• Optimal doses of temozolomide and bortezomib (phase I) [ Designated as safety issue: No ]
  
• Maximum tolerated dose of temozolomide and bortezomib (phase I) [ Designated as safety issue: Yes ]
  
• Antitumor activity as measured by RECIST criteria (phase II) [ Designated as safety issue: No ]
  

• Correlation of changes in NF-kB state of activation with changes observed in tumor tissue [ Designated as safety issue: No ]
  
• Clinical antitumor activity (phase I) [ Designated as safety issue: No ]
  
• Collect PBMCs from patients before and after therapy and define the degree of inhibition of NF-kB activity (phase II) [ Designated as safety issue: No ]
  
• Collect accessible tumor samples and define the degree of inhibition of NF-kB activity (phase II) [ Designated as safety issue: No ]
  
• Correlation of clinical benefits with the degree of inhibition of NF-kB (phase II) [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Define the optimal doses of temozolomide and bortezomib based upon the optimal biologic dose, defined as the dose that achieves the greatest degree of inhibition of NF-κB activation* in peripheral blood mononuclear cells (PBMCs) in patients with advanced refractory solid tumors or melanoma. (Phase I)
• Determine the maximum tolerated dose of bortezomib and temozolomide in patients with advanced refractory solid tumors or melanoma. (Phase I)
• Estimate the antitumor activity, in terms of objective regressions (by RECIST criteria) or prolonged stabilization of disease (> 6 months) in these patients. (Phase II)

Secondary

• Correlate changes in the NF-κB state of activation observed in the PBMCs with changes observed in tumor tissue from patients treated with these regimens. (Phase I)
• Describe any clinical antitumor activity observed in patients treated with this regimen. (Phase I)
• Collect PBMCs from patients treated with this regimen before and after therapy and define the degree of inhibition of NF-κB activity*. (Phase II)
• Collect accessible tumor samples from patients who can safely be biopsied either pretreatment or pre- and posttreatment and define the degree of inhibition of NF-κB activity*. (Phase II)
• Correlate clinical benefit with the degree of inhibition of NF-κB in patients treated with this regimen. (Phase II) NOTE: *Defined by intracellular phosphorylated-IkB, total IkB, nuclear p65 (relA), and nuclear p21 levels, circulating blood levels of chemokines and pro-angiogenic factors, MIP-1α or IL-8 and VEGF, and Electrophoretic Mobility Shift Analysis (EMSA) of NF-kB in nuclear extracts

OUTLINE:

• Phase I: Patients receive bortezomib IV on days 1, 4, 8, 11, 22, 25, 29, 32, 43, 46, 50, and 53 and oral temozolomide once daily on days 8-63. Treatment repeats every 63 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients receive escalating doses of bortezomib and temozolomide until the maximum tolerated dose is determined. The maximum tolerated dose is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose limiting toxicity.

• Phase II: Patients receive bortezomib and temozolomide as in phase I at the maximum tolerated dose determined in phase I.

Blood is collected and analyzed for 20S proteasome inhibition pretreatment and 1 hour post-bortezomib on days 1, 8, and 32 (phase I) or day 1 only (phase II). Blood is collected pretreatment, day 8 (pre-temozolomide and post-bortezomib) and day 29 (post-temozolomide and bortezomib) in order to examine biologic assays for inhibition of NF-κB. Tumor tissue (if accessible) is obtained pretreatment and on day 29 in order to examine biologic assays for inhibition of NF-κB. IκB phosphorylation in peripheral blood mononuclear cells and/or tumor biopsies is monitored by western/immunoblot.