Tipifarnib and Bortezomib in Treating Patients With Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of tipifarnib when given together with bortezomib and to see how well they work in treating patients with relapsed multiple myeloma. Tipifarnib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving tipifarnib together with bortezomib may kill more cancer cells.

Detailed Description
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OBJECTIVES: Primary I. Determine the maximum tolerated dose and dose-limiting toxicity of tipifarnib when administered with bortezomib in patients with relapsed multiple myeloma. (Phase I) II. Determine the response rate in patients treated with this regimen. (Phase II) III. Determine the toxicity profile of this regimen in these patients. (Phase II) Secondary I. Determine the progression-free survival of patients treated with this regimen. (Phase II) Tertiary I. Determine whether this regimen overcomes CAM-DR in primary myeloma cells and establish whether ex vivo efficacy predicts a clinical response in these patients. II. Determine if activated Akt predicts clinical resistance and if levels of phosphorylated Akt are reduced by tipifarnib and bortezomib in these patients. III. Determine whether molecular profiles from primary isolates (suspension vs adhered) correlate with clinical response in patients treated with this regimen. OUTLINE: This is a phase I dose-escalation study of tipifarnib followed by a phase II study. Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: Approximately 52-64 patients will be accrued for this study.

Official Title
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A Dose Escalation Study of R115777 (Zarnestra) Combined With Velcade® (PS-341) in Patients With Relapsed Multiple Myeloma.

Conditions
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Refractory Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Drug: bortezomib
* Drug: tipifarnib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple myeloma Stage II or III disease Relapsed disease after ≥ 2 prior therapies*, confirmed by the presence of 1 of the following: New lytic lesion A 25% increase in urine or serum monoclonal protein Patients who received prior bortezomib must have responded to therapy Measurable disease, defined by 1 or more of the following criteria: Serum M-component ≥ 1.0 g/dL by serum protein electrophoresis Urine M-protein excretion > 200 mg per 24-hour collection, by urine protein electrophoresis Performance status - Karnofsky 60-100% More than 8 weeks Platelet count ≥ 100,000/mm^3 Absolute neutrophil count ≥ 1,000/mm^3 Bilirubin ≤ 2 mg/dL Direct bilirubin ≤ 2 times upper limit of normal (ULN) AST or ALT ≤ 2 times ULN Creatinine ≤ 1.5 times ULN Calcium ≤ 12 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow study medication Capable of following directions regarding study medication, or has a daily caregiver who will be responsible for administering study medication No peripheral neuropathy ≥ grade 2 No hypersensitivity to any of the following: Bortezomib Boron Mannitol Imidazole compounds (e.g., clotrimazole, ketoconazole, miconazole, econazole) No serious medical or psychiatric illness that would preclude study compliance No other life-threatening illness (unrelated to tumor) No other active or invasive malignancy within the past 3 years except for nonmelanoma skin cancer No serious infection No prior allogeneic bone marrow transplantation More than 30 days since prior and no concurrent immunotherapy More than 30 days since prior and no concurrent cytotoxic chemotherapy More than 14 days since prior high-dose corticosteroids No concurrent therapeutic corticosteroids (e.g., > 10 mg prednisone per day) No concurrent hormonal therapy No concurrent antiemetic corticosteroids More than 14 days since prior and no concurrent radiotherapy More than 1 year since prior bortezomib More than 14 days since prior investigational drugs No prior tipifarnib No other concurrent cancer-related treatment No concurrent administration of the following enzyme-inducing anti-epileptic drugs: Phenytoin Phenobarbital Carbamazepine No concurrent magnesium- or aluminum-based antacids within 2 hours before or after tipifarnib administration Concurrent pamidronate or other bisphosphonates allowed

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bortezomib, tipifarnib)<br>Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD. | Drug: bortezomib<br>* Given IV<br>Drug: tipifarnib<br>* Given orally<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I) |  | Up to day 21 | 
| Response rate (complete response [CR] + partial response [PR]) determined using the Bladé Response criteria (phase II) | Exact 95% confidence intervals constructed. | Up to 6 weeks | 
| Toxicities, graded according to the NCI CTCAE v3.0 (phase II) |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients overcoming CAM-DR | An exact 95% confidence interval for that proportion will be computed. | Prior to therapy | 
| Proportion of patients overcoming CAM-DR | An exact 95% confidence interval for that proportion will be computed. | Day 11 of course 1 | 
| Relationship of overcoming CAM-DR and clinical response | Compared using a chi-square contingency table test at the two-sided 0.05 significance level. | Prior to therapy | 
| Relationship of overcoming CAM-DR and clinical response | Compared using a chi-square contingency table test at the two-sided 0.05 significance level. | Day 11 of course 1 | 
| Clinical resistance and levels of phosphorylated Akt | P-Akt levels both pre and post treatment will be obtained and compared using a paired t test. Logistic regression will be used with P-Akt activity as independent variable in a logistic regression modeling probability of response. Odds ratio indicating change in odds of response associated with a unit change in P-Akt level will be computed as well as a 95% confidence interval for that odds ratio. | Prior to therapy | 
| Clinical resistance and levels of phosphorylated Akt | P-Akt levels both pre and post treatment will be obtained and compared using a paired t test. Logistic regression will be used with P-Akt activity as independent variable in a logistic regression modeling probability of response. Odds ratio indicating change in odds of response associated with a unit change in P-Akt level will be computed as well as a 95% confidence interval for that odds ratio. | Day 11 of course 1 | 
| Correlation of molecular profiles from primary isolates with clinical response | Compared using paired t tests at the 0.05 significance level. | Prior to therapy | 
| Correlation of molecular profiles from primary isolates with clinical response | Compared using paired t tests at the 0.05 significance level. | Day 11 of course 1 | 
| Progression-free survival (phase II) | Summarized with Kaplan-Meier curve and related statistics. | Up to 2 years |