Bortezomib and Temozolomide in Treating Patients With Advanced Refractory Solid Tumors or Melanoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or stopping them from dividing. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving temozolomide together with bortezomib may kill more tumor cells. PURPOSE: To determine the best dose of bortezomib and temozolomide and to see how well they work in treating patients with advanced refractory solid tumors or melanoma.

Official Title
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(Inhibition of NF-kB Signaling in Melanoma Therapy) A Phase I/II Clinical Trial of PS-341, a Proteasome Inhibitor, in Combination With an Extended Continuous Oral Schedule of Temozolomide in Patients With Advanced Refractory Solid Tumors With the Phase II Component Only in Patients With Melanoma

Conditions
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Melanoma, Brain and Central Nervous System Tumors, Solid Tumor

Intervention / Treatment
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* Drug: PS-341 (VELCADE)
* Drug: temozolomide
* Other: immunoenzyme technique
* Drug: PS-341 (VELCADE)
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - for Phase I Histologically proven malignancy (confirmed by Vanderbilt pathologists), advanced non-hematologic malignancy that is not curable by standard surgery, radiation therapy, or chemotherapy. Patients with melanoma, especially those with accessible tumors will be sought for this trial, but this part of the trial will not be limited to only melanoma patients No available effective therapy (ie; therapy known to be curative, to prolong survival, to reduce tumor-related symptoms, or to have a tangible, beneficial effect upon the patient) Adequate performance status for the study, Eastern Cooperative Oncology Group (ECOG) 0-1 Adequate baseline organ system function, usually: Absolute neutrophil count > or equal to 1500/uL Hemoglobin > or equal to 9.0g/dL Platelet count > or equal to 100,000/uL Institutional Normalized Ratio (INR) < 1.5 prior to any invasive biopsy of tumor tissue Creatinine < or equal to 1.5x institutional upper limit of normal (IULN) (this may be adjusted for drugs totally dependent upon or independent of renal clearance) Aspartate and alanine aminotransferase < or equal to 2.5x IULN, bilirubin < or equal to 1.5x IULN Agreement to use a barrier method of contraception, if potentially fertile Ability to understand and willingness to grant informed consent Patients with brain metastases are eligible only if the brain lesions are under control for a minimum of 4 weeks, with no progressive symptoms, and off systemic steroids. Patients with primary brain tumors are eligible if their dose of systemic steroids is stable for at least 5 days. Completed prior chemotherapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation therapy. All treatment related toxicity must have resolved as well. Patients can not receive concomitant radiation therapy Patients must be 18 years of age or above and competent to sign an institutionally Institutional Review Board approved informed consent Exclusion Criteria - for Phase I Patients with Grade 2 or greater peripheral neuropathy Above a maximum of 320 mg/m2 of CDDP for lifetime previously administered would make patient ineligible. No prior taxanes. Uncontrolled or serious infection New York Heart Association Class III or IV heart disease or uncontrolled angina Myocardial infarction, cerebrovascular accident, or pulmonary embolism within the past 6 months Concurrent therapy for cancer Inability to comply with protocol-specified procedures (ie, treatment, monitoring, or follow-up) Inclusion Criteria - for Phase II For the phase II trial, all patients must have advanced and incurable melanoma. Disease must be measurable. Histologic proof of disease past the primary site No other active malignancy including solid tumors or hematologic cancers within 24 months other than CIS, non-melanoma skin cancer, DCIS of breast, and melanoma in situ Melanoma patients can have up to 2 regimens of prior biologic therapies and a single regimen of systemic chemotherapy for disseminated disease.. Chemotherapy is allowed only in the chemotherapy treated patients cohort. Prior TMZ or DTIC is only allowed in those patients enrolled into the prior chemotherapy cohort All patients must have ECOG 0-1. Adequate baseline organ system function, usually: Absolute neutrophil count > or equal to 1500/uL Hemoglobin > or equal to 9.0g/dL Platelet count > equal to 100,000/uL INR < 1.5 prior to any invasive biopsy of tumor tissue Creatinine < or equal to 1.5x institutional upper limit of normal (IULN) (this may be adjusted for drugs totally dependent upon or independent of renal clearance) Aspartate and alanine aminotransferase < or equal to 2.5x IULN, bilirubin < or equal to 1.5x IULN Completed prior chemotherapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation therapy. No prior PS-341 is allowed. All treatment related toxicity must have resolved as well. Patients can not receive concomitant radiation therapy. Prior TMZ or DTIC is only allowed in those patients enrolled into the prior chemotherapy cohort Patients must be 18 years of age or above and competent to sign an institutionally IRB approved informed consent. Exclusion criteria - for Phase II Patients with Grade 2 or greater peripheral neuropathy. Uncontrolled or serious infection requiring parenteral antibiotics New York Heart Association Class III or IV heart disease or uncontrolled angina Myocardial infarction, cerebrovascular accident, or pulmonary embolism within the past 6 months Concurrent therapy for cancer xiii. Inability to comply with protocol-specified procedures (ie, treatment, monitoring, or follow-up) Patients with brain metastases are ineligible unless the lesions have been resected or irradiated a minimum of 2 months prior to treatment, be off of steroids, and show no evidence for active disease on MRI, Above a maximum of 320 mg/m2 of CDDP for lifetime previously administered would make patient ineligible. No prior taxanes

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I<br> | Drug: PS-341 (VELCADE)<br>* Dose Levels PS-341 (day 1) Level -1 0.7 mg/m2 Level 1 1.0 mg/m2 Level 2 1.0 mg/m2 Level 3 1.3 mg/m2 Level 4 1.5 mg/m2<br>* Other names: bortezomib;Drug: temozolomide<br>* Temozolomide (day 8) Level - 1 50 mg/m2 Level 1 50 mg/m2 Level 2 75/mg/m2 Level 3 75 mg/m2 Level 4 75 mg/m2<br>* Other names: TMZ;Other: immunoenzyme technique<br>* Not noted<br>* Other names: None noted;|
| Experimental: Phase II<br> | Drug: PS-341 (VELCADE)<br>* 1.3 mg/m2 by IV on days 1, 4, 8, and 11 of every 21 days<br>Drug: Temozolomide<br>* 75 mg/m2 by mouth, daily, during weeks 2-8 (42 days) of every 9-week course.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal Doses of Temozolomide and Bortezomib (Phase I) | The optimal biologic dose (OBD) defined as the dose that achieves the greatest degree of inhibition of NF-κB activation in peripheral blood mononuclear cells when co-administered with Temozolomide | up to 42 days | 
| Number of Patients With Clinical Anti-tumor Activity Phase II) | Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. Patients with CR + PR + SD | every 9 weeks to a maximum of 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Inhibition in NF-kB Activation (Phase I) | Patient with a minimum of 50% reduction from baseline on day 8 or day 29 in NF-kB, measured by picograms/milliliter in peripheral mononuclear blood cells | at baseline, on day 8 and on day 29 | 
| Patients With Clinical Anti-tumor Activity (Phase I) | Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions | every 9 weeks up to a maximum of 54 weeks | 
| Patients With Inhibition of NF-kB (Phase II) | Patient with a minimum of 50% reduction from baseline on day 8 or day 29 in NF-kB, measured by picograms/milliliter in peripheral mononuclear blood cells | at baseline, on day 8 and on day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III melanoma, stage IV melanoma, recurrent melanoma, unspecified adult solid tumor, protocol specific, recurrent adult brain tumor, melanoma (skin)