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A Phase I Study of PS-341 in Combination With 5-FU/LV in Solid Tumors

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of PS-341 in Combination With 5-FU/LV in Solid Tumors


I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of PS-341
when administered as a bolus injection two times a week (on days 1 and 4) for 2 weeks
followed by one week of rest.

II. To evaluate the pharmacodynamics of PS-341 by determining the 20S proteasome and NFkB
inhibition in blood of patients treated with intravenous PS-341 combined with weekly 5-FU
and LV.


I. To identify any objective tumor response in patients treated with intravenous PS-341.

II. To evaluate the relationship between inhibition of the 20S proteasome and NFkB and
clinical toxicity.

III. To obtain preliminary data on molecular correlates of response to PS-341 and 5-FU and
LV including genes involved in apoptosis, cell cycle control, transcriptional regulation and
adhesion/angiogenesis based on the mechanisms of PS-341 IV. To examine the pharmacokinetics
of 5-FU when co-administered with PS-341.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib.

Patients receive bortezomib IV on days 1 and 4 and fluorouracil IV and leucovorin calcium IV
on day 1 weekly for 2 weeks. Treatment repeats every 3 weeks in the absence of disease
progression or unacceptable toxicity.

Cohorts of 3 to 6 patients receive escalating doses of bortezomib until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience dose-limiting toxicity.

Inclusion Criteria:

- Patients must have histologically or cytological confirmed malignancy which is
metastatic or unresectable solid tumor for which standard curative or palliative
measures do not exist or are no longer effective

- All patients will have advanced malignancy confirmed by review of their biopsy
specimens by the Division of Pathology of the City of Hope National Medical Center,
the University of Southern California/LA County/Norris Comprehensive Cancer Center,
or the University of California at Davis

- ECOG performance status =< 2 (Karnofsky >= 60%) and an estimated survival of at least
3 months

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin =< within the institutional normal

- AST/ALT =< 2.5 x the upper limits of institutional normal

- Serum creatinine =< 1.5 mg/dl

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or 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 participating in this study, she should inform her treating physician

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

Exclusion Criteria:

- Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks
prior to entering the study and 6 weeks from nitrosourea-containing chemotherapy; all
patients should have recovered from all toxicities of prior chemo and radiation

- 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, unstable angina pectoris, or cardiac

- Pregnant and nursing women are excluded from this study because PS-341 is an
investigational agent, and the anti-proliferative activity of PS-341 may be harmful
to the developing fetus or nursing infant

- HIV-positive patients receiving anti-retroviral therapy (HAART) are excluded from the
study because of possible pharmacokinetic interactions

- Patients with EKG evidence of acute ischemia or significant conduction abnormality
(bifascicular block, defined as left anterior hemiblock in the presence of right
bundle branch block, 2nd or 3rd degrees AV blocks); any history of cardiac or
cerebrovascular disease due to hypotension and tachycardia

- Patients who had any major surgery within 2 weeks

Type of Study:


Study Design:

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

Outcome Measure:

MTD, defined as the highest dose tested in which none or only one patient experienced DLT attributable to the study drug(s), when at least 6 patients were treated at that dose and are evaluable for toxicity, graded according to the NCI CTC version 2.0

Outcome Time Frame:

Up to 21 days

Safety Issue:


Principal Investigator

Heinz-Josef Lenz

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Southern California


United States: Food and Drug Administration

Study ID:




Start Date:

September 2000

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms



University of Southern California Los Angeles, California  90033