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All Drugs and Chemicals

Bortezomib

Lead-In Portion: The lead-in portion of this study will investigate the safety and tolerability, and determine the MTD of LDE225, in combination with bortezomib in this patient population.

Expansion Portion: Eligible patients will receive LDE225 orally once daily for 21 days with the dose-level determined in the lead-in portion of the study. Eligible patients will also receive a standard regimen of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.

Lead-In: LDE225 will be administered orally at three dose levels starting at 400mg. If acceptable tolerability is demonstrated, escalations may continue up to 800 mg. LDE225 will be administered orally as a single daily dose for 21 days in combination with a fixed dose of bortezomib to be given on Days 1, 4, 8, 11 of each 21 day cycle.

Dose Expansion: LDE225 will be given as a single oral daily dose for 21 days at the MTD determined in the lead-in phase.

Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.

LDE225

In both the lead-in and dose expansion portions of the study, bortezomib, 1.3 mg/m2, will be administered by subcutaneous injection (SQ) on Days 1, 4, 8, 11 of each 21 day cycle.

Jesus G. Berdeja, M.D.

The purpose of the study is to determine whether the combination of LDE225 (sonidegib) plus bortezomib is safe and effective in the treatment of relapsed or relapsed/refractory multiple myeloma.

Although multiple myeloma (MM) is considered fatal, survival has dramatically improved with the introduction of more effective treatment options. Despite these advances, all patients eventually relapse and MM is generally considered incurable. LDE225 (Sonidegib) is an oral, investigational smoothened (SMO) inhibitor that has shown anti-tumor activity in certain cancers. Bortezomib is a highly active drug for the treatment of MM and has produced response rates in relapsed and/or refractory patients. This study will investigate the tolerability and feasibility of combining LDE225 with bortezomib in patients with bortezomib-sensitive relapsed or relapsed/refractory MM.

Safety/Efficacy Study of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

Phase II Trial of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma With a Dose-Finding Lead-In

During the safety lead-in, a standard 3+3 dose escalation design was used to establish the MTD for LDE225 in combination with bortezomib. The MTD would be determined by the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) during one cycle (21 days) of therapy. If 2 of 6 patients within a dose level experienced a DLT, that dose level would be defined as exceeding MTD and no further dose escalation would occur. The previous dose level would be considered the MTD.

Time to progression (TTP) is measured from Day 1 of study drug administration to disease progression using International Myeloma Working Group (IMWG) Uniform Response Criteria.

Number of patients with confirmed Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Progressive Disease (PD) or Stable Disease (SD) according to International Myeloma Working Group (IMWG) Uniform Response Criteria. CR=5% or less plasma cells in bone marrow, disappearance of soft tissue plasmacytoma, negative immunofixation on serum and urine. VGPR=Serum and urine M-protein detectable by immunofixation but not by electrophoresis, disappearance of any soft tissue plasmacytomas that were present at baseline. PR= at least 50% reduction from baseline in serum M-protein and at least 90% reduction from baseline in 24hr urinary M-protein. PD=Increase of 25% or more from nadir in serum or urine proteins. SD= not meeting criteria for CR, VGPR, PR or PD.

Novartis

SCRI Development Innovations, LLC

All patients who received at least one dose of LDE225 plus bortezomib.

Cohort 1 will receive LDE225 orally on a daily basis, at 400mg/m\^2 every 21 days.

Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Cohort 1: LDE225 400mg/m^2

Cohort 2 will receive LDE225 orally on a daily basis, at 600 mg every 21 days. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Cohort 2: LDE225 600mg/m^2

Cohort 3 will receive LDE225 orally on a daily basis, at 800mg/m\^2 every 21 days.

Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Cohort 3: LDE225 800mg/m^2

Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg.

Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.

LDE225 Plus Bortezomib

Age, Continuous

Gender

Caucasian

Black or African AMerican

Unknown

Race/Ethnicity, Customized

United States

Region of Enrollment

Early termination of study during dose-escalation did not support continuation of study.

Charles Davis, Sr Mgr Regulatory Strategy & Operations

Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg.

Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity

Maximum Tolerated Dose (MTD) of LDE225 Plus Bortezomib

Safety Lead-In: LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg for 21 days.

Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.

Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.

This outcome measure was to be assessed during the expansion phase of the study. The study closed early and did not proceed to this phase of the study. There is no data to report for this outcome measure.

Time to Disease Progression

Of 7 enrolled patients, 1 was deemed ineligible and was excluded from efficacy analyses. At a median follow-up of 6 weeks, 3 patients in Cohort 1 had progressive disease and 3 had stable disease. Study was terminated after reviewing data from this first lead-in cohort.

Spots Global Cancer Trial Database for smoothened (smo) inhibitors