A Study of Oral LY317615 in Relapsed or Refractory Diffuse Large B-Cell Lymphomas.

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00042666
• Collaborator: (none)
• Enrollment: 55
• Locations: 3
• Arm: 1
• Duration (Months): 75
• Patients Per Site: 18.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will measure the effectiveness and any side effects of LY317615 in participants with diffuse large B-cell lymphoma (DLBCL: a sub-type of Non-Hodgkins Lymphoma).

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma	Drug: LY317615	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Evaluation of Oral LY317615 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
• Study Start Date: Jun 1, 2002
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY317615 500 milligrams (mg), oral, daily (QD), up to six (6) 28-day cycles	Drug: LY317615; 500 mg, oral, QD, up to six 28 day cycles; Other Names: enzastaurin

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Relapsed or Refractory DLBCL Who Are Progression-Free for at Least 2 Cycles (28-Day Cycles) After Receiving Enzastaurin (LY317615) (Clinical Response Rate) [Randomization to measured progressive disease (PD) up to 34.3 months]

   Clinical Response Rate in participants with DLBCL was calculated as (number of participants who were progression-free for at least two 28-day cycles [clinical responder]) divided by (total number of participants analyzed) multiplied by 100. Progression free survival (PFS) defined as the time from randomization to the first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v 1.0) as 20% increase in the sum of the of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Overall Response Rate) [Randomization to measured PD or death up to 34.3 months]

   Overall response rate was defined as best study response (CR or PR) using modified Southwest Oncology Group (SWOG) Response criteria. CR defined as the disappearance of detectable clinical and radiographic evidence of disease; regression of lymph nodes, nodal masses and spleen to normal size and absence of lymphoma in bone marrow infiltrate. PR was defined as a ≥50% decrease in the sum of the products of their diameters (SPD) in the 6 largest dominant nodes or nodal masses; no increase in size in the other nodes or liver or spleen; regression of nodes/lesions in organs by ≥50% in the SPD; or no new disease sites. The percentage participants was calculated as: (number of participants with CR or PR) divided by (number of participants qualified for tumor response analysis) multiplied by 100.

2. Progression Free Survival (PFS) [Randomization to PD or death due to any cause up to 34.3 months]

   PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of last follow-up visit. Progression is determined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v 1.0) as 20% increase in the sum of the of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

3. Duration of Overall Response (DOR) [Time of response to PD up to 34.3 months]

   Duration of CR or PR was defined as the time from first objective assessment to first time of disease progression or death from any cause using the modified SWOG Response criteria. CR defined as the disappearance of detectable clinical and radiographic evidence of disease, regression of lymph nodes, nodal masses and spleen to normal size and absence of lymphoma in bone marrow infiltrate. PR was defined as a ≥50% decrease in the SPD in the 6 largest dominant nodes or nodal masses, no increase in size in the other nodes, liver or spleen, regression of nodes/lesions in organs by ≥50% in the SPD, and no new disease sites. PD defined as >50% increase in SPD of the dominant nodal/non-nodal sites or new lesions. For participants who died, the duration of response was censored at death. For participants still alive, duration of overall response was censored at the last visit or follow-up visit. DOR was not analyzed due to low number of responders (CR or PR).

4. Number of Participants With Adverse Events (AEs) or Who Died [Randomization to study completion [Baseline up to 37 cycles (28-day cycles, 34.3 months) and 30-day follow-up]]

   Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs. Participants who died due to PD, AEs while on treatment or died during the 30-day post-treatment period are included. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

5. Pharmacokinetics (PK): Area Under the Concentration Time Curve at Steady State for One Dosing Interval (AUC0-24,ss) of Enzastaurin and Its Metabolite LY326020 [Cycle 1 Day 1 predose, 1 to 4 hours postdose and Cycle 1 Day 28 predose and at least 1-hour postdose (28-day cycle)]

   AUC0-24,ss during 1 dosing interval at steady state for Enzastaurin and its metabolite LY326020.

6. PKCβ Expression by IHC in Readily Assessable DLBCL Tumors From Participants [Baseline]

   Protein expression was measured (cytoplasmic staining) using an IHC assay from a small subset of tumor tissue samples that were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, where higher staining indicated a greater PKCβ expression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A diagnosis of recurrent or refractory DLBCL.

• Adequate organ functions.

• Able to swallow capsules.

Exclusion Criteria:

• More than 3 prior treatments for this disease.

