Multiple MyelomaPhase 2NCT02254551
Safety/Efficacy Study of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma
A Phase 2 study testing LDE225 and Bortezomib in people with Multiple Myeloma, run by SCRI Development Innovations, LLC at 5 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- LDE225 and Bortezomib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 5 sitesUnited States
- Study dates
- Jan 2015to Oct 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have measurable MM requiring systemic therapy defined as at least one of the following:
- Serum M-protein ≥ 0.5 g/dL
- Urine M-protein ≥ 200 mg/24 hrs
- Serum free light chain assay: involved free light chain level ≥ 10 mg/dL provided the serum free light chain ratio is abnormal
- Must have progressed during or after at least two previous treatment regimens. Patients who have received previous high dose therapy or autologous stem cell transplantation are eligible.
- ECOG Performance Status score of 0-2.
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- Patients with adequate bone marrow, liver and renal function.
- Patient is able to swallow and retain oral medication.
- QTcF ≤450 msec for males and ≤ 470 msec for females on the screening ECG.
- Female patients must not be of childbearing potential or must agree to use adequate contraceptive measures.
- Male patients willing to use adequate contraceptive measures.
- Willingness and ability to comply with study and follow-up procedures.
- Ability to understand the nature of this study and give written informed consent.
Who cannot join
- Received any treatment for myeloma-directed treatment within 21 days. Localized radiation and dexamethasone must be completed within 7 days prior to study treatment
- Refractory to bortezomib, defined as progression on or within 60 days of last bortezomib dose.
- Received any investigational drug within 28 days or 5 half-lives (whichever is longer) prior to the first dose of LDE225. For other anti-neoplastic therapy (e.g., chemotherapy, targeted therapy or radiation), a minimum of 14 days between termination of the study drug and administration of LDE225 is required.
- Patients who have previously been treated with systemic LDE225 or with other Hedgehog (Hh) pathway inhibitors.
- Received major surgical procedures within 28 days of beginning study drug, or minor surgical procedures within 7 days. No waiting is required following port-a-cath placement.
- Those who are pregnant or lactating.
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- Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.
- Patients with > Grade 2 peripheral neuropathy (per NCI CTCAE V4.0) within 14 days prior to study enrollment.
- Patients with a presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and malabsorption syndrome).
- Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.
- Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on LDE225 treatment.
- Receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4 or CYP3A5, drugs that are BCRP substrates, or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4 or CYP3A5 inhibitors should be discontinued at least 7 days prior to starting LDE225. Strong CYP3A4 or CYP3A5 inducers should be discontinued at least 2 weeks weeks weeks prior to starting treatment with LDE225.
- Therapeutic doses of warfarin sodium or any other warfarin-derivative anticoagulants are not permitted since LDE225 is a competitive inhibitor of CYP2C9 based on the in vitro data. In this situation therapeutic anticoagulation may be accomplished using low molecular weight heparin (LMWH) or similar agents.
- Those diagnosed with cardiac conditions currently or within last 6 months.
- Those experiencing angina pectoris within 3 months.
- Those who experienced acute myocardial infarction within 3 months.
- Those with inadequately controlled hypertension defined as systolic blood pressure [SBP] > 180 mmHg or diastolic blood pressure (DBP) > 100 mmHg. Patients with values above these levels must have their blood pressure controlled with medication prior to starting treatment. Patients with a history of labile hypertension, or a history of poor compliance with an antihypertensive regimen are to be excluded.
- Pregnant or lactating women, where pregnancy is confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
- Patients who are not willing to apply highly effective contraception during the study and after the final dose of study treatment.
- Sexually active males who are unwilling to use a condom during intercourse while taking drug and for 6 months after stopping investigational medications and agree not to father a child in this period.
- Those with a serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
- Those presenting with other active cancers, or history of treatment for invasive cancer within 3 years. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
- Those with psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
Tennessee Oncology
Chattanooga, Tennessee, 37404
Oncology Hematology Care
Cincinnati, Ohio, 45236
Colorado Blood Cancer Institute
Denver, Colorado, 80218
Tennessee Oncology PLLC
Nashville, Tennessee, 37203
Texas Transplant Institute/Methodist Healthcare
San Antonio, Texas, 78229
About this study
Official title: Phase II Trial of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma With a Dose-Finding Lead-In
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.
Read the detailed description
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.
