Combination Chemotherapy in Treating Patients With Advanced Solid Tumors
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Purpose
Phase I trial to study the effectiveness of combination chemotherapy in treating patients who have metastatic or unresectable solid tumors. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.
| Condition | Intervention | Phase |
|---|---|---|
|
Unspecified Adult Solid Tumor, Protocol Specific |
Drug: bortezomib Drug: fluorouracil Drug: leucovorin calcium Other: pharmacological study Other: laboratory biomarker analysis |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase I Study of PS-341 in Combination With 5-FU/LV in Solid Tumors |
- 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 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]
- Incidence of adverse events, graded according to NCI CTC version 2.0 [ Time Frame: Up to 7 years ] [ Designated as safety issue: Yes ]The toxicities observed at each dose level will be summarized in terms of type, severity, time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and course.
- Survival [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]Will be summarized with Kaplan-Meier plots.
- Time to failure [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]Will be summarized with Kaplan-Meier plots.
| Enrollment: | 30 |
| Study Start Date: | September 2000 |
| Primary Completion Date: | January 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment
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.
|
Drug: bortezomib
Given IV
Other Names:
Drug: fluorouracil
Given IV
Other Names:
Drug: leucovorin calcium
Given IV
Other Names:
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
|
Detailed Description:
PRIMARY OBJECTIVES:
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.
SECONDARY OBJECTIVES:
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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 immediately
- 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 therapy
- 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 arrhythmia
- 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
Contacts and Locations| United States, California | |
| University of Southern California | |
| Los Angeles, California, United States, 90033-0804 | |
| Principal Investigator: | Heinz-Josef Lenz | University of Southern California |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00007878 History of Changes |
| Other Study ID Numbers: | NCI-2012-03190, PHI-27 (USC 0C-00-03), NCI-T99-0048, LAC-USC-0C003, CHNMC-PHI-27, CDR0000068327, U01CA062505 |
| Study First Received: | January 6, 2001 |
| Last Updated: | May 3, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Neoplasms Fluorouracil Bortezomib Leucovorin Levoleucovorin Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antimetabolites, Antineoplastic Antineoplastic Agents Therapeutic Uses |
Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Vitamin B Complex Vitamins Micronutrients Growth Substances Antidotes Protective Agents Protease Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013