Trial Information

Phase II Organ Preservation Trial Using Cisplatin Concomitant With Radiation Therapy in Advanced Laryngeal Cancer Patients Who Have Responded to Induction Chemotherapy With Taxotere, Cisplatin, and 5-Fluorouracil (TPF)

The optimal treatment of patients with laryngeal cancer remains controversial. Standard
treatment options have included laryngectomy with or without radiation (RT) and radiation
alone with surgical salvage (RTSS).

Because of the significant functional morbidity associated with laryngectomy, the Department
of Veterans Affair Cooperative Studies Program completed a randomized, prospective study of
332 patients that compared a new organ preservation treatment strategy to conventional
laryngectomy and radiation. The experimental treatment arm involved three cycles of
neoadjuvant chemotherapy followed by definitive radiation among patients who had a partial
(>50%) clinical tumor response. Final results of this study demonstrated comparable 2, 3, 4,
and 10 year survival rates between treatment groups, with successful laryngeal preservation
in 66% of the surviving patients randomized to receive neoadjuvant chemotherapy.

This study led to a dramatic re-assessment of the treatment approach for advanced laryngeal
and hypopharyngeal cancer patients, who face total laryngectomy. Based on these results,
Second approach was designed and tested in a Phase II study at the University of Michigan
.In this study, 97 patients were treated with one cycle of induction chemotherapy.
Seventy-five percent had a >50% reduction of tumor and were treated with chemo-RT (cisplatin
100 mg/m2 x 3 cycles), and 25% were non-responders who underwent total laryngectomy followed
by RT. The overall 3-year survival rate was 85%,and the larynx preservation rate was 70%.
This study included over 30 percentage of patients with advanced stage 4 disease, however
did not specifically evaluate there outcome and therefore did not directly address the role
of organ preservation in advanced disease which is considered a controversial issue in head
and neck literature.

In this study all patients (25 %) who did not respond to the initial chemotherapy were
referred to total laryngectomy and therefore there were 30 %of patients who eventually
underwent total laryngectomy.Lately several series suggest the option of partial
laryngectomy as an alternative to total laryngectomy as initial treatment for advanced
larynx cancer ,in cases in which the cricoids cartilage and arytenoids are not
involved.Supracricoid subtotal laryngectomy spares at least one arytenoid and offers organ
preservation and can also be performed according to many articles as salvage surgery in
cases of radiation failure,and therefore if performed in the right indications can improve
the percentage of total laryngectomy free patients without compromising survival. This will
reflect of course on quality of life It has been suggested lately that the use of aggressive
induction chemotherapy may improve outcome. The combination of Taxotere with Cisplatin and
5-fluorouracil has been shown to be more effective than the standard cisplatin and
5-fluorouracil without an elevation in side effects .It has been suggested that the three
cycles of induction chemotherapy may lower the rate of distant metastases which is high in
advanced disease

Objectives

Primary

To determine the laryngeal preservation rate in a treatment paradigm that uses clinical
response to a single cycle of induction chemotherapy to select patients for either
concurrent cisplatin-radiation or surgery(if possible organ preserving partial
laryngectomy) as compared to historical controls To determine the survival rate among T4
laryngeal patients in a treatment paradigm that uses clinical response to a single cycle of
induction chemotherapy to select patients to either ,two more cycles of induction followed
by concurrent cisplatin-radiation or surgery .

Secondary To determine the survival rate in a treatment paradigm that uses clinical
response to a single cycle of induction chemotherapy to select patients for either
concurrent cisplatin-radiation or surgery including organ preserving partial laryngectomy
(if possible) as compared to historical controls.

To determine if the use of three cycles of induction chemotherapy lowers the rate of distant
metastases in advanced cases; namely: positive nodal disease and T4.

To evaluate the quality of life (QOL) of this treatment paradigm.

To evaluate partial supracricoid laryngectomy as salvage to chemoradiation failure.

compare PET scan results with the pathological specimen of the larynx.

To determine correlation between changes in biological markers such as EGFR degradation
EGFR mutation, p53 overexpression, Bcl-XL, Bcl-2 expression, and HPV observed in tumor
biopsies taken shortly after the administration of TPF, compared with pre-treatment
biopsies. And compared to those found in the completion of treatment in cases of
failures.

Study Design

Chemotherapy/Radiation/Surgery schedule Days #1-4: Patients will undergo induction
chemotherapy with (TPF) docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 on day 1, and
5-FU CI 750mg /m2 /24 hours days 1-4. See section 7.2.

Day #22: Patients will undergo a direct laryngoscopy with biopsy the biopsy will be done
with in 3 days. Patients will also undergo a repeat CT scan of the neck within a week (+/-)
of their perspective biopsies.

Patient with a < 50% response (NR) to induction chemotherapy will undergo salvage
supracricoid partial laryngectomy if possible or laryngectomy followed by RT. Cisplatin
will be added to radiation for patients whose surgical pathology reveals high-risk features
(i.e. extracapsular spread, > 2 positive lymph nodes, perineural invasion, or positive
margins). Cisplatin will be dosed 35 mg/m2 weekly at the discretion of the prescribing
physician. See section 7.2 for prescribing details for cisplatin.

Responding patients with > 50% response will be divided to two groups those with N2 disease
or stage T4 will undergo two more cycles with induction TPF others will directly undergo
treatment with RT (Total dose 70 Gy) in combination with cisplatin weekly (35mg/m2 ).Those
who receive two more chemotherapy courses will be assessed clinically and by CT scan if no
PD will continue to chemo and RT ,those with PD will undergo surgery Eight weeks following
the completion of RT, patients will undergo a repeat direct laryngoscopy and a PET scan. The
primary tumor site will be biopsied. Neck nodes that are persistent, clinically suspicious
nodes, including PET positive nodes, will be biopsied. Patients with positive laryngeal
biopsies following chemoradiation will undergo salvage surgery if possible supracricoid
partial laryngectomy, otherwise laryngectomy. If the laryngeal biopsy is negative but
clinically positive neck lymph nodes remain, patients will undergo neck nodal dissection.

Once patients are disease-free following chemoradiation and nodal neck dissections (if
needed), patients will be followed every 6 weeks in the first year, followed by every 3
months in the second, every 6 month between 2 and 5 years. Patients whose physical
examination or whose imaging studies are concerning for recurrent disease will undergo
biopsy. If positive, they will undergo salvage laryngectomy.

Chemotherapy with Cisplatin, Docetaxel, and 5-Fluorouracil (TPF)

Docetaxel (Taxotere): Docetaxel 75 mg/m2 administered as an i.v. infusion over one hour on
day #1.

With Docetaxel administration, all patients will receive dexamethasone 8 mg PO BID for 3
consecutive days, starting 1 day before docetaxel administration, or 10-20 mg IV on Day 1
prior to treatment with Docetaxel.

Cisplatin: Cisplatin 100 mg/m2, administered as an i.v. infusion will run over one hour on
day #1 following docetaxel.

An aggressive antiemetic regimen is required before the administration of cisplatin,
consisting of a serotonin antagonist, APREPITANT and a steroid.

5-Fluorouracil: 5-Fluorouracil 750 mg/m2 in 0.9% normal saline as a 24-hour continuous
infusion, day's #1-4. The infusion will start after cisplatin administration.

Evaluation of Response to Treatment

Careful evaluation of tumor extent will be separately recorded for the primary tumor and
regional nodes at specified intervals. These will be based on laryngoscopies performed
pre-treatment, day 21 after start of induction chemotherapy, and 8 weeks after completion of
chemoradiation. Standardized response criteria will be used. CT scans will be used at the
discretion of the clinician to supplement clinical exams.

7.4.2 Biopsy of any persistent neck nodes is required if at the 8 week post -radiation
evaluation is either clinical or radiologically positive. . Patients whose PET shows a CR
at 8 weeks post will undergo clinical observation.

Diagnostic CT scans and/or PET scans will be obtained prior to scheduled endoscopies for
tumor assessment. Post treatment a ct will be performed.

Outpatient clinical examinations will be performed at the completion of radiation therapy,
at 6 week intervals during year 1 of follow-up,every 3 months during year 2 of follow-up,
and 6-monthly during year 3 of follow-up. 8 Translational Studies

Tissue samples obtained at the time of laryngeal biopsies will be sent to laboratories
for analysis of histologic growth pattern, p53 overexpression, Bcl-XL, Bcl-2 expression, HPV
, EGFR expression, phosphorylated EGFR and stem cells levels . The tissue will be obtained
during routine biopsies prior to the beginning of treatment, after completion of induction
chemotherapy and after Radiation .the following techniques will be used:
Immunohistochemistry, PCR and Western blot.

10 Response Assessment Criteria:

The patient's tumor will be tattooed by the surgeon,who will then measure the product of the
longest primary tumor dimension and its perpendicular; following chemotherapy, the extent of
the tumor will be measured for response. Treatment decisions (i.e. surgery vs Chemo+RT) are
based on response of the tumor at the primary site.

Tumor responses to chemotherapy or chemoradiation will be determined clinically by the
surgeon performing the DL.

Radiologic imaging studies will be used in conjunction with the physical examination in
determining tumor response to chemotherapy or chemoradiation.

Clinical PR: Significant (>50%) reduction in the product of the longest primary tumor
dimension and its perpendicular compared to pre-treatment clinical (endoscopic) measurements
or imaging study as necessary.

Non-Responders (< PR): A 50% or less reduction in the product of the longest primary tumor
dimension and its perpendicular compared to pre-treatment clinical (endoscopic) measurement
or imaging study as necessary.

Criteria for Discontinuation of Treatment

1. Unacceptable adverse event(s).

2. Intercurrent illness, which prevents further administration of treatment.

3. Patient preference.

4. Progressive disease.

5. Life threatening or other unacceptable drug-related toxicity.

6. General or specific changes in the patient's condition that render the patient
unacceptable for further treatment in the judgment of the investigators.

Radiation Therapy

13.1. General Considerations: All the patients in this study will receive either definitive
radiotherapy or post operative irradiation. For those patients found to have a PR to
induction therapy on repeat DL, definitive radiotherapy with Cisplatin will begin. Post
operative radiation should begin as soon as adequate healing has been established. Usually,
this will be within three to four weeks of the surgical procedure but must begin by six
weeks.

13.2 Radiation Fields: The treatment volumes will be individual as for each patient
depending upon the extent of disease. Tumor volumes will be outlined on the planning CT
scans with the aid of pre-chemotherapy CT and, if available, PET scans, to ensure adequate
irradiation of the pre-chemotherapy tumor volume. Treatment techniques will aim at adequate
irradiation of the clinical and the sub-clinical disease. The therapy goals, specifying the
intended doses to the primary tumor and lymph node metastases, and the intended doses to
each lymph node level treated adjuvantly, will be detailed in the therapy chart. A CT-based
display of the isodoses will be recorded, such that it will be feasible to assess whether
the intended (prescribed) isodoses cover the targets adequately.

Doses:

Radiation with chemotherapy: Tumor doses will be expressed in Gy. The prescribed doses
should encompass the targets. Treatment plans will be generated demonstrating adequate
coverage of the target volume. The dose across the target volume should not vary by more
than +/- 10% of the prescribed dose.The treatment will be given either using IMRT planning
or 3D. Treatment will be given once daily, five days per week, two Gy per fraction to gross
disease, and 1.6-2.0 Gy per fraction to subclinical disease. Total gross dose will be 70 Gy
and subclinical disease dose will be 50-60 Gy.

Post Operative Radiation Therapy: The patient will be treated with conventional
fractionation, 1.8-2.0 Gy per fraction, and five fractions per week in a continuous course.
The dose to the tumor bed and lymph nodes will be 56-64 Gy, depending of the existence of
extranodal extension or the existence of close surgical margins. Patients with gross
residual disease or positive resection margins will receive total 66-70 Gy to the sites of
residual disease.

Salvage Surgery

The extent of salvage surgery for either the primary tumor or regional nodes is dictated by
the extent of the disease .

Salvage surgery may be required at the times of scheduled tumor assessments or any time
tumor progression or recurrence is demonstrated by adequate biopsies of areas clinically
suspicious for tumor involvement.

Primary site: Extent of surgery will vary between total laryngectomy and supracricoid
subtotal laryngectomy in accordance with the inclusion and exclusion criteria specified).

Neck: Bilateral selective neck dissections will be performed in conjunction with salvage
total laryngectomy for any patient initially staged N0 in the neck. Ipsilateral modified
radical or radical neck dissection is required for any patient initially staged N+ who
recurs or persists with cancer in that neck. At 8 weeks post radiation, neck dissection
alone without laryngectomy is required for any patient with initial staging neck node > 3 cm
in size who is PET positive or with biopsy proven palpable neck disease. 14.5

Informed Consent

All patients with stage III and IV squamous cell carcinoma of the larynx who are candidates
for surgical resection will be screened for participation in this study.

.

Reporting Potentially Serious Adverse Events

Definitions

An adverse event is any new, undesirable medical experience or Change of an existing
condition which occurs during or after treatment, whether or not considered product-related.

A serious adverse event is any untoward medical occurrence that

Suggests significant hazard or side effect that:

1. Results in death.

2. Is life-threatening (places the patient at immediate risk of death).

3. requires or prolongs inpatient hospitalization Is disabling or incapacitating.