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A Phase II Study of Induction Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, Cisplatin, Cetuximab and Bevacizumab (XPE-A) in Patients With Locally Advanced Head and Neck Cancer (CTRC# 11-36)

Phase 2
18 Years
Open (Enrolling)
Carcinoma, Squamous Cell of Head and Neck

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Trial Information

A Phase II Study of Induction Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, Cisplatin, Cetuximab and Bevacizumab (XPE-A) in Patients With Locally Advanced Head and Neck Cancer (CTRC# 11-36)

Locally advanced squamous cell carcinoma of the head and neck (SCCHN) is treated with
various combinations of radiation and chemotherapy. Docetaxel and cisplatin have been
combined in Phase II trials in recurrent or metastatic head and neck cancer with very
encouraging results. Induction therapy with docetaxel/cisplatin followed by
chemoradiotherapy was investigated in a randomized Phase II study in nasopharyngeal cancer
and showed superior PFS and OS in comparison with chemoradiation alone. Cetuximab is a
chimerized EGFR monoclonal antibody that has produced positive results in Phase III trials
in combination with either radiation for locally advanced disease or chemotherapy for
metastatic disease. Upregulation of vascular endothelial growth factor (VEGF) has been
associated with cetuximab resistance. Bevacizumab, an anti-VEGF antibody is currently being
investigated in SCCHN with promising results. The investigators have previously shown that
cisplatin, docetaxel and cetuximab (TPE) followed by radiotherapy, cisplatin and cetuximab
(XPE) is feasible and highly efficacious in locally advanced SCCHN (Argiris, A. et al.JCO
2011). In this Phase II study the investigators evaluate the addition of bevacizumab to
induction therapy with TPE (TPE-A) and to subsequent XPE (XPE-A).

Specific aims:

To evaluate the rate of complete responses with induction therapy (primary endpoint) and
progression-free survival, overall survival and objective response rates. Also, the
investigators plan to investigate a panel of EGFR and angiogenesis biomarkers in pre- and
post- treatment tumor biopsies. Finally, the investigators will evaluate the associated
treatment toxicities and the quality of life.

Subject population:

The investigators will enroll patients with previously untreated locally advanced SCCHN (see
detailed eligibility criteria).

Treatment plan:

Induction therapy consists of 3 cycles of bevacizumab 15mg/kg on day 1, cetuximab weekly
days 1,8,15 (loading dose of cetuximab 400mg/m2 on cycle 1, day 1, then 250 mg/m2 on all
subsequent administrations), cisplatin 75mg/m2 on day 1, docetaxel 75mg/m2 on day 1,
repeated every 21 days. After 3 cycles of induction therapy, patients will receive standard
radiation 70-74 Gy/ 200 cGy/ daily, 5 days/ week with concurrent weekly cisplatin 30mg/m2,
cetuximab 250mg/m2 and bevacizumab 15mg/kg every 3 weeks x 3. There is optional surgery for
non-responders in the primary (stable disease) after TPE-A.

Statistical design and sample size:

Phase II, two-stage study with complete response rate after induction therapy as the primary
endpoint. The sample size is 33 patients.

Inclusion Criteria:

- Patients with AJCC 6th edition stage III-IVB head and neck cancer, all sites,
including unknown primary tumors.

- Prior to entry in the study the resectability and alternative treatment options for
each patient will be determined by a team composed of an Ear, Nose, and Throat
Surgeon, a Radiation Oncologist and a Medical Oncologist. Stage determination,
optimal local treatment, and its timing according to this protocol will be determined
at this evaluation. The unequivocal demonstration of distant metastasis (M1) confers

- Histologically or cytologically confirmed diagnosis of squamous cell or poorly
differentiated carcinomas, or WHO types I-III of the nasopharynx.

- Unidimensionally measurable disease is required (RECIST 1.1).

- No prior chemotherapy, biologic/molecular targeted therapy (including any prior
therapy which specifically and directly targets the EGFR pathway), or radiotherapy
for head and neck cancer.

- Prior surgical therapy will consist only of incisional or excisional biopsy, and
organ sparing procedures such as debulking of airway compromising tumors or neck
dissection in a patient with an existing primary tumor. Any non-biopsy procedure must
have taken place > 4 weeks but < 3 months of initiating protocol treatment.

- ECOG performance status 0-1.

- Age 18 years or older.

- Informed consent must be obtained from all patients prior to beginning therapy.
Patients should have the ability to understand and the willingness to sign a written
informed consent document.

- All patients should have their tumor tissue tested for HPV (in situ hybridization
and/or p16 staining by immunohistochemistry), and results must be known prior to
study entry, and will consent to have available archival tumor samples, unstained
slides or blocks from previous diagnostic or therapeutic procedures submitted for
correlative studies, including assessment of target molecules EGFR, VEGF and related
biomarkers. Also, patients must agree to submit blood samples for correlative studies
at least at baseline.

- Absolute neutrophil count at or above 1500/µl, Platelet count at or above 100,000/µl

- Creatinine clearance 60 ml/min or higher calculated using the Cockcroft-Gault

Calculated Creatinine Clearance = (140-age) X actual body wt (kg) 72 X serum creatinine
Multiply this number by 0.85 if the patient is female

- Total bilirubin within normal limits and AST/ALT less than 3 times the upper limit of

- Urine dipstick must be < 0-1+ within 2 weeks (14 days) of randomization. If urine
dipstick result is > 1+, a calculation of Urine Protein Creatinine (UPC) ratio is
required. Patients must have a UPC ratio < 1.0 to participate in the study.

NOTE: UPC ratio of spot urine is an estimation of the 24-urine protein excretion - a UPC
ratio of 1 is roughly equivalent to a 24-hour urine protein of 1gm. UPC ratio is
calculated using one of the following formula:

- [urine protein]/[urine creatinine] - if both protein and creatinine are reported in

- [(urine protein) × 0.088]/[urine creatinine] - if urine creatinine is reported in

- Patients with a prior history of squamous cell or basal carcinoma of the skin or
in situ cervical cancer must have been curatively treated. Patients with a
history of other prior malignancy must have been treated with curative intent
and must have remained disease-free for 3 years post diagnosis.

- Patients may not be receiving any other investigational agents.

Exclusion Criteria:

- History of severe allergic reactions attributed to docetaxel or compounds of similar
chemical or biologic composition to docetaxel, or other drugs formulated with
polysorbate 80.

- Prior severe infusion reaction to a monoclonal antibody or known hypersensitivity to
any component of bevacizumab

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.

- All patients will have a baseline EKG. If abnormalities consistent with active
coronary artery disease are detected, the patient will be referred to a cardiologist
for appropriate evaluation and management prior to treatment on study

- No patients with significant baseline sensory or motor neurologic deficits (> grade I
neuropathy) will be treated on this study.

- Because patients with immune deficiency are at increased risk of lethal Infections
when treated with marrow-suppressive therapy, HIV-positive patients are excluded from
the study. Appropriate studies will be undertaken in patients with HIV and those
receiving combination anti- retroviral therapies when indicated.

- Patients with HPV positive tumors (P16+ by immunohistochemistry and/or HPV+ by in
situ hybridization) AND smoking history =<10 pack-years

- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
and/or diastolic blood pressure >100 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 12 months prior to Day 1

- No history of stroke or transient ischemic attack within 6 months prior to Day 1

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1

- History of hemoptysis (> or = to 1/2 teaspoon of bright red blood per episode) within
1 month prior to Day 1

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Patients should not be on therapeutic anticoagulation therapy (prophylactic use of
warfarin 1mg per day is allowed) and INR should be <1.5 at registration

- The use of anti-platelet agents (e.g. dipyridamole (Persatine), ticlopidine (Ticlid),
clopidogrel (Plavix)) is allowed only if patient is not receiving aspirin or NSAID's
known to inhibit platelet function.

- Major surgical procedure (including neck dissection), open biopsy, or significant
traumatic injury within 28 days prior to Day 1 or anticipation of need for major
surgical procedure during the course of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Pregnant or breast-feeding women will be excluded.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

Evaluate the rate of complete responses with induction therapy - Change in baseline regarding treatment/tumor response after 3 cycles of chemotherapy (3months); After 8 weeks of chemo + radiation; 1 year up to 10 years. This outcome will be measured with regards to number of participants via RECIST criteria.

Outcome Time Frame:

1-10 years

Safety Issue:


Principal Investigator

Athanassios Argiris, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Texas Health Science Center at San Antonio


United States: Institutional Review Board

Study ID:

CTRC 11-36



Start Date:

December 2011

Completion Date:

March 2022

Related Keywords:

  • Carcinoma, Squamous Cell of Head and Neck
  • Locally advanced head and neck cancer
  • Squamous cell carcinoma of the head and neck
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



Cancer Therapy and Research Center at UTHSCSA San Antonio, Texas  78229