Brain and Central Nervous System Tumors, Melanoma, Solid Tumor
Conditions
Keywords
stage III melanoma, stage IV melanoma, recurrent melanoma, unspecified adult solid tumor, protocol specific, recurrent adult brain tumor, melanoma (skin)
Brief summary
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.
Interventions
DRUGPS-341 (VELCADE)
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
DRUGtemozolomide
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
OTHERimmunoenzyme technique
Not noted
DRUGTemozolomide
75 mg/m2 by mouth, daily, during weeks 2-8 (42 days) of every 9-week course.
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Optimal Doses of Temozolomide and Bortezomib (Phase I) | up to 42 days | 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 |
| Number of Patients With Clinical Anti-tumor Activity Phase II) | every 9 weeks to a maximum of 54 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Inhibition in NF-kB Activation (Phase I) | at baseline, on day 8 and on day 29 | 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 |
| Patients With Clinical Anti-tumor Activity (Phase I) | every 9 weeks up to a maximum of 54 weeks | 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 Inhibition of NF-kB (Phase II) | at baseline, on day 8 and on day 29 | 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 |
Countries
United States
Participant flow
Recruitment details
This study remained open to accrual from 6/3/03 to 3/11/08.
Pre-assignment details
19 participants were enrolled to the phase I portion of this trial and 28 were enrolled to the phase II portion of this trial. There were also 3 participants that were consented to take part in this trial, but were determined to be ineligible.
Participants by arm
| Arm | Count |
|---|---|
| Phase I | 19 |
| Phase II | 28 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 0 | 3 |
| Overall Study | Progression of disease | 14 | 20 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Phase II | Phase I | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 15 Participants | 33 Participants |
| Age Continuous | 58 years | 58 years | 58 years |
| Region of Enrollment United States | 28 participants | 19 participants | 47 participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 19 Participants | 15 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 28 / 28 |
| serious Total, serious adverse events | 6 / 19 | 4 / 28 |
Outcome results
Primary
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
Time frame: every 9 weeks to a maximum of 54 weeks
Population: Patients who were available to measure response to the study drugs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Number of Patients With Clinical Anti-tumor Activity Phase II) | Complete Response | 0 participants |
| Phase I | Number of Patients With Clinical Anti-tumor Activity Phase II) | Partial Response | 1 participants |
| Phase I | Number of Patients With Clinical Anti-tumor Activity Phase II) | Stable Disease | 5 participants |
| Phase I | Number of Patients With Clinical Anti-tumor Activity Phase II) | Progressive Disease | 22 participants |
Primary
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
Time frame: up to 42 days
Population: All Phase I patients who received the study drugs
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Optimal Doses of Temozolomide and Bortezomib (Phase I) | bortezomib | 1.3 mg/m2 |
| Phase I | Optimal Doses of Temozolomide and Bortezomib (Phase I) | temozolomide | 75 mg/m2 |
Secondary
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
Time frame: every 9 weeks up to a maximum of 54 weeks
Population: Patients who received treatment and who were available for measurement of lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Patients With Clinical Anti-tumor Activity (Phase I) | Complete Response | 0 participants |
| Phase I | Patients With Clinical Anti-tumor Activity (Phase I) | Partial Response | 4 participants |
| Phase I | Patients With Clinical Anti-tumor Activity (Phase I) | Stable Disease | 1 participants |
| Phase I | Patients With Clinical Anti-tumor Activity (Phase I) | Progressive Disease | 14 participants |
Secondary
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
Time frame: at baseline, on day 8 and on day 29
Population: Phase I patients for whom blood was taken at baseline,on day 8 and on day 29 of each cycle. There was no correlation of change in NF-kB activation with changes in tumor tissue
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Patients With Inhibition in NF-kB Activation (Phase I) | 0 participants |
Secondary
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
Time frame: at baseline, on day 8 and on day 29
Population: Patients with advanced, incurable melanoma who are chemotherapy-naive and patients who had undergone prior chemotherapy with either Dacarbazine or Temozolomide with treatment failure. No degree of inhibition of NF-kB was observed. Phase II not completed due to lack of efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Patients With Inhibition of NF-kB (Phase II) | 0 participants |