- Conditions
- Multiple Myeloma
- Being tested
- LDE225, Bortezomib
- Keywords
- relapsed multiple myeloma, refractory multiple myeloma, LDE225, Sonidegib, bortezomib, smoothened (SMO) inhibitors, Velcade
- Medical subject headings
- Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LDE225Drug
Also called Sonidegib
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.
BortezomibDrug
Also called Velcade
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.
| Study group | Role | What they receive |
|---|---|---|
| LDE225 Plus Bortezomib | Experimental | 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. Receives: Drug: LDE225; Drug: Bortezomib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of LDE225 Plus Bortezomib
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.
Measured: every 3 weeks up to 48 weeks
Time to Disease Progression
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.
Measured: every 3 weeks up to 48 weeks, then every 3 months thereafter up to 3 years from initiation of study treatment.
Secondary outcomes (1)
Overall Response
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.
Measured: Every 3 weeks up to 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Oct 2014 (estimated)
- Study startJan 2015
- Primary completionOct 2015
- Study completionOct 2015
Why it stopped: Safety lead-in data did not support continuation of study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Multiple MyelomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- SCRI Development Innovations, LLC
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Sponsor
- Investigators
- Jesus G. Berdeja, M.D., Study chair, SCRI Development Innovations, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02254551
- Sponsor's protocol ID
- SCRI MM 50
- Status last verified
- Dec 2016
- First submitted
- 29 Sep 2014
- Last updated
- 16 Feb 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma With a Dose-Finding Lead-In
- ClinicalTrials.gov ID
- NCT02254551
- Acronym / sponsor ID
- SCRI MM 50
- Conditions
- Multiple Myeloma
- Keywords
- relapsed multiple myeloma, refractory multiple myeloma, LDE225, Sonidegib, bortezomib, smoothened (SMO) inhibitors, Velcade
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Safety lead-in data did not support continuation of study.
- Enrolment
- 7 participants (actual)
- Lead sponsor
- SCRI Development Innovations, LLCUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- Jan 2015
- Primary completion
- Oct 2015 (actual)
- Study completion
- Oct 2015 (actual)
- First posted
- 2 Oct 2014 (estimated)
- Results
- Posted 16 Feb 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LDE225 Plus Bortezomib | Experimental | Drug: LDE225, Drug: BortezomibLead-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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Patients must have measurable MM requiring systemic therapy defined as at least one of the following:
- Must have progressed during or after at least two previous treatment regimens. Patients who have received previous high dose therapy or autologous stem cell transplantation are eligible.
- ECOG Performance Status score of 0-2.
- Patients with adequate bone marrow, liver and renal function.
- Patient is able to swallow and retain oral medication.
Key exclusion criteria (23 listed)
- Received any treatment for myeloma-directed treatment within 21 days. Localized radiation and dexamethasone must be completed within 7 days prior to study treatment
- Refractory to bortezomib, defined as progression on or within 60 days of last bortezomib dose.
- Received any investigational drug within 28 days or 5 half-lives (whichever is longer) prior to the first dose of LDE225. For other anti-neoplastic therapy (e.g., chemotherapy, targeted therapy or radiation), a minimum of 14 days between termination of the study drug and administration of LDE225 is required.
- Patients who have previously been treated with systemic LDE225 or with other Hedgehog (Hh) pathway inhibitors.
- Received major surgical procedures within 28 days of beginning study drug, or minor surgical procedures within 7 days. No waiting is required following port-a-cath placement.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LDE225Also: SonidegibLead-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. | Drug | LDE225 Plus Bortezomib |
| BortezomibAlso: VelcadeIn 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. | Drug | LDE225 Plus Bortezomib |
Primary outcome
Maximum Tolerated Dose (MTD) of LDE225 Plus Bortezomib
Time frame: every 3 weeks up to 48 weeks
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 Disease Progression
Time frame: every 3 weeks up to 48 weeks, then every 3 months thereafter up to 3 years from initiation of study treatment.
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.
1 secondary outcome
Overall Response
Time frame: Every 3 weeks up to 48 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jesus G. Berdeja, M.D. study chair
SCRI Development Innovations, LLC
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing LDE225 and Bortezomib in people with Multiple Myeloma, run by SCRI Development Innovations, LLC at 5 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of LDE225 Plus Bortezomib (time frame: every 3 weeks up to 48 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2017.