Study of Efficacy and Safety of LDE225 in Adult Patients With Relapsed/Refractory Acute Leukemia

Study Overview
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Brief Summary
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The study will evaluate the efficacy, safety and tolerability of two dosing schedules of LDE225 in patients with relapsed/refractory acute leukemia or elderly patients with untreated acute leukemia.

Official Title
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A Phase II Multi-center, Open Label, Randomized Study to Assess Safety and Efficacy of Two Different Schedules of Oral LDE225 in Adult Patients With Relapsed/Refractory or Untreated Elderly Patients With Acute Leukemia

Conditions
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Acute Leukemias

Intervention / Treatment
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* Drug: LDE225


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have relapsed or primary refractory non-M3 acute myeloid leukemia or relapsed or refractory non-T-cell acute lymphoblastic leukemia or untreated acute myeloid leukemia in elderly patients. Performance status of 0, 1 or 2 per WHO classification. Adequate renal and liver function. Adequate blood creatine kinase value (CK < 1.5ULN) Exclusion Criteria: Allogeneic stem cell transplantation within the last 4 months and/or active graft versus host disease requiring systemic immunosuppressant therapy, or autologous stem cell transplantation within the last 4 weeks. Patient for which immediate allogeneic stem cell transplantation is the treatment of choice. Pregnant or nursing (lactating) women. Active CNS leukemic involvement

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDE225-400<br>Patients who were randomized to Schedule A, and received 400 mg LDE225 twice daily for the first two weeks only and then after two weeks, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study. | Drug: LDE225<br>* LDE225 will be supplied as 200 mg capsules by Novartis. Patients will receive study treatment on an outpatient basis. LDE225 will be dispensed every two weeks for the first four weeks and at the start of every four weeks thereafter, as needed.<br>|
| Experimental: LDE225-800<br>Patients who were randomized to Schedule B, received 800 mg LDE225 once daily until disease progression, toxicity, withdrawal of consent, death, discretion of the investigator or early termination of the study. | Drug: LDE225<br>* LDE225 will be supplied as 200 mg capsules by Novartis. Patients will receive study treatment on an outpatient basis. LDE225 will be dispensed every two weeks for the first four weeks and at the start of every four weeks thereafter, as needed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission (CR) | Complete Response (CR) was based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CR. A treatment cycle was defined as 4 weeks. The outcome measure for the study is based on standardized response criteria as defined by the International Working Group (IWG) for AML. The IWG was established by a group of investigators interested in the design and conduct of clinical trials in acute myeloid leukemia (AML). The criteria established by this group (a set of recommendations for response assessment) are well established, endorsed by major institutions and Health Authorities, and are widely used in clinical trials. No statistical analysis was planned for this primary outcome. | at screening, every week up to Week 9, every 2 weeks thereafter until CR, every 4 weeks after CR up to 24 months | 
| Complete Remission With Incomplete Blood Count Recovery (CRi) | The other primary efficacy endpoint was CRi based on the International Working Group (IWG) criteria based on weekly peripheral blood count measurements and bone marrow biopsy/aspiration collection. Efficacy assessments were performed to determine CRi. A treatment cycle was defined as 4 weeks. No statistical analysis was planned for this primary outcome. | within 3 days after clearance of blasts from peripheral blood (PB), monthly thereafter until CR or reappearance of blasts in the PB, after CR every other month until discontination up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parmacokintics (PK) Parameter: AUC0-8h | AUC0-8h is the area under the concentration-time curve from time zero to 8 hours. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-8h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters. | Week 1 Day 1,Week 9 Day 1 | 
| Parmacokintics (PK) Parameter: AUC0-24h | AUC0-24 is the area under the concentration-time curve from time zero to 24 hours done only on 800 mg once a day schedule. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. AUC0-24h was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters. | Week 1 Day 1,Week 9 Day 1 | 
| Overall Response Rate (ORR) | ORR was the rate of complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial response (PR) according to IWG criteria. CR, CRi or PR will be assessed through bone marrow biopsy/aspirate and peripheral blood blasts counts. | Every 8 weeks for the first 6 months and every 12 weeks until 53 weeks after the last patient is enrolled or until relapse up to 24 months | 
| Parmacokintics (PK) Parameter: Cmax | Cmax is the maximum observed plasma concentration after drug administration.The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the pharmacokineticist. Cmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters. | Week 1 Day 1, Week 9 Day 1 | 
| Parmacokintics (PK) Parameter: Tmax | Tmax is the time to reach Cmax. The PK parameters were determined in plasma using non-compartmental methods. A PK sample was excluded from analyses if the patient vomited within the first 4 hours following the last oral dose of study drug. Other PK samples were excluded as deemed appropriate by the Pharmacokineticist. Tmax was derived from the PK concentrations collected at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose on W1D1 and W9D1. The PK concentration at each time point is not an endpoint in the protocol, but these concentrations are used to derive the PK parameters. | Week 1 Day 1,Week 9 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, acute myeloid leukemia, acute lymphoblastic leukemia, leukemia, acute, LDE225, adult patients, relapsed/refractory, ALL