PS-341 and Radiation to Treat Advanced Cancer of the Head and Neck
This study will test the safety and effects of the experimental drug PS-341 plus radiation therapy in patients with head and neck cancer. PS-341 can slow or halt the growth of cancer cells grown in culture or in mice. In addition, the drug appears to enhance the effectiveness of radiation treatment.
Patients 18 years of age and older with head and neck cancer that cannot be treated adequately with surgery and cannot be cured with standard radiation and chemotherapy may be eligible for this study. Patients whose cancer has spread to the brain may not participate.
Before treatment begins participants are evaluated with CT or MRI scans of the head, neck and chest area to determine the extent of the cancer; an electrocardiogram and blood tests; and a neurocardiovascular evaluation that includes measuring blood pressure in different body positions and involves injections of phenylephrine and nitroglycerine. Some patients may undergo a procedure in which a tube is inserted into the larynx (voice box), bronchi (breathing tubes) and esophagus (food tube) and tissue samples removed. This procedure is done under general anesthesia in the operating room.
Patients receive radiation treatments Monday through Friday and injections of PS-341 twice a week during the radiation therapy. After 3 weeks of treatment, PS-341 injections are stopped for 2 weeks. Some patients continue to receive radiation treatments during the 2-week break, and others do not, depending upon when they enter the trial. The total duration of radiation treatment varies from 6 to 8 weeks, depending on whether the patient received radiation in the region of the head and neck cancer before entering the study.
Patients have a blood sample drawn before and after each new PS-341 injection to measure the drug action in the blood and to see how strong and how long the effects on the blood last. They are seen in the clinic at least once a week for a history and physical examination. A blood sample is collected at each visit to look for toxic effects of PS-341. Near the end of treatment, the neurocardiovascular evaluation is repeated, and if the results are abnormal, it is repeated again 3 months after treatment is completed. X-rays or MRI scans are done 12 weeks after radiation therapy has ended and then every few months after that to determine the extent of disease. Patients whose tumor is accessible are asked to undergo a biopsy (removal of a small piece of tumor tissue) on the first and second day after receiving the first PS-341 dose to examine the effect of the drug on the tumor.
The PS-341 dose is increased in successive groups of at least 3 patients until the highest dose that can be given safely with radiation is reached. Patients who develop severe side effects from the drug temporarily stop taking it to allow the side effects to improve. If needed, the dose may be decreased. Radiation therapy may also be stopped temporarily in patients who develop severe effects on the mouth, throat or skin. Side effects may be treated with increased fluid (by mouth, stomach tube, or vein), anti-nausea or anti-diarrhea medications, pain medications and medications to boost red or white cell counts or platelets. The drug Florinef may be given to help regulate body fluids and blood pressure.
Squamous Cell Carcinoma
Radiation: radiation therapy
|Study Design:||Primary Purpose: Treatment|
|Official 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|
- Toxicity and maximum tolerated dose (MTD) as assessed by CTC version 2.0 during treatment and weekly for 3 months after treatment. [ Designated as safety issue: Yes ]
- Response rate as assessed by RECIST criteria at end of treatment and 3 months after treatment. [ Designated as safety issue: No ]
|Study Start Date:||February 2001|
|Study Completion Date:||February 2013|
|Primary Completion Date:||August 2010 (Final data collection date for primary outcome measure)|
- The ubiquitin-proteasome pathway regulates the degradation of important regulatory proteins and transcription factors that control the cell cycle and cell death. Proteasome inhibition can lead to block of different phases of the cell cycle, and block expression of genes that prevent cell death induced by radiation or other cytotoxic therapeutic agents.
- In preclinical studies, proteasome inhibitor PS-341 has demonstrated cytotoxic, radiosensitizing, and anti-tumor activity against squamous cell carcinomas of the head and neck (SCCHN).
- The primary objective of this phase I dose escalation clinical study is to determine the maximum tolerated dose of PS-341 to be given concomitant with radiation in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
- Secondary objectives include detection of 20S proteasome inhibition, cell cycle block, apoptosis and inhibition of transcription factor NF-kappaB activation in tumor tissue biopsies following PS-341 and radiation.
- Persistent or recurrent SCCHN,
- Eligible for local primary or re-irradiation,
- ECOG performance less than or equal to 2, life expectancy > 3 months,
- Adequate organ function (PLT > 100, 000/microL, neutrophils > 1500/mciroL, serum creatinine < 1.5 times the upper limits normal (ULN), serum bilirubin < 1.5 times the ULN, serum transaminases < 2.5 times the ULN)
- No systemic chemotherapy within the past 4 weeks and recovered from chemotherapy toxicity,
- > 6 months since prior radiation.
- Phase I dose escalation, standard 3+3 statistical design, up to 51 subjects,
- PS-341 will be given in escalating doses of 0.6, 0.9 and 1.2 mg/m(2) in cohorts of 3 or more patients by IV bolus on M, Th (or T, F), and radiation will be given in 1.8 Gy fractions M-F to 60 Gy in previously radiated or 72Gy in previously unirradiated patients.
- Radiation and/or drug will be given in two courses split by a two week rest to allow recovery from combined modality therapy.
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Carter Van Waes, M.D.||National Institute on Deafness and Other Communication Disorders (NIDCD)|