Oral Enzastaurin in Participants With Relapsed Mantle Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purposes of this study are to determine the safety of oral enzastaurin and any side effects that might be associated with it and whether enzastaurin can help participants with mantle cell lymphoma.

Official Title
-----------------
A Phase 2 Study of Oral Enzastaurin HCl in Patients With Relapsed Mantle Cell Lymphoma

Conditions
-----------------
Mantle-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: enzastaurin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Mantle cell lymphoma Previous treatment for mantle cell lymphoma Previously relapsed mantle cell lymphoma with no more than 4 chemotherapy regimens. Have discontinued all previous therapies for cancer, except corticosteroids up to 25 milligrams per day (mg/day) Adequate organ function Exclusion Criteria: Inability to swallow tablets Must not have significant heart problems

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: enzastaurin<br>* 500 milligrams (mg), oral, daily, up to six 28-day cycles<br>* Other names: LY317615;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Freedom From Progression (FFP) for at Least 3 Cycles | Using the Standardized Response Criteria for non-Hodgkin's lymphomas, participants were considered to have progressive disease if there was a 50% increase in the sum of the products of the greatest diameters (SPD) of the dominant nodal and non-nodal sites or appearance of new-involved site or lesion. The percentage of FFP was computed as the number of participants documented to be progression free after 3 cycles of treatment divided by the number of treated participants and then multiplied by 100. | Baseline through at least 3 cycles of treatment (28-day cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) Plus Unconfirmed Complete Response (CRu) Plus Partial Response (PR) (Objective Response Rate) |  | Baseline to 22.01 months | 
| Progression-Free Survival (PFS) | PFS time was defined as the time from the date of enrollment to the first date of documented progressive disease or death due to any cause, whichever occurred first. Using the Standardized Response Criteria for non-Hodgkin's lymphomas, participants were considered to have progressive disease if there was a 50% increase in the sum of the products of the greatest diameters (SPD) of the dominant nodal and non-nodal sites or appearance of new-involved site or lesion. Progression-free survival time was censored at the date of the last assessment visit for participants who were still alive and who had not had documented progressive disease. | Baseline to measured progressive disease or death due to any cause up to 22.01 months | 
| Overall Survival (OS) | OS was defined as the time from the date of enrollment to the date of death due to any cause. For each participant who was not known to have died as of the data-inclusion cut-off date, OS was censored for that analysis at the date of the last assessment visit prior to the cut-off date. | Baseline to date of death from any cause at least up to 23.10 months | 
| Duration of CR, CRu, PR or Stable Disease (SD) [Duration of Overall Response] | Duration of overall response for responders was measured from the date that measurement criteria were met for CR, CRu, PR or SD (whichever status occurred first) until the first date of documented progressive disease or death due to any cause, whichever occurred first. Using the Standardized Response Criteria for non-Hodgkin's lymphomas Guidelines, CR was defined as the disappearance of all lesions. CRu was the disappearance of clinical and radiographic evidence of disease, normal appearance of spleen and greater than 75% regression in lymph node mass. PR was defined as at least a 50% decrease in the six largest dominant nodes. SD was when the response was poorer than partial response with no new lesions consistent with progressive disease. Duration of response was censored at the date of the last assessment visit for responders who were still alive and had not had documented progressive disease. | Date of progression or death due to any cause up to 22.01 months | 
| Time to New Treatment | Time to new treatment was as the time from enrollment to the date new treatment for the cancer under study was initiated. Time to new treatment was censored at the date of the last assessment visit for participants who were not documented to have initiated a new treatment. | Baseline to date of new treatment up to 23.10 months | 
| Change in Scores From Baseline to Cycle 6 in Functional Assessment of Cancer Therapy Lymphoma Version 4 ( FACT-Lym v.4) | The B symptoms, tumor-related symptoms, participant functioning, and health-related quality of life were assessed with FACT-Lym v. 4. FACT-Lym v. 4 consists of 42 items with 5-point rating scales for each item, where 0 = not at all and 4 = very much. Physical well-being, social/family well-being and functional well-being subscales consist of 7 items each with scores ranging from 0-28. The emotional well-being subscale consists of 6 items with a score ranging from 0-24. The lymphoma tumor - specific subscale consists of 15 items with a score ranging from 0-60. Fact-Lymphoma total score ranges from 0-168. A higher score represents better quality of life. | Baseline, Cycles 2, 4 and 6 (28-day cycle) | 
| Change From Baseline to Cycle 6 in European Quality of Life-5D (EuroQol-5D) Index Score (Overall Health Status) | Overall health status and participant utility values were measured with the EuroQol-5D questionnaire. EuroQol-5D describes health status in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension is divided into 3 levels: 1 (no problem), 2 (some problem), and 3 (extreme problem). The questionnaire records the level of problems on each of 5 dimensions and is converted into the EuroQol-5D index based on preference weights (Dolan 1997), where a score of 0.0 = death and 1.0 = perfect health. | Baseline, Cycles 2, 4 and 6 | 
| Number of Participants With Protein Kinase C Beta (PKCβ) Expression by Immunohistochemistry (IHC) Staining | IHC staining of tumor samples was carried out to determine PKCβ expression. Staining intensity was measured on a semiquantitative scale of 0 (or negative) to 3 (high intensity). The final score combined the components of staining intensity and the percentage of positive cells and was defined as [1 * (percentage of cells staining at 1)] + [2 * (percentage of cells staining at 2)] + [3 * (percentage of cells staining at 3)]. Score ≥100 and staining intensity ≥2 indicates high expression for PKCβ, while score <100 and staining intensity ≤1 indicates low expression for PKCβ. | Baseline | 
| Number of Participants With High Ki-67 Expression by IHC Staining | IHC staining of tumor samples was carried out to determine Ki-67 expression. High expression is defined as the percentage of positive cells ≥40%. | Baseline | 
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) (Safety of Enzastaurin) | Data presented are the number of participants who experienced SAEs, AEs, deaths due to progressive disease (PD), and deaths due to AEs while on treatment and death during the 30-day post-treatment follow-up. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | Each cycle (28-day cycle) up to 21 cycles and 30-day follow-up | 
| Average Steady-State Plasma Concentration (Cav,ss,) of Enzastaurin and Total Analytes (Pharmacokinetics of Enzastaurin and Total Analytes) | The Steady-state plasma concentrations of total analytes (enzastaurin plus its active metabolite, LSN326020) observed after once-daily dosing were evaluated using sparse sampling methodology. | Cycles 1 [1-4 hours (h) and 4-8 h postdose], 2 (predose, 2-4 h and 6-8 h postdose), and 3 (predose and 2-8 h postdose) of Day 1 of each 28-day cycle |