Bortezomib and Gemcitabine in Treating Older Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of solid tumors by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with gemcitabine may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib and gemcitabine in treating older patients with advanced solid tumors.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose of weekly bortezomib and gemcitabine in treating elderly patients with advanced solid tumors. Secondary To characterize the quantitative and qualitative toxicities of bortezomib and gemcitabine in these patients. To obtain preliminary information about the anti-tumor activity of bortezomib and gemcitabine. To characterize gemcitabine and metabolite pharmacokinetics in patients receiving concurrent bortezomib therapy. OUTLINE: This is a phase I dose escalation study of bortezomib and gemcitabine. Patients receive gemcitabine intravenously (IV) over 30 minutes followed 1 hour later by bortezomib IV over 3-5 seconds on days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of gemcitabine and bortezomib until the maximum tolerated dose of the combination is determined. Blood is collected periodically for pharmacokinetic and pharmacogenetic studies. After completion of study treatment, patients are followed every 3 months for up to 1 year.

Official Title
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Phase I Study of Bortezomib and Gemcitabine in Elderly Patients With Solid Tumors (X05227)

Conditions
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Breast Cancer, Colorectal Cancer, Head and Neck Cancer, Kidney Cancer, Lung Cancer, Ovarian Cancer, Pancreatic Cancer, Prostate Cancer, Sarcoma

Intervention / Treatment
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* Drug: bortezomib
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of advanced non-hematologic malignancy, including any of the following: Breast cancer Lung cancer Colon cancer Pancreatic cancer Head and neck cancer Sarcoma Must have failed or become intolerant to prior standard therapy and is no longer likely to respond to such therapy (for all diseases except pancreatic cancer) Pancreatic cancer patients may be enrolled with no prior therapy requirements since gemcitabine is the current standard of care 1st line therapy Measurable or nonmeasurable disease Concurrent enrollment in the University of Minnesota study Population Pharmacokinetics and Pharmacogenetics of Gemcitabine in Adult Patients with Solid Tumors (Human Subjects Code 0508M72989) required ECOG performance status of 0-1 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL Bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 3.0 times ULN (5 times ULN if liver has tumor involvement) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times ULN (5 times ULN if liver has tumor involvement) Calculated or measured creatinine clearance > 30 mL/minute Fertile patients must use effective contraception during and for 3 months after study participation Recovered from all prior therapy Prior systemic chemotherapy, immunotherapy, or biological therapy allowed At least 3 months since prior bortezomib and/or gemcitabine At least 2 weeks since prior systemic therapy At least 3 weeks since prior investigational agents (for reasons other than the treatment of cancer) At least 2 weeks since prior radiotherapy Exclusion Criteria: Symptomatic brain metastases Serious concomitant medical or psychiatric disorders (e.g., active infection or uncontrolled diabetes) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study Myocardial infarction within the past 6 months New York Heart Association (NYHA) Class III or IV heart failure Uncontrolled angina Severe uncontrolled ventricular arrhythmias Electrocardiographic evidence of acute ischemia or active conduction system abnormalities Peripheral neuropathy ≥ grade 2 Known hypersensitivity to bortezomib, boron or mannitol Prior radiotherapy to ≥ 25% of the bone marrow Prior radiotherapy to the whole pelvis Concurrent filgrastim (G-CSF) or other hematologic support during course 1 of study treatment

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine / Bortezomib<br>Gemcitabine will be administered as a 30 minute intravenous infusion at the patient's assigned dose on day 1 and day 8 of a 21 day cycle. Bortezomib will be given 1 hour after gemcitabine by IVP over 3 to 5 seconds followed by a standard saline on days 1 and 8 of a 21 day treatment cycle until disease progression or for a maximum of 6 cycles. | Drug: bortezomib<br>* Bortezomib will be given 1 hour after gemcitabine by intravenous pyelogram (IVP) over 3 to 5 seconds followed by a standard saline flush or through a running intravenous (IV) line at the patient's assigned dose (1.0 up to 1.8 mg/m^2) on days 1 and 8 of a 21 day treatment cycle until disease progression or for a maximum of 6 cycles.<br>* Other names: Velcade;Drug: gemcitabine hydrochloride<br>* Gemcitabine will be administered as a 30 minute intravenous infusion at the patient's assigned dose (800 up to 1000 mg/m^2) on day 1 and day 8 of a 21 day cycle.<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of bortezomib and gemcitabine | A minimum of a 3 week period (1 cycle) must be completed by all patients within a dose level before dose escalation to the next level may occur. A cycle is defined as treatment day 1 and 8 with follow-up through day 21. | Day 21 (Week 3 - Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Toxicity will be graded using the NCI's Common Terminology Criteria for Adverse Events (CTCAE 3.0) | 30 Days after Last Treatment | 
| Disease response as measured by RECIST criteria | The best overall response is the best response recorded from the start of treatment until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since the treatment began. | Week 4 | 
| Characterization of gemcitabine and metabolite pharmacokinetics (as part of co-enrollment in Population Pharmacokinetics and Pharmacogenetics of Gemcitabine in Adult Patients with Solid Tumors) | Pharmacokinetics will be done in conjunction with the dosing day 1 of cycle 1 whenever possible. | Pre-Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent pancreatic cancer, recurrent breast cancer, recurrent small cell lung cancer, recurrent non-small cell lung cancer, recurrent colon cancer, recurrent prostate cancer, recurrent head and neck cancer, ovarian cancer, recurrent uterine cancer, recurrent kidney cancer, recurrent osteosarcoma