Sorafenib and Bortezomib Treatment for Relapsed or Refractory Multiple Myeloma Patients

Phase 1

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: Bortezomib; Drug: Sorafenib

• Registration Number: NCT00536575
• Lead Sponsor: SCRI Development Innovations, LLC

Brief Summary

This is a single-arm Phase I/II study of sorafenib and bortezomib with dose optimization in initial patients. The initial patients on the dose-finding portion of this study will be enrolled through a single institution. Following establishment of the Phase II dose the study will open enrollment throughout the Sarah Cannon Research Institute (SCRI) Oncology Research Consortium.

The purpose of this study is to develop the combination of bortezomib (which is proven to be clinically active in patients with multiple myeloma) with sorafenib (a potent inhibitor of angiogenesis). This regimen will be developed in a schedule that is convenient for patients, and that is as minimally toxic to patients as possible.

Detailed Description

Primary Objective:

To evaluate the efficacy of sorafenib with weekly bortezomib, as measured by objective response rate and progression-free survival in patients with relapsed/refractory multiple myeloma.

Secondary Objective:

To evaluate the feasibility and toxicity of sorafenib with weekly bortezomib in the treatment of patients with relapsed/refractory multiple myeloma.

Study Timeline

• Study First Submitted: 2007-09-26
• Study First Submitted QC: 2007-09-27
• Study First Posted: 2007-09-28
• Study Start: 2007-11
• Primary Completion: 2010-02
• Study Completion: 2010-08
• Status Verified: 2013-01
• Results First Submitted: 2013-01-23
• Results First Submitted QC: 2013-01-23
• Last Update Submitted: 2013-01-23
• Results First Posted: 2013-02-27
• Last Update Posted: 2013-02-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

• Eligible participants must have been previously diagnosed using standard criteria and have received no more than 2 prior regimens for the treatment of multiple myeloma.
• Participant must be defined as Relapsed or Refractory Disease by one of the following criteria prior to enrollment: Relapsed Disease after high-dose therapy (autologous stem cell transplantation) as part of the first-line line treatment program. These patients may have received a maximum of 1 previous regimen, Refractory Disease or Relapsed Disease after > 1 prior therapy for multiple myeloma. Prior bortezomib treatment permitted if the patient achieved a documented response.
• ECOG performance status 0, 1, or 2.
• WBC >= 3000; ANC >= 1000; platelets >= 50,000 (Patients with platelets >= 30,000 are eligible if thrombocytopenia is felt to be due to extensive bone marrow involvement with myeloma).
• Serum creatinine < 2.0 mg/dL for a calculated or measured creatinine clearance > 30 mL/minute
• Total bilirubin < 1.5 x ULN
• ALT and AST < 2.5 x the ULN ( < 5 x ULN for patients with liver involvement)
• INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
• Patients must have measurable or evaluable disease. In patients with disease limited to bone and bone marrow, serial paraprotein measurements are acceptable for evaluable disease.

Exclusion Criteria

• Patients with > grade 1 peripheral neuropathy.
• Thrombolic or embolic events such as a cerebrovascular accident, including transient ischemic attacks, within the past 6 months.
• Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
• Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
• Known brain metastasis. Patients with neurological symptoms must undergo CT scan/MRI of the brain to exclude brain metastasis.
• Patients with other medical conditions that would potentially interfere with their participation in this trial.
• Patients with other active malignancies, or history of treatment for other invasive cancers, within 3 years of study entry.
• Patients with previous evidence of hypersensitivity to sorafenib, bortezomib, boron, or mannitol.
• Women who are pregnant or lactating are ineligible. All patients of childbearing potential are required to use adequate methods of contraception while receiving study treatment, and for at least 2 weeks after the last dose of sorafenib. Men should continue to use contraception until at least 3 months after their last dose of sorafenib.
• Evidence of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome.
• Cardiac disease: Congestive heart failure > class II NYHA (see Appendix D.) Patients must not have unstable angina (anginal symptoms at rest), new onset angina (began within the last 3 months), or myocardial infarction within the past 6 months.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
• Active clinically serious infection > CTCAE Grade 2.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intervention	Bortezomib	The trial was designed as a single-arm Phase I/II study of sorafenib and bortezomib with dose optimization in initial patients. Phase I consisted of cohorts of 3 patients at each of three dose levels. Patients received bortezomib (Dose Level 1 - 1.3 mg/m2; Dose Level 2 - 1.6 mg/m2) by IV bolus on days 1, 8, 15, and 22 of each 5-week cycle with continuous oral dosing of sorafenib at 200 mg twice daily. Dose level 3 was planned as bortezomib 1.6 mg/m2 IV bolus on days 1, 8, 15, and 22 with sorafenib 400 mg by mouth twice daily throughout each 5-week cycle.
Intervention	Sorafenib	The trial was designed as a single-arm Phase I/II study of sorafenib and bortezomib with dose optimization in initial patients. Phase I consisted of cohorts of 3 patients at each of three dose levels. Patients received bortezomib (Dose Level 1 - 1.3 mg/m2; Dose Level 2 - 1.6 mg/m2) by IV bolus on days 1, 8, 15, and 22 of each 5-week cycle with continuous oral dosing of sorafenib at 200 mg twice daily. Dose level 3 was planned as bortezomib 1.6 mg/m2 IV bolus on days 1, 8, 15, and 22 with sorafenib 400 mg by mouth twice daily throughout each 5-week cycle.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR), the Percentage of Patients Who Experience an Objective Benefit From Treatment	24 months	The percentage of patients who experience an objective benefit from treatment, determined by the treating physician after reviewing key laboratory values from blood and urine.

Trial Locations

Locations (2)

Center for Cancer and Blood Disorders; 🇺🇸 Bethesda, Maryland, United States

Tennessee Oncology, PLLC; 🇺🇸 Nashville, Tennessee, United States