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

Phase 1/Phase 2
18 Years
Not Enrolling
Refractory Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

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

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.

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I)

Outcome Time Frame:

Up to day 21

Safety Issue:


Principal Investigator

Darrin Beaupre

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

August 2005

Completion Date:

Related Keywords:

  • Refractory Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612