants assessed for DLTs weekly during the first cycle of treatment and every 3 weeks in subsequent cycles until at least one DLT occurs in 33% or more of participants at that dose; participants assessed for the duration of the study, up to 7 years
Progression-free Survival at 8 Months	Defined as the proportion of patients who are progression free (CR, PR and SD) at 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney. Complete Response (CR)= disappearance of all target lesions, Partial Response (PR)= At least a 30% decrease in the sum of the longest diameter of target lesions, and Stable Disease (SD)= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (20% increase in the sum).	8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Determine the Safety of Sunitinib in Combination With Erlotinib		For the duration of the study, up to 7 years
Median Time to Progression	The Kaplan-Meier method will be used to estimate the median time to progression.	For the duration of the study, up to 7 years
Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease		From the start of treatment until the criteria for response is met.
Maximum Percent Change in Tumor Measurement	The maximum percent change in Tumor Measurement is the greatest percent change in longest diameter (LD) for the target lesions from the baseline LD. For patients with no change in LD, the maximum percent change is the lowest increase in LD from the baseline LD.	Baseline through end of study, up to 7 years

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Christopher W. Ryan, MD, OHSU Knight Cancer Institute

Publications and helpful links

General Publications

• Ryan CW, Curti BD, Pattee KJ, et al.: A dose-escalation phase II study of sunitinib (S) plus erlotinib (E) in advanced renal carcinoma (RCC). [Abstract] American Society of Clinical Oncology 2008 Genitourinary Cancers Symposium, Feb 14-16, 2008, San Francisco, CA. A-361, 2008.
• Feng Z, Curti BD, Quinn DI, Strother JM, Chen Z, Agnor R, Beer TM, Ryan CW. A Phase II, Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma. Clin Genitourin Cancer. 2022 Oct;20(5):415-422. doi: 10.1016/j.clgc.2022.04.018. Epub 2022 May 5.

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: January 19, 2007
• First Submitted That Met QC Criteria: January 19, 2007
• First Posted (Estimate): January 23, 2007

Study Record Updates

• Last Update Posted (Actual): May 3, 2017
• Last Update Submitted That Met QC Criteria: May 1, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: stage IV renal cell cancer; recurrent renal cell cancer; stage III 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Sunitinib
• Other Study ID Numbers: CDR0000526204; P30CA069533 (U.S. NIH Grant/Contract); OHSU-2683 (Other Identifier: Oregon Health & Science University IRB); OHSU-SOL-06051-LM (Other Identifier: OHSU Knight Cancer Institute)