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

Phase 1/Phase 2
18 Years
Not Enrolling
Multiple Myeloma

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Trial Information

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

In Phase I, patients will receive intravenous PS-341 (Velcade) and 3 different dose levels
of oral R115777 (Zarnestra). Dose Limiting Toxicity (DLT) will be determined over a period
of one cycle and dose escalation to the next level will not occur until all patients
projected at each level complete one cycle of therapy. Once DLT is determined, patients in
Phase I and all patients enrolled for the phase II component will be treated at the maximum
tolerated dose (MTD) to complete 8 cycles of therapy. Treatment will continue beyond 8
cycles if there is evidence of continued response. The study regimen will consist of two
weeks of treatment followed by one week off for a total cycle duration of three weeks. If
disease stabilization occurs (noted on 2 consecutive cycles) after the standard 8 cycles are
given, treatment will be discontinued.

Patients are to be monitored for adverse events throughout the treatment phases and for a
minimum of 30 days after their last dose of drugs. Follow up will include history and
physical exam with laboratory evaluation at least every 3 months. Laboratories will include
CMP, CBC, SPEP, UPEP, and quantitative immunoglobulins. A skeletal survey will be performed
at least every 6 months.

Inclusion Criteria:

- Voluntary written informed consent

- Female subject is either post-menopausal/surgically sterilized or willing to use an
acceptable method of birth control for the duration of the study.

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

- Diagnosis of stage II or III multiple myeloma and have relapsed after at least one
prior therapies confirmed by the presence of:

1. A new lytic lesion

2. A 25% increase in urine or serum monoclonal protein

- Patient can have received PS-341 (Velcade) previously and does not require a previous

- Patients must have measurable disease. One or more of the following must be present
to qualify for this study:

1. Serum M-component greater than or equal to 1.0 gm/dl (10.0 g/L) by serum protein

2. Urine M-protein excretion > 200 mg/24 (0.2 g/24h) hours, by urine protein

3. Abnormal serum free light chain ratio with elevated Kappa or Lambda light chains
in serum

- Baseline measurements must be done within 21 days of study entry.

- Karnofsky Performance Status Scale > 60.

- Greater than or equal to 18 years of age.

- Expected survival of greater than 8 weeks.

- Swallow intact study medication tablets.

- Can follow directions or has a caregiver who will be responsible for administering
study medication.

Exclusion Criteria:

- Previously treated with R115777 (Zarnestra).

- Undergone an allogeneic bone marrow transplant.

- A platelet count of <100,000 x 10 to the 9 power/L within 14 days before enrollment.

- Absolute neutrophil count of <1.0 x 10 to the 9 power/L within 14 days before

- Measured creatinine > 1.5 X the upper limits of normal within 14 days before

- Greater than or equal to Grade 2 peripheral neuropathy within 14 days before

- Hypersensitivity to bortezomib, boron, mannitol or imidazole compounds

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result obtained during screening.

- Received other investigational drugs within 14 days of enrollment or immunotherapy
within 30 days of enrollment.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Ongoing radiation therapy or radiation therapy within 14 days prior to first

- Cytotoxic chemotherapy within 30 days prior to first treatment.

- Therapy with high-dose corticosteroids within 14 days prior to first treatment.

- Presence of any of the following excludes a patient from entering the study until
such condition is resolved (determined within 14 days prior to the first treatment):

1. Elevated total bilirubin > 2mg/dl, or direct bilirubin > 2 times the ULN.

2. Serum glutamic oxaloacetic transaminase (AST, formerly SGOT) or serum glutamic
pyruvic transaminase (ALT, formerly SGPT) > 2 times the ULN

3. Serum calcium > 12 mg/dL.

4. Concurrent serious infection.

5. Life-threatening illness (unrelated to tumor).

- History of any other ACTIVE and INVASIVE cancer other than the present condition
(except non-melanoma skin cancer), unless in complete remission and off of all
therapy for that disease for a minimum of 3 years.

- Prohibited/allowable medications or precautions:

1. Enzyme-inducing anti-epileptic medications (e.g. phenytoin, phenobarbital,
carbamazepine) are not allowed.

2. Non-enzyme anti-epileptic medications will be allowed.

Type of Study:


Study Design:

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

Outcome Measure:

Dose Limiting Toxicity (DLT)

Outcome Description:

Determine the dose limiting toxicity at 3 weeks post treatment

Outcome Time Frame:

Average of 6 months

Safety Issue:


Principal Investigator

Melissa Alsina, M.D.

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:

June 2007

Related Keywords:

  • Multiple Myeloma
  • Velcade (PS-341)
  • Bortezomib
  • Zarnestra (R115777)
  • Tipifarnib
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



H. Lee Moffitt Cancer Center & Research InstituteTampa, Florida  33612