Clinical trial NCT00140556: Angiogenic and EGFR Blockade With Curative Chemoradiation for Advanced Head and Neck Cancer
Official title: Concurrent Angiogenic and EGFR Blockade in Conjunction With Curative Intent Chemoradiation for Locally Advanced Head and Neck Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Head and Neck Cancer
Pharynx Cancer
Keywords: head and neck cancer
targeted therapy
bevacizumab
erlotinib
Tarceva
radiotherapy
concurrent chemotherapy
pharynx cancer
tonsil cancer
hyperfractionation
angiogenesis
epidermal growth factor
vascular endothelial growth factor
magnetic resonance spectroscopy
cancer of the head and neck
upper aerodigestive tract neoplasms
pharynx neoplasms
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: OSI Pharmaceuticals
First posted: 2005-09-01
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Radiotherapy (RT) with concurrent chemotherapy represents the state of the art in curative intent treatment for locally advanced squamous carcinoma of the head and neck. Tumor hypoxia and high levels of angiogenesis (blood vessel formation) are associated with treatment failure. Preclinical models reveal that radiotherapy itself may induce tumor secretion of vascular endothelial growth factor (VEGF). Curability may consequently be reduced by multiple mechanisms. Over-expression of epidermal growth factor receptor (EGFR) also occurs commonly and increases the risk of treatment failure. The addition of EGFR blockade to RT alone increases the chance of a cure. Concurrent VEGF and EGFR blockade could be synergistic with one another and improve the effectiveness of concurrent chemoradiation for advanced head and neck cancer.

This study will add angiogenic and epidermal growth factor receptor (EGFR) blockade into an established program of curative intent concurrent chemoradiation for locally advanced head and neck cancer. The safety and effectiveness of delivering the drugs bevacizumab and Tarceva in conjunction with twice daily irradiation and concurrent cisplatin (CDDP) chemotherapy will be determined.

Detailed description: Pre Radiation Period:

* Bevacizumab (10 mg/kg) on days -14 and 0, or
* Tarceva (100 mg) daily from -14-0, or
* Bevacizumab (10 mg/kg) on days -14 and 0; Tarceva (100 mg) daily from -14-0

Chemoradiation Period:

* Radiotherapy may be delivered via conventional 2-D, conformal 3-D, or intensity modulated (IMRT) technique as is clinically indicated. Radiotherapy and CDDP doses will be delivered uniformly to all treatment cohorts:

  * RT: 1.25 Gy BID M-F with a 6 hour interfraction interval
  * Treatment break during week 4. Total dose 70 Gy/7 weeks
  * CDDP: 33 mg/m2 M-W on weeks 1 and 5 of RT with standard DUMC hydration and anti-emetic regimens
* Bevacizumab (10mg/kg): Monday of weeks 1, 3, 5, 7 of RT
* Tarceva (100 mg): Daily for weeks 1-7 of treatment, except for days receiving CDDP

Safety Assessments:

* Baseline and then weekly assessments of blood pressure and urine protein : creatinine ratios during lead in and chemoRT phases of treatment
* Baseline carotid Doppler ultrasound evaluation
* Carotid Doppler ultrasound evaluation 1 month post-chemoRT

Efficacy Assessments:

* MR Imaging/Spectroscopy to be done at baseline, end of lead-in phase, end of week 1 of chemoRT, and end of chemoRT
* Angiogenic and EGFR related cytokines. Specifically, blood samples will be obtained to assay levels of VEGF, b-FGF, IL-8, D-dimer, EGF, TGF. These samples will be obtained on the same dates as the MR studies with an additional set of samples obtained at the midpoint of the lead in phase of treatment (day -7).

Clinical Assessments:

* All patients will undergo a minimum of once weekly interval history and physical examination including fiberoptic pharyngoscopy/laryngoscopy when indicated in the Department of Radiation Oncology to monitor for side effects and response to treatment as per standard routine for the care of patients with head and neck cancer.
* Patient compliance with Tarceva administration monitored via diary MRI/MRS (Magnetic Resonance Spectroscopy) DE-MRI

Eligibility criteria: Inclusion Criteria:

* Locally advanced squamous carcinoma of the head and neck (AJCC stages II/IV, M0, and excluding T1N1 and T1N2) undergoing curative intent concurrent chemoradiation.
* Previous treatment of any sort other than a biopsy is not allowed.
* Eligible anatomic sites:

  * oral cavity
  * oropharynx
  * hypopharynx
  * supraglottic
  * glottic larynx
* KPS \> 60

Exclusion Criteria:

* Nasopharynx primary
* History of malignancy other than basal cell skin cancer.
* History of claudication, bleeding, or thromboembolic disorders. Patients receiving heparin or Coumadin therapy are ineligible.
* Primary tumor or lymph node encasement of the carotid artery
* Blood pressure of \>150/100 mmHg
* Unstable angina
* New York Heart Association (NYHA) Grade II or greater congestive heart failure
* History of myocardial infarction within 6 months
* History of stroke within 6 months
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0; anticipation of need for major surgical procedure during the course of the study.
* Minor surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to Day 0
* Pregnant (positive pregnancy test) or lactating
* Urine protein : creatinine ratio ≥ 1.0 at screening
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0
* Serious, non-healing wound, ulcer, or bone fracture
* AST, ALT, or bilirubin \> 1.5 x normal
* PT or PTT \> 1.5 x normal
* Platelets \< 100,000
* WBC \< 2000
* Hgb \< 10
* Creatinine clearance \< 60 mL/hr
* Refusal to provide written informed consent

Primary outcomes:
measure: Tumor Resolution
timeFrame: Within 30 days of completing RT
Secondary outcomes:
measure: Local Regional Control
timeFrame: 1 yr following chemoradiation
measure: Failure Free Survival
timeFrame: 3 yrs
Other outcomes:
Locations:
city: Durham
country: United States
facility: Department of Radiation Oncology; Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Department of Radiation Oncology; Duke University Medical Center
name: David M Brizel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol. 1999 Nov;53(2):113-7. doi: 10.1016/s0167-8140(99)00102-4.
citation: Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, George SL, Huang AT, Prosnitz LR. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998 Jun 18;338(25):1798-804. doi: 10.1056/NEJM199806183382503.
citation: Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):349-53. doi: 10.1016/s0360-3016(01)01630-3.
citation: Dewhirst MW, Poulson JM, Yu D, Sanders L, Lora-Michiels M, Vujaskovic Z, Jones EL, Samulski TV, Powers BE, Brizel DM, Prosnitz LR, Charles HC. Relation between pO2, 31P magnetic resonance spectroscopy parameters and treatment outcome in patients with high-grade soft tissue sarcomas treated with thermoradiotherapy. Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):480-91. doi: 10.1016/j.ijrobp.2004.06.211.
citation: Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004 May;5(5):429-41. doi: 10.1016/s1535-6108(04)00115-1.
citation: Craciunescu O, Brizel D, Cleland E, Yoo D, Muradyan N, Carroll M, Barboriak D, MacFall J. Dynamic contrast enhanced-MRI in head and neck cancer patients: variability of the precontrast longitudinal relaxation time (T10). Med Phys. 2010 Jun;37(6):2683-92. doi: 10.1118/1.3427487.
citation: Yoo DS, Kirkpatrick JP, Craciunescu O, Broadwater G, Peterson BL, Carroll MD, Clough R, MacFall JR, Hoang J, Scher RL, Esclamado RM, Dunphy FR, Ready NE, Brizel DM. Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer. Clin Cancer Res. 2012 Mar 1;18(5):1404-14. doi: 10.1158/1078-0432.CCR-11-1982. Epub 2012 Jan 17.
citation: Craciunescu OI, Yoo DS, Cleland E, Muradyan N, Carroll MD, MacFall JR, Barboriak DP, Brizel DM. Dynamic contrast-enhanced MRI in head-and-neck cancer: the impact of region of interest selection on the intra- and interpatient variability of pharmacokinetic parameters. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):e345-50. doi: 10.1016/j.ijrobp.2011.05.059. Epub 2011 Oct 8.