A Study of Oral LGH447 in Patients With Relapsed and/or Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this dose escalation study is to estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of LGH447 as a single agent when administered orally once daily to adult patients with Multiple Myeloma (MM).

Official Title
-----------------
A Multi-Center, Open-Label, Dose Escalation, Phase 1 Study of Oral LGH447 in Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: LGH447
* Drug: midazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of multiple myeloma that is relapsed and/or refractory for which no curative option exists. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. During the dose expansion part of the study patients must have measurable disease defined by at least 1 of the following 2 measurements: Serum M-protein ≥ 0.5 g/dL Urine M-protein ≥ 200 mg/24 hours Serum free light chain (FLC) > 100 mg/L of involved FLC Exclusion Criteria: Patients who are currently receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with LGH447: Strong inhibitors or inducers of CYP3A4 CYP3A4 substrates with narrow therapeutic index Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGH447<br>Eligible patients will be treated with oral LGH447 until disease progression or occurrence of unacceptable toxicity. | Drug: LGH447<br> <br> |
| Experimental: LGH447 and midazolam<br>Eligible patients will receive midazolam on two separate days, the first dose will be administered prior to the start of LGH447 and the second will be co-administered with LGH447. After that, the patients will continue to be treated with oral LGH447 until disease progression or occurrence of unacceptable toxicity. | Drug: LGH447<br> <br> Drug: midazolam<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the MTD and/or RDE | Incidence rate of dose limiting toxicity | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events and serious adverse events. | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | 18 months | 
| Pharmacokinetic (PK) effects of LGH447 | Summary of PK parameters such as AUC, Cmax, | 18 months | 
| Pharmacodynamic (PD) effects of LGH447 | Changes between pre and post treatment levels in bone marrow aspirates and whole blood. | 18 months | 
| Anti-Myeloma activity associated with LGH447 | Overall Response Rate (ORR), Duration of Response (DOR), and Progression Free Survival (PFS) based on International Myeloma Working Group Response Criteria. | 18 months | 
| Effect of multiple-doses of LGH447 on the PK of midazolam | PK parameters of midazolam and 1-hydroxymidazolam, such as AUC and Cmax, as well as metabolic ratio of midazolam. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myeloma, Multiple Myeloma, MM