Tipifarnib and Bortezomib in Treating Patients With Relapsed Multiple Myeloma

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00243035
First received: October 20, 2005
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Refractory Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: bortezomib
Drug: tipifarnib
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Dose Escalation Study of R115777 (Zarnestra) Combined With Velcade® (PS-341) in Patients With Relapsed Multiple Myeloma.

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I) [ Time Frame: Up to day 21 ] [ Designated as safety issue: Yes ]
  • Response rate (complete response [CR] + partial response [PR]) determined using the Bladé Response criteria (phase II) [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Exact 95% confidence intervals constructed.

  • Toxicities, graded according to the NCI CTCAE v3.0 (phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Proportion of patients overcoming CAM-DR [ Time Frame: Prior to therapy ] [ Designated as safety issue: No ]
    An exact 95% confidence interval for that proportion will be computed.

  • Proportion of patients overcoming CAM-DR [ Time Frame: Day 11 of course 1 ] [ Designated as safety issue: No ]
    An exact 95% confidence interval for that proportion will be computed.

  • Relationship of overcoming CAM-DR and clinical response [ Time Frame: Prior to therapy ] [ Designated as safety issue: No ]
    Compared using a chi-square contingency table test at the two-sided 0.05 significance level.

  • Relationship of overcoming CAM-DR and clinical response [ Time Frame: Day 11 of course 1 ] [ Designated as safety issue: No ]
    Compared using a chi-square contingency table test at the two-sided 0.05 significance level.

  • Clinical resistance and levels of phosphorylated Akt [ Time Frame: Prior to therapy ] [ Designated as safety issue: No ]
    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.

  • Clinical resistance and levels of phosphorylated Akt [ Time Frame: Day 11 of course 1 ] [ Designated as safety issue: No ]
    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.

  • Correlation of molecular profiles from primary isolates with clinical response [ Time Frame: Prior to therapy ] [ Designated as safety issue: No ]
    Compared using paired t tests at the 0.05 significance level.

  • Correlation of molecular profiles from primary isolates with clinical response [ Time Frame: Day 11 of course 1 ] [ Designated as safety issue: No ]
    Compared using paired t tests at the 0.05 significance level.

  • Progression-free survival (phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Summarized with Kaplan-Meier curve and related statistics.


Estimated Enrollment: 64
Study Start Date: August 2005
Primary Completion Date: February 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (bortezomib, tipifarnib)

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
Given IV
Drug: tipifarnib
Given orally
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00243035

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
Investigators
Principal Investigator: Darrin Beaupre H. Lee Moffitt Cancer Center and Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00243035     History of Changes
Other Study ID Numbers: NCI-2012-02675, NCI-2012-02675, MCC-VEL-04-111, CDR0000446083, NCI-7032, VEL-04-111, 7032, R01CA083978
Study First Received: October 20, 2005
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Tipifarnib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014