Study to Evaluate Erlotinib With or Without SNDX-275 (Entinostat) in the Treatment of Patients With Advanced NSCLC

• Sponsor: Syndax Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00602030
• Collaborator: (none)
• Enrollment: 141
• Locations: 30
• Arms: 5
• Actual Duration (Months): 48.8
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of entinostat in combination with erlotinib in the treatment of Advanced Non-Small Cell Lung Cancer (NSCLC).

Condition or Disease	Intervention/Treatment	Phase
Non-Small-Cell Lung Carcinoma; Carcinoma, Non-Small Cell Lung	Drug: Entinostat; Drug: Placebo; Drug: Erlotinib	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study With a Lead in Phase of Erlotinib With or Without SNDX-275 in Patients With NSCLC After Failure In Up to Two Prior Chemotherapeutic Regimens for Advanced Disease
• Actual Study Start Date: Jan 8, 2008
• Actual Primary Completion Date: Feb 4, 2010
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lead-in Phase: Erlotinib + Entinostat 5 mg Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Drug: Entinostat; Entinostat tablets on Days 1 and 15 of a 28-day cycle.; Other Names: SNDX-275 ; Drug: Erlotinib; Erlotinib 150 mg tablets once daily.; Other Names: Tarceva
Experimental: Lead-in Phase: Erlotinib + Entinostat 10 mg Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Drug: Entinostat; Entinostat tablets on Days 1 and 15 of a 28-day cycle.; Other Names: SNDX-275 ; Drug: Erlotinib; Erlotinib 150 mg tablets once daily.; Other Names: Tarceva
Experimental: Double-blind Phase: Erlotinib + Entinostat 10 mg Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Drug: Entinostat; Entinostat tablets on Days 1 and 15 of a 28-day cycle.; Other Names: SNDX-275 ; Drug: Erlotinib; Erlotinib 150 mg tablets once daily.; Other Names: Tarceva
Placebo Comparator: Double-blind Phase: Erlotinib + Placebo Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Drug: Placebo; Placebo-matching entinostat tablets on Days 1 and 15 of a 28-day cycle.; Drug: Erlotinib; Erlotinib 150 mg tablets once daily.; Other Names: Tarceva
Experimental: Crossover Phase: Erlotinib + Entinostat 10 mg Participants in the Double-blind Phase Erlotinib + Placebo arm who experienced disease progression crossed over to receive open-label erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities.	Drug: Entinostat; Entinostat tablets on Days 1 and 15 of a 28-day cycle.; Other Names: SNDX-275 ; Drug: Erlotinib; Erlotinib 150 mg tablets once daily.; Other Names: Tarceva

Outcome Measures

Primary Outcome Measures

1. Identification of Safe-dose for the Phase 2 Double-blind Phase in the Lead-in Phase [Cycle 1 of Lead-in Phase]

   Safe recommended Phase 2 dose was determined based on dose-limiting toxicities (DLT) in Cycle 1. A DLT was defined as any of the following occurring in Cycle 1: Grade 3 or greater nonhematologic toxicity that was considered related to either entinostat or erlotinib or a Grade 4 hematologic toxicity lasting more than 7 days and/or resulting in a dose delay. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale was used where Grade 1=mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=life-threatening and 5=death. The dose that was found to be safe is reported.

2. 4-Month Progression-free Survival (PFS) Rate in the Double-blind Phase [Month 4]

   PFS rate at 4 months was defined as the percentage of participants who are progression-free at 4 months.

Secondary Outcome Measures

1. Objective Response Rate (ORR) in the Double-blind Phase [Month 6]

   ORR was defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) as assessed by the investigator. CR=disappearance of all target lesions; disappearance of non-target lesions and normalization of tumor marker level. PR=At least a 30% decrease in the sum of the longest diameter of target lesions, taking at reference the baseline sum longest diameter.

2. 6-Month PFS Rate in the Double-blind Phase [Month 6]

   PFS rate at 6 months is defined as the percentage of participants who are progression-free at 6 months.

3. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase [First dose of study drug to within 30 days past last dose (Up to 7 months)]

   An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Worsening of a pre-existing medical condition was considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. A TEAE is an AE that starts after the administration of study drug. A SAE is any AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth effect or other significant medical hazard. TEAE severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=Life-threatening and 5=Death.

4. Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

   Laboratory tests included tests of Hematology and Chemistry. The individual laboratory values were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=Life-threatening and 5=Death.

5. Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

6. Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

7. Vital Sign Values: Heart Rate in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

8. Vital Sign Values: Respiration Rate in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

9. Vital Sign Values: Temperature in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

10. Vital Sign Values: Weight in the Double-blind Phase [Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)]

11. Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase [Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose]

12. Tmax: Time to Cmax of Entinostat in the Lead-in Phase [Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose]

13. AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase [Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose]

14. AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase [Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose]

Eligibility Criteria

Criteria

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

Inclusion Criteria

• Cytologically or histologically confirmed NSCLC of stage IIIb or IV

• Received at least 1 but no more than 2 prior chemotherapy or chemoradiotherapy regimens for advanced NSCLC (that did not include erlotinib and valproic acid) and progressed based on radiologic evidence

• At least 1 measurable lesion by conventional or spiral computed tomography (CT) scan

• Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 and life expectancy of at least 6 months

• Paraffin-embedded tumor specimen available for correlative studies

• Male or female over 18 years of age

• Hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 10^{9/L; absolute neutrophil count (ANC) ≥ 1.5 x 10}9/L without the use of hematopoietic growth factors

• Bilirubin and creatinine less than 2 times the upper limit of normal for the institution

• Albumin ≥ 2.5 g/dL

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 times the upper limit of normal for the institution

• Prothrombin time less than 1.5 times the upper limit of normal for the institution

• Potassium, magnesium and phosphorus within the normal range for the institution (supplementation is permissible)

• Willing to use accepted and effective methods of contraception during the study (both men and women as appropriate) and for 3 months after the last dose of SNDX-275

• Patient or legally acceptable representative has granted written informed consent before any study-specific procedure (including special screening tests) are performed

Exclusion Criteria

• Prior stem cell transplant

• Clinical evidence of central nervous system (CNS) involvement

• Prior treