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Phase II Trial of Combined Modality Combretastatin A-4 Phosphate (CA4P)-Based Therapy for Patients With Newly Diagnosed Anaplastic Thyroid Cancer [Induction Chemotherapy With Doxorubicin/Cisplatin; Combined Modality Therapy With CA4P and Radiation; Followed by 2 Cycles of CA4P Consolidation]


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Head and Neck Cancer

Thank you

Trial Information

Phase II Trial of Combined Modality Combretastatin A-4 Phosphate (CA4P)-Based Therapy for Patients With Newly Diagnosed Anaplastic Thyroid Cancer [Induction Chemotherapy With Doxorubicin/Cisplatin; Combined Modality Therapy With CA4P and Radiation; Followed by 2 Cycles of CA4P Consolidation]


OBJECTIVES:

Primary

- Determine the objective response rate in patients with newly diagnosed regionally
advanced anaplastic thyroid cancer treated with induction chemotherapy comprising
doxorubicin and cisplatin followed by combretastatin A4 phosphate (CA4P) and
radiotherapy.

- Determine whether this regimen alters the natural history of anaplastic thyroid cancer
by virtue of doubling the median survival of these patients from 10 to 20 months.

Secondary

- Determine a tolerable dose of CA4P when administered with radiotherapy in these
patients. (Phase I portion of the study closed as of 5/6/04; patients now receive a
fixed dose of CA4P)

- Determine the safety profile of this regimen in these patients.

- Determine clinical predictors of response (e.g., pretreatment tumor microvessel density
and immature vessel staining, changes in sICAM-1 levels and tumor blood flow, and
pharmacokinetic parameters) in patients treated with this regimen.

- Correlate the diminution in blood flow with tumor pain and response in patients treated
with this regimen.

OUTLINE: This is a multicenter study of combretastatin A4 phosphate (CA4P). (Phase I portion
of the study closed as of 5/6/04; patients now receive a fixed dose of CA4P)

- Induction phase: Patients receive doxorubicin IV over 5-10 minutes and cisplatin IV
over 30-60 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously
(SC) on days 3-21 or pegfilgrastim SC on day 2.

- Combined modality phase: Beginning on day 22, patients undergo radiotherapy twice
daily, 5 days a week, for 3-4 weeks. Patients also receive CA4P IV over 10 minutes
weekly on the fifth day of radiotherapy.

Cohorts of 6 patients receive 1 of 2 escalating doses of CA4P to determine a tolerable dose.
The tolerable dose is defined as the dose at which less than 2 of 6 patients experience
dose-limiting toxicity. (Phase I portion of the study closed as of 5/6/04; patients now
receive a fixed dose of CA4P)

- Consolidation phase: Beginning 4-6 weeks after the completion of the combined modality
phase, patients receive CA4P IV over 10 minutes on days 1, 8, and 15. Treatment repeats
every 28 days for 2 courses.

Treatment in all phases continues in the absence of disease progression or unacceptable
toxicity.

Patients are followed every 2 months for 1 year and then every 3 months for 2 years from
study entry.

PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study within 18 months.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed anaplastic or poorly differentiated variant thyroid
carcinoma of either of the following:

- Regionally advanced disease

- Confined to the neck and/or superior mediastinum (i.e., above the level of
the carina)

- Measurable or evaluable* disease

- Completely resected disease without measurable or evaluable disease NOTE: *At a
minimum, abnormalities on physical exam or radiographic studies that may not be
precisely measured but readily followed

- Must have original/diagnostic tumor blocks available to confirm histopathology and
for tumor microvessel density immunohistochemistry

- Patients with no available original/diagnostic tumor blocks must have tumor
accessible for pretreatment needle core biopsy

- Must undergo indirect and direct laryngoscopy to ensure patency of the trachea/airway
if deemed inoperable, with bulky thyroid/neck masses and/or suspicion of airway
obstruction

- No distant metastases, including but not limited to, brain metastases, disease below
the level of the carina, pulmonary parenchyma, and hepatic or bony metastases

- Superior mediastinal disease (i.e., above the level of the carina) in addition
to regional neck disease is allowed provided the disease can be contained in a
single radiotherapy port

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- At least 12 weeks

Hematopoietic

- Absolute granulocyte count ≥ 1,500/mm^3

- Platelet count ≥ 75,000/mm^3

- Hemoglobin ≥ 8.5 g/dL

Hepatic

- Bilirubin ≤ 1.5 mg/dL

- ALT and AST ≤ 3.5 times upper limit of normal

Renal

- Creatinine ≤ 1.5 mg/dL

Cardiovascular

- LVEF ≥ 50% by echocardiogram

- EKG normal

- No prior angina

- No prior myocardial infarction (e.g., significant Q waves), QTc > 450 msec, or other
clinically significant abnormalities on ECG

- No congestive heart failure

- No uncontrolled atrial arrhythmias or clinically significant arrhythmias, including
any of the following:

- Conduction abnormality

- Nodal junctional arrhythmias and dysrhythmias

- Sinus bradycardia or tachycardia

- Supraventricular arrhythmias

- Atrial fibrillation or flutter

- Syncope or vasovagal episodes

- No significant heart wall abnormality or heart muscle damage by echocardiogram

- No uncontrolled hypertension (i.e., blood pressure consistently greater than 150/100
mm Hg irrespective of medication)

- Hypertension is allowed provided there is clinical documentation of controlled
blood pressure for 2 months before study entry

- No symptomatic peripheral vascular disease or cerebrovascular disease

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled hypokalemia or hypomagnesemia

- No concurrent serious infection

- No other nonmalignant uncontrolled medical illness or one whose control may be
jeopardized by the complications of study therapy

- No grade 2 or greater pre-existing motor or sensory peripheral neuropathy

- No psychiatric disorder or other condition that would preclude study compliance

- No conditions associated with QTc prolongation

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No concurrent biologic therapy

- No concurrent immunotherapy

Chemotherapy

- No prior chemotherapy

- No other concurrent chemotherapy

Endocrine therapy

- No concurrent hormonal therapy, except for the following:

- Gonadotropin-releasing hormone agonists for patients with hormone-refractory
prostate cancer

- Hormone replacement therapy

- Oral contraceptives

- Megestrol for anorexia/cachexia

Radiotherapy

- No prior radiotherapy

- No concurrent radiotherapy

Surgery

- See Disease Characteristics

- Prior attempt at resection or cytoreduction (e.g., debulking) surgery irrespective of
surgical margins allowed provided there are no distant metastases

- At least 1 week but no more than 8 weeks since prior surgery and recovered

Other

- No other concurrent cytotoxic therapy

- No other concurrent antineoplastic therapy

- No other concurrent investigational therapy

- No concurrent medications known to prolong the QTc interval unless the medication can
be held for at least 4 days during each treatment course

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Median survival

Outcome Time Frame:

at months 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 27, 30, 33, and 36

Safety Issue:

No

Principal Investigator

Panayiotis Savvides, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Ireland Cancer Center at University Hosptials Case Medical Center, Case Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CWRU3302

NCT ID:

NCT00077103

Start Date:

November 2003

Completion Date:

December 2007

Related Keywords:

  • Head and Neck Cancer
  • anaplastic thyroid cancer
  • Thyroid Neoplasms
  • Head and Neck Neoplasms

Name

Location

Hillman Cancer Center at University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15236
Josephine Ford Cancer Center at Henry Ford HospitalDetroit, Michigan  48202
Ireland Cancer Center at University Hosptials Case Medical Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065