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A Phase I and Pharmacologic Study of the Proteasome Inhibitor PS-341 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I and Pharmacologic Study of the Proteasome Inhibitor PS-341 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Malignancies


PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of bortezomib and paclitaxel administered in
combination with carboplatin in patients with advanced solid tumors.

II. Compare the tolerability and efficacy of the different sequences of this regimen in
these patients.

III. Determine the clinical toxic effects and pharmacokinetics of this regimen in these
patients.

IV. Determine, preliminarily, the therapeutic activity of this regimen in these patients.

V. Evaluate p53 accumulation as a marker of PS-341 activity, and the effect of
paclitaxel/carboplatin on PS-341 induced accumulation of p53.

VI. Exam the effect of PS-341 on the levels of other proteasome targets, e.g. mdm2, p27,
p21, cyclins B, D1,E; IκB and other ubiquitinated proteins in tumor tissue, when available.

OUTLINE: This is a dose-escalation study of bortezomib and paclitaxel. Patients are assigned
to 1 of 2 treatment groups.

Group A: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on
day 1 and bortezomib IV over 3-5 seconds on days 2, 5, and 8.

Group B: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, and 8 and paclitaxel
IV over 3 hours and carboplatin IV over 30 minutes on day 2.

Treatment in both groups repeats every 3 weeks in the absence of disease progression or
unacceptable toxicity. After 6 courses of paclitaxel and carboplatin, patients with stable
or responding disease may continue with bortezomib alone at the discretion of the
investigator. Cohorts of 3-6 patients in each group receive escalating doses of bortezomib
and paclitaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as
the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 3 months.

PROJECTED ACCRUAL: A total of 24-96 patients will be accrued for this study within 25
months.


Inclusion Criteria:



- Histologically confirmed malignancy for which no known standard therapy that is
potentially curative or definitely capable of extending life expectancy exists

- No hematologic malignancies

- No symptomatic CNS metastases

- Brain metastases allowed if previously treated (radiotherapy and/or surgery)and
patient is stable for at least 8 weeks

- Performance status - ECOG 0-2

- At least 12 weeks

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Bilirubin no greater than 1.5 times upper limit of normal (ULN)

- AST no greater than 2.5 times ULN

- Creatinine no greater than 1.5 times ULN

- No New York Heart Association class III or IV heart disease

- HIV negative

- No peripheral neuropathy grade 2 or greater

- No uncontrolled infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- More than 4 weeks since prior biologic therapy

- More than 4 weeks since prior immunotherapy

- No prior bone marrow transplantation

- No concurrent immunotherapy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
and recovered

- No other concurrent chemotherapy

- More than 4 weeks since prior radiotherapy

- No prior radiotherapy to more than 30% of bone marrow

- No concurrent radiotherapy

- No concurrent investigational ancillary therapy

- No concurrent enrollment in another study involving a pharmacologic agent (e.g.,
drugs, biologics, immunotherapy, or gene therapy) for symptom control or therapeutic
intents

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of paclitaxel, bortezomib, and carboplatin defined as the highest safely-tolerated dose where =< 1 patient experience dose-limiting toxicity (DLT) with the next higher dose having at least 2 patients who experience DLT as assessed by CTC version 2.0

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Alex Adjei

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02436

NCT ID:

NCT00028587

Start Date:

December 2001

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific

Name

Location

Mayo ClinicRochester, Minnesota  55905