• Serious heart problems.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Royal Oak	Michigan	United States
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Minneapolis	Minnesota	United States
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rochester	Minnesota	United States

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern Time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00042666
• Other Study ID Numbers: 4849; H6Q-MC-JCAI; NCT00054080
• First Posted: Aug 6, 2002
• Last Update Posted: Aug 10, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse

Study Results

Participant Flow

Pre-assignment Detail	Participant Flow is reporting participants who discontinued from study drug. Per the protocol, a participant completed the study if the planned duration of treatment (6 cycles) was completed in the absence of disease progression or other reasons for discontinuation.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 milligrams (mg) enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Period Title: Overall Study
STARTED	55
Received at Least 1 Dose of Study Drug	55
Completed at Least 1 Cycle of Study Drug	42
COMPLETED	1
NOT COMPLETED	54

Baseline Characteristics

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Overall Participants	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.4 (11.17)
Sex: Female, Male (Count of Participants)
Female	28 50.9%
Male	27 49.1%
Race/Ethnicity, Customized (Count of Participants)
White	50 90.9%
Black or African American	2 3.6%
Asian	1 1.8%
Hispanic	2 3.6%
Region of Enrollment (Count of Participants)
United States	55 100%
PKCβ expression by IHC in DLBCL Tumors (Count of Participants)
PKCβ Negative	1 1.8%
PKCβ +1	1 1.8%
PKCβ +3	1 1.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Relapsed or Refractory DLBCL Who Are Progression-Free for at Least 2 Cycles (28-Day Cycles) After Receiving Enzastaurin (LY317615) (Clinical Response Rate)
Description	Clinical Response Rate in participants with DLBCL was calculated as (number of participants who were progression-free for at least two 28-day cycles [clinical responder]) divided by (total number of participants analyzed) multiplied by 100. Progression free survival (PFS) defined as the time from randomization to the first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v 1.0) as 20% increase in the sum of the of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Randomization to measured progressive disease (PD) up to 34.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants who remained on study for at least 1 cycle of treatment.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	42
Number (95% Confidence Interval) [percentage of participants]	21.8 39.6%

2. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Overall Response Rate)
Description	Overall response rate was defined as best study response (CR or PR) using modified Southwest Oncology Group (SWOG) Response criteria. CR defined as the disappearance of detectable clinical and radiographic evidence of disease; regression of lymph nodes, nodal masses and spleen to normal size and absence of lymphoma in bone marrow infiltrate. PR was defined as a ≥50% decrease in the sum of the products of their diameters (SPD) in the 6 largest dominant nodes or nodal masses; no increase in size in the other nodes or liver or spleen; regression of nodes/lesions in organs by ≥50% in the SPD; or no new disease sites. The percentage participants was calculated as: (number of participants with CR or PR) divided by (number of participants qualified for tumor response analysis) multiplied by 100.
Time Frame	Randomization to measured PD or death up to 34.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	55
Number [percentage of participants]	3.64 6.6%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of last follow-up visit. Progression is determined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v 1.0) as 20% increase in the sum of the of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Randomization to PD or death due to any cause up to 34.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug. Five (5) participants were censored.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	55
Median (95% Confidence Interval) [months]	1.51

4. Secondary Outcome

Title	Duration of Overall Response (DOR)
Description	Duration of CR or PR was defined as the time from first objective assessment to first time of disease progression or death from any cause using the modified SWOG Response criteria. CR defined as the disappearance of detectable clinical and radiographic evidence of disease, regression of lymph nodes, nodal masses and spleen to normal size and absence of lymphoma in bone marrow infiltrate. PR was defined as a ≥50% decrease in the SPD in the 6 largest dominant nodes or nodal masses, no increase in size in the other nodes, liver or spleen, regression of nodes/lesions in organs by ≥50% in the SPD, and no new disease sites. PD defined as >50% increase in SPD of the dominant nodal/non-nodal sites or new lesions. For participants who died, the duration of response was censored at death. For participants still alive, duration of overall response was censored at the last visit or follow-up visit. DOR was not analyzed due to low number of responders (CR or PR).
Time Frame	Time of response to PD up to 34.3 months

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	2
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) or Who Died
Description	Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs. Participants who died due to PD, AEs while on treatment or died during the 30-day post-treatment period are included. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Randomization to study completion [Baseline up to 37 cycles (28-day cycles, 34.3 months) and 30-day follow-up]

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) was administered orally at dose in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	55
Non-serious AEs	51 92.7%
Serious AEs	21 38.2%
Deaths Due to PD	3 5.5%
Deaths Due to AEs	1 1.8%
Deaths in 30-day follow-up	11 20%

6. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Time Curve at Steady State for One Dosing Interval (AUC0-24,ss) of Enzastaurin and Its Metabolite LY326020
Description	AUC0-24,ss during 1 dosing interval at steady state for Enzastaurin and its metabolite LY326020.
Time Frame	Cycle 1 Day 1 predose, 1 to 4 hours postdose and Cycle 1 Day 28 predose and at least 1-hour postdose (28-day cycle)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had evaluable PK data to calculate AUC0-24,ss.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	33
Enzastaurin	14800 (83.2)
LY326020	14200 (39.6)

7. Secondary Outcome

Title	PKCβ Expression by IHC in Readily Assessable DLBCL Tumors From Participants
Description	Protein expression was measured (cytoplasmic staining) using an IHC assay from a small subset of tumor tissue samples that were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, where higher staining indicated a greater PKCβ expression.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Participants who had paired diagnositic and relapsed tumor assessed for PKCβ expression.

Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin (LY317615) tablets were administered in the morning within 30 minutes following a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
Measure Participants	3
2+ at Diagnosis and 2+ at Relapse	1 1.8%
0 at Diagnosis and 1+ at Relapse	1 1.8%
3+ and 0 at Diagnosis and 3+ at Relapse	1 1.8%

Adverse Events

Adverse Event Reporting Description	Study-specific clinical outcomes due to PD were not considered to be a SAE unless the investigator deemed it related to the use of the study drug.
Arm/Group Title	Enzastaurin
Arm/Group Description	500 mg enzastaurin tablets were administered in the morning within 30 minutes of a meal for 28 days (1 cycle) to be continued for up to 6 cycles in the absence of disease progression.
All Cause Mortality
	Enzastaurin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Enzastaurin
	Affected / at Risk (%)	# Events
Total	21/55 (38.2%)
Blood and lymphatic system disorders
Anaemia	1/55 (1.8%)	1
Cardiac disorders
Angina unstable	2/55 (3.6%)	2
Gastrointestinal disorders
Abdominal pain	3/55 (5.5%)	3
Constipation	1/55 (1.8%)	1
Gastritis	1/55 (1.8%)	1
Rectal haemorrhage	1/55 (1.8%)	1
General disorders
Asthenia	2/55 (3.6%)	2
Fatigue	1/55 (1.8%)	1
Oedema peripheral	1/55 (1.8%)	1
Pyrexia	1/55 (1.8%)	1
Infections and infestations
Clostridium difficile sepsis	1/55 (1.8%)	1
Herpes zoster	1/55 (1.8%)	1
Pneumonia	2/55 (3.6%)	2
Pneumonia pneumococcal	1/55 (1.8%)	1
Septic shock	1/55 (1.8%)	1
Urinary tract infection	1/55 (1.8%)	1
Investigations
Blood creatinine increased	1/55 (1.8%)	1
Metabolism and nutrition disorders
Dehydration	4/55 (7.3%)	4
Hypercalcaemia	1/55 (1.8%)	1
Nervous system disorders
Syncope	1/55 (1.8%)	1
Psychiatric disorders
Confusional state	2/55 (3.6%)	2
Renal and urinary disorders
Azotaemia	1/55 (1.8%)	1
Renal failure acute	1/55 (1.8%)	1
Ureteric obstruction	2/55 (3.6%)	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/55 (1.8%)	1
Respiratory failure	1/55 (1.8%)	1
Vascular disorders
Hypotension	1/55 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Enzastaurin
	Affected / at Risk (%)	# Events
Total	51/55 (92.7%)
Blood and lymphatic system disorders
Anaemia	4/55 (7.3%)	4
Thrombocytopenia	5/55 (9.1%)	5
Gastrointestinal disorders
Constipation	5/55 (9.1%)	5
Diarrhoea	10/55 (18.2%)	12
Flatulence	4/55 (7.3%)	4
Nausea	15/55 (27.3%)	15
Vomiting	11/55 (20%)	11
General disorders
Asthenia	5/55 (9.1%)	5
Chills	5/55 (9.1%)	5
Fatigue	18/55 (32.7%)	21
Oedema	5/55 (9.1%)	5
Oedema peripheral	13/55 (23.6%)	16
Pyrexia	9/55 (16.4%)	9
Infections and infestations
Upper respiratory tract infection	4/55 (7.3%)	7
Urinary tract infection	3/55 (5.5%)	3
Investigations
Blood creatinine increased	4/55 (7.3%)	4
Weight decreased	3/55 (5.5%)	3
Metabolism and nutrition disorders
Decreased appetite	9/55 (16.4%)	9
Dehydration	4/55 (7.3%)	4
Hypercalcaemia	3/55 (5.5%)	4
Hyperkalaemia	3/55 (5.5%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	3/55 (5.5%)	7
Back pain	6/55 (10.9%)	9
Myalgia	4/55 (7.3%)	7
Pain in extremity	4/55 (7.3%)	6
Nervous system disorders
Dizziness	6/55 (10.9%)	6
Headache	3/55 (5.5%)	3
Neuropathy peripheral	3/55 (5.5%)	3
Psychiatric disorders
Anxiety	3/55 (5.5%)	3
Insomnia	4/55 (7.3%)	4
Renal and urinary disorders
Chromaturia	4/55 (7.3%)	4
Respiratory, thoracic and mediastinal disorders
Cough	11/55 (20%)	15
Dyspnoea	9/55 (16.4%)	9
Skin and subcutaneous tissue disorders
Night sweats	5/55 (9.1%)	5
Rash	4/55 (7.3%)	4
Vascular disorders
Orthostatic hypotension	3/55 (5.5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.