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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

Phase 1
18 Years
Not Enrolling
Squamous Cell Carcinoma

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Trial Information

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


- 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

- > 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

- Radiation and/or drug will be given in two courses split by a two week rest to allow
recovery from combined modality therapy.

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

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. Because no dosing or toxicity data are currently
available on the use of PS-341 in patients less than 18 years of age, children are not
included in this study. Further, SCCHN in patients less than 18 years of age is
exceedingly rare.

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 is greater than 1,500/microliter

platelets are greater than 100,000/microliter

total bilirubin is less than 1.5 times the ULN

AST(SGOT)/ALT(SGPT) is less than 2.5 times the ULN

serum creatinine is less than 1.5 times the ULN


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

The effects of PS-341 on gametogenesis and the developing human fetus at the recommended
therapeutic dose are unknown. For this reason, 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.


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 the sites, at least one month must elapse between the end of
radiation and the beginning of therapy under this protocol and toxicities must have

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 repetition 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 absence of symptoms.

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

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Toxicity and maximum tolerated dose (MTD) as assessed by CTC version 2.0 during treatment and weekly for 3 months after treatment.

Safety Issue:


Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

February 2001

Completion Date:

February 2013

Related Keywords:

  • Squamous Cell Carcinoma
  • Cell Cycle
  • NFKB
  • Combined Modality
  • Radiosensitizer
  • Ubiquitin
  • Head and Neck Cancer
  • Squamous Cell Carcinoma
  • Radiation Therapy
  • Protease Inhibitor
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892