Protocol Number: 01-C-0104

Title:

A Phase I Study of Concomitant Therapy with Proteasome Inhibitor PS-341 and Radiation in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Number:

01-C-0104

Summary:

Squamous cell carcinomas of the head and neck (SSCHN) account for 4 percent of all cancers. Most are initially treated with surgery, radiation, or both. For those patients whose cancer has spread and is not treatable by surgery, radiation and chemotherapy are often combined. These current treatments may help control growth but do not offer a chance for a cure. This study will investigate the effects of a new investigational chemotherapy drug, PS-341, on both the cancer and the patient when it is administered twice a week at the same time as radiation therapy. This drug has been shown to slow down or stop the growth of cancer cells in culture and in mice. In addition, when the cells are treated with the drug and radiation, the killing effect of the radiation seems to be increased.

Eligible participants are patients over 18 years old with confirmed SCCHN which is persistent or recurrent and inoperable; with distant metastases following standard treatment; or with local disease that can be treated by radiation. Scans such as CT and MRI will be done to determine the extent of the cancer; an EKG, blood work, pregnancy test, and HIV test will also be done. An examination will be done under anesthesia during which a small piece of the tumor will be removed for diagnosis and research. Patients will be divided into two groups: those who had radiation therapy more than 6 months ago and those who had no radiation therapy but who had surgery or chemotherapy more than 4 weeks ago.

PS-341 will be administered every Monday and Thursday for as long as radiation lasts: 7 weeks for retreatment cases or 8 weeks for primary treatment. The first radiation treatment will be given 24 hours after the first dose of PS-341 and will continue to be given once a day, Monday through Friday. A biopsy may be requested on the Tuesday and Wednesday following the first dose of PS-341. Before and after each injection, a blood sample will be taken. In addition, patients will be seen once a week in the clinic, where a history and physical exam will be done and another blood sample taken. Twelve weeks after radiation is completed, and every few months thereafter, an X-ray or MRI scan will be done to determine the extent of the cancer. Patients will also be seen every month for the first year after radiation to monitor for and treat any adverse effects. Blood will be collected at each visit.

Dosage will be increased for each group of patients as long as there are no severe side effects. PS-341 has certain known side effects, such as nausea, vomiting, loss of appetite, decreased blood pressure, lightheadedness, fast heart rate, and decreases in white blood cells and platelets. It has not been found to cause any deaths in humans in studies thus far. However, it is an investigational drug and has not yet been given to large numbers of patients or followed up for long periods.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA

Patients must meet the following inclusion criteria:

Patients with histologically confirmed SCCHN which is persistent or recurrent and unresectable; or patients presenting with or developing distant metastases following standard curative measures, and who have local regional disease amenable to radiation or re-irradiation therapy are eligible. Patients with a history of treatment for other prior malignancy will be eligible, provided they remain disease-free more than 2 years after initial treatment, or were treated for non-melanoma skin cancer, or in situ cervical cancer.

Because of greater potential for acute toxicity in previously irradiated patients, patients will be stratified based on whether they have received prior radiation. Stratum A: Prior radiation therapy (greater than 6 months) with or without prior surgery or chemotherapy. Stratum B: No prior radiation therapy, but greater than or equal to 4 weeks after surgery or chemotherapy.

Age greater than 18 years of age.

ECOG performance status less than or equal to 2 (Karnofsky greater than 50%).

Life expectancy greater than 3 months.

Patients must have adequate organ and marrow function as defined below:

absolute neutrophil count greater than 1,500/microliter

platelets greater than 100,000/microliter

total bilirubin less than 1.5 X ULN

AST(SGOT)/ALT(SGPT) less than 2.5 X ULN

serum creatinine less than 1.5 X ULN

or

creatinine clearance greater than 60 mL/min/1.73 m(2) for patients with creatinine levels equal to or greater than 1.5 X ULN.

Men and women of child-bearing potential must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or a participating spouse are enrolled in this study, she should inform her treating physician immediately.

Because the potential risk of toxicity in nursing infants secondary to PS-341 treatment of the mother is unknown but may be harmful, breastfeeding should be discontinued if the mother is treated with PS-341.

Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients who have had surgery, chemotherapy, or immunotherapy within 4 weeks, or radiotherapy to the head and neck within 6 months prior to entering the study. For palliative radiation at othe sites, at least one month must elapse between the end of radiation and the beginning of therapy under this protocol and toxicities must have resolved.

Patients undergoing therapy with other investigational agents.

Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other toxicities.

Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, myocardial infarction within the past 6 months, unstable angina pectoris, or unstable cardiac arrhythmia requiring assessment for clinical intervention.

Pregnant and nursing women are excluded from this study because PS-341 is an investigational agent with unknown effects on the fetus and nursing infant.

HIV-positive patients are excluded from the study because of possible pharmacokinetic interactions with medication necessary to control HIV or its complication and owing to uncertain interaction of PS-341 with immune function.

Patients with postural hypotentsion due to severe baroreceptor dysfunction after previous radiation and/or surgery defined as a) postural hypotension that cannot be corrected with volume repetion to systolic blood pressure greater than 100 mm Hg and absence of orthostatic changes or symptoms; b) postural hypotension that cannot be corrected with volume repletion to systolic blood pressure greater than 120 mm Hg with orthostatic changes and asence of symptoms.

Patients with hyponatremia not correctable to greater than or equal to 130 mEq/L will be excluded.

Special Instructions: Currently Not Provided

Keywords:

Cell Cycle

NFKB

Combined Modality

Radiosensitizer

Ubiquitin

Recruitment Keywords:

Head and Neck Cancer

Squamous Cell Carcinoma

Radiation Therapy

Protease Inhibitor

Conditions:

Squamous Cell Carcinoma

Investigational Drug(s):

PS-341

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer Phase III Trial

Advances in radiotherapy for head and neck cancer

Cancer statistics, 1999

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