PS-341 and Radiation to Treat Advanced Cancer of the Head and Neck
| Status: | Completed |
|---|---|
| Conditions: | Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/27/2019 |
| Start Date: | February 22, 2001 |
| End Date: | February 8, 2013 |
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
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.
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.
Background:
- 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).
Objectives:
- 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.
Eligibility:
- 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.
Design:
- 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.
- 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).
Objectives:
- 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.
Eligibility:
- 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.
Design:
- 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.
- 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. 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
or
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.
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 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
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 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
excluded.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Click here to add this to my saved trials
