Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

A Phase I, and Biologic Correlative Study of Erlotinib, in Combination With Cetuximab and Bevacizumab in Patients With Metastatic Renal Cell Carcinoma

This randomized phase I/II trial studies the side effects, best way to give, and best dose of erlotinib and bevacizumab when given with cetuximab and how well giving erlotinib and cetuximab together with or without bevacizumab works in treating patients with metastatic or unresectable kidney, colorectal, head and neck, pancreatic, or non-small cell lung cancer. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving erlotinib together with cetuximab and/or bevacizumab may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage III Colon Cancer; Stage III Rectal Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Untreated Metastatic Squamous Neck Cancer With Occult Primary; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: bevacizumab; Biological: cetuximab; Drug: erlotinib hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of erlotinib when combined with cetuximab in patients with metastatic or unresectable renal cell, colorectal, head and neck, pancreatic, or non-small cell lung cancer (part 1).

II. Determine the MTD of bevacizumab when combined with cetuximab and erlotinib in these patients (part 2).

III. Determine the toxic effects, both quantitatively and qualitatively, of these regimens in these patients.

IV. Determine the antitumor activity of these regimens, in terms of tumor response, short-term survival, and progression-free survival, in these patients.

SECONDARY OBJECTIVES:

I. Compare, preliminarily, the toxicity and antitumor activity profiles of these regimens in these patients.

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

Part 1: Patients receive oral erlotinib once daily on days 1-28. Patients also receive cetuximab IV over 3 hours on day 1 and over 1 hour on days 8, 15, and 22.

Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Part 2: Patients receive erlotinib as in part 1 at the MTD and cetuximab as in part 1. Patients also receive bevacizumab IV over 1½ hours on day 1 and over 1 hour on day 15.

Cohorts of 3-6 patients receive escalating doses of bevacizumab until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

In both groups, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

After completion of study treatment, patients are followed at 1 month.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center at The UT Health Science Center at San Antonio

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:

• One of the following histologically confirmed diagnoses:

  • Renal cell cancer

    • Clear cell histology

    • Metastatic or unresectable disease AND meets 1 of the following criteria:

      • Recurrent disease
      • Refractory to interleukin-2 (IL-2)- or interferon-based therapy
      • Previously untreated AND not a candidate for IL-2-based therapy

  • Colorectal, head and neck, pancreatic, or non-small cell lung cancer

    • Metastatic or unresectable disease
    • Progression after prior standard treatment

• No evidence of CNS disease, including the following (part 2 only):

  • Primary brain tumor
  • Brain metastases
• Paraffin embedded tumor blocks available
• Performance status - ECOG 0-2
• Performance status - Karnofsky 60-100%
• More than 12 weeks
• Absolute neutrophil count ≥ 1,500 mm^3
• Platelet count ≥ 100,000 mm^3
• Bilirubin ≤ 1.5 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastasis is present)
• PTT and INR ≤ 1.5, unless receiving full-dose warfarin (part 2 only)
• Creatinine ≤ 1.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• Calcium < 10 mg/dL (hypocalcemic agents allowed)
• No proteinuria*
• Protein < 1 g on 24-hour urine collection*
• No unstable angina pectoris
• No cardiac arrhythmia
• No symptomatic congestive heart failure

• None of the following are allowed for part 2:

  • Myocardial infarction within the past 6 months
  • New York Heart Association class II-IV heart disease
  • Serious cardiac arrhythmia requiring medication
  • Peripheral vascular disease ≥ grade II
  • Recent history of cerebrovascular accident
  • Uncontrolled hypertension (blood pressure ≥ 150/85 mm Hg despite medication)
  • Other clinically significant cardiovascular disease
• No gastrointestinal (GI) tract disease resulting in an inability to take oral medication
• No GI tract disease resulting in a requirement for IV alimentation
• No active peptic ulcer disease
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (part 2 only)
• No ongoing or active infection
• No active infection requiring parenteral antibiotics (part 2 only)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after study treatment
• No significant traumatic injury within the past 28 days (part 2 only)
• No history of abnormalities of the cornea (e.g., dry eye syndrome, Sjögren's syndrome, or congenital abnormality [e.g., Fuch's dystrophy])
• No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the breast or cervix
• No psychiatric illness or social situation that would preclude study compliance
• No serious or non-healing wound ulcer or bone fracture (part 2 only)
• No other uncontrolled illness
• See Disease Characteristics
• More than 4 weeks since prior immunotherapy
• No prior cetuximab
• No prior bevacizumab
• Concurrent epoetin alfa or darbepoetin alfa allowed
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• More than 4 weeks since prior radiotherapy
• No prior surgical procedures affecting absorption
• Prior nephrectomy or resection of metastatic lesions allowed provided patient has fully recovered
• More than 7 days since prior core biopsy*
• More than 28 days since prior major surgery or open biopsy*
• No concurrent major surgery*
• Recovered from all prior therapy
• No prior erlotinib
• Concurrent bisphosphonates allowed

• Concurrent full-dose anticoagulants allowed provided the following criteria are met (part 2 only):

  • In-range INR (usually between 2 and 3) AND on a stable dose of warfarin or low molecular weight heparin
  • No active bleeding
  • No pathological conditions that carry a high risk of bleeding (e.g., tumor involving major vessels or varices)
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (erlotinib hydrochloride, cetuximab, bevacizumab); Part 1: Patients receive oral erlotinib once daily on days 1-28. Patients also receive cetuximab IV over 3 hours on day 1 and over 1 hour on days 8, 15, and 22. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Part 2: Patients receive erlotinib as in part 1 at the MTD and cetuximab as in part 1. Patients also receive bevacizumab IV over 1½ hours on day 1 and over 1 hour on day 15. Cohorts of 3-6 patients receive escalating doses of bevacizumab until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. In both groups, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Other: laboratory biomarker analysis; Correlative studies; Biological: bevacizumab; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF; Biological: cetuximab; Given IV; Other Names: C225; IMC-C225; C225 monoclonal antibody; MOAB C225; monoclonal antibody C225; Drug: erlotinib hydrochloride; Given orally; Other Names: OSI-774; erlotinib; CP-358,774

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of erlotinib hydrochloride combined with cetuximab determined by dose-limiting toxicities (DLT) graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3 (Part I)	The occurrence and maximal grade of toxicity for the whole duration of treatment will be listed and tabulated by type.	28 days
MTD of bevacizumab combined with cetuximab and erlotinib hydrochloride determined by DLT graded according to the CTCAE version 3 (Part II)	The occurrence and maximal grade of toxicity for the whole duration of treatment will be listed and tabulated by type.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumor activity defined as the number and extent (complete or partial) objective responses as well as objective stable disease as measured by RECIST criteria	The estimated rate and their 95% confidence interval, will be reported.	6 months
Median time to progression		Up to 1 month
Progression-free survival		From the start of the treatment until the date the criteria for progression are met or the date the patient is taken off study for any reason, assessed up to 1 month

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alain Mita, Cancer Therapy and Research Center at The UT Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (ACTUAL): October 1, 2007
• Study Completion (ACTUAL): May 1, 2008

Study Registration Dates

• First Submitted: January 7, 2005
• First Submitted That Met QC Criteria: January 7, 2005
• First Posted (ESTIMATE): January 10, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): June 11, 2014
• Last Update Submitted That Met QC Criteria: June 10, 2014
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Mouth Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Paranasal Sinus Diseases; Nose Diseases; Colorectal Neoplasms; Cranial Nerve Diseases; Pancreatic Diseases; Neoplasm Metastasis; Neuroectodermal Tumors, Primitive; Neoplasms, Squamous Cell; Neoplasms, Cystic, Mucinous, and Serous; Nasopharyngeal Neoplasms; Neoplasms, Basal Cell; Neuroectodermal Tumors, Primitive, Peripheral; Salivary Gland Diseases; Mouth Neoplasms; Olfactory Nerve Diseases; Nose Neoplasms; Neuroblastoma; Carcinoma, Renal Cell; Head and Neck Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Nasopharyngeal Carcinoma; Recurrence; Rectal Neoplasms; Carcinoma, Adenoid Cystic; Pancreatic Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Granuloma; Colonic Neoplasms; Neoplasms, Unknown Primary; Oropharyngeal Neoplasms; Salivary Gland Neoplasms; Esthesioneuroblastoma, Olfactory; Carcinoma, Basal Cell; Papilloma; Laryngeal Neoplasms; Laryngeal Diseases; Carcinoma, Verrucous; Carcinoma, Mucoepidermoid; Mucoepidermoid Tumor; Paranasal Sinus Neoplasms; Papilloma, Inverted; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Erlotinib Hydrochloride; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: NCI-2012-02639 (REGISTRY: CTRP (Clinical Trial Reporting Program)); P30CA054174 (U.S. NIH Grant/Contract); U01CA069853 (U.S. NIH Grant/Contract); CDR0000401514; NCI-6588; CTRC-IDD-0332 (OTHER: Cancer Therapy and Research Center at The UT Health Science Center at San Antonio); 6588 (OTHER: CTEP)