Clinical trial NCT00030368: Bortezomib and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors
Official title: A Phase I Study of PS-341 in Combination With Paclitaxel in Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-04-09
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase I trial to study the effectiveness of combining bortezomib with paclitaxel in treating patients who have advanced or metastatic solid tumors. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining bortezomib with paclitaxel may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of bortezomib when given in combination with paclitaxel in patients with locally advanced or metastatic solid tumors.

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

Patients receive bortezomib IV on days 2 and 9 and paclitaxel IV over 1 hour on days 1 and 8. For the first course only, patients do not receive paclitaxel on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 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 or greater than 80% 20S proteasome inhibition. Once the MTD is determined, an additional 6-9 patients are accrued and treated at that dose.

Patients are followed at 21 days.

PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed locally advanced or metastatic solid tumor for which there is no curative treatment
* No known brain metastases
* Performance status - ECOG 0-2
* Performance status - Karnofsky 60-100%
* WBC at least 3,000/mm\^3
* Absolute neutrophil count at least 1,500/mm\^3
* Platelet count at least 100,000/mm\^3
* Bilirubin normal
* AST/ALT no greater than 2.5 times upper limit of normal (ULN)
* Creatinine no greater than ULN
* Left ventricular function at least lower limit of normal if received prior doxorubicin
* No grade II or IV tilt-table test
* No symptomatic congestive heart failure
* No unstable angina pectoris
* No cardiac arrhythmia
* No thrombotic event within the past 6 months
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No prior allergic reaction to compounds of similar chemical or biological composition to study drugs
* No other concurrent uncontrolled illness
* No ongoing or active infection
* No psychiatric illness or social situation that would preclude study compliance
* At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
* Prior paclitaxel allowed
* At least 2 weeks since prior hormonal therapy
* No concurrent steroids or hormonal therapy except steroids to prevent hypersensitivity reactions to paclitaxel or hormonal therapy for non-disease-related conditions (e.g., insulin for diabetes)
* At least 4 weeks since prior radiotherapy
* At least 4 weeks since prior surgery
* Recovered from prior therapy
* No other concurrent investigational agents
* No concurrent combination anti-retroviral therapy for HIV-positive patients
* No concurrent anticoagulation therapy
* Concurrent pamidronate or zoledronate allowed for treatment of hypercalcemia or for palliation of skeletal metastases

Primary outcomes:
measure: Dose-limiting toxicity (DLT) defined as Common Terminology Criteria (CTC) version 2.0 grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity with the exception of asymptomatic neutropenia [ANC < 500]
timeFrame: 21 days
measure: Maximum-tolerated dose (MTD) based on the incidence of DLT
timeFrame: 21 days
measure: Dose of PS-341 that results in not more than 70% to 80% 20S proteasome inhibition [20S-PI] in combination with a paclitaxel
timeFrame: At baseline and at 1 hour of weeks 1, 2 and 4
Secondary outcomes:
measure: Response according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee
timeFrame: Up to 21 days
measure: Change in the level of p27 and Bax proteins in peripheral blood mononuclear cells
timeFrame: From baseline to 6 hours of day 1 (week 1) and day 2 (week 2)
measure: Change in plasma levels of TNF, IL-1, IL-6, and C-reactive protein
timeFrame: From baseline to 6 hours of day 2 (weeks 1 and 2)
measure: Change in NF-kb biomarkers TRAP I and c-IAP-2 in tumor tissue blocks
timeFrame: From baseline to 6 hours of day 2 (weeks 1 and 2)
measure: Change in phosphorylation of c-Jun and JNK in tumor tissue blocks
timeFrame: From baseline to 6 hours of day 2 (weeks 1 and 2)
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: Charles Shapiro
role: PRINCIPAL_INVESTIGATOR
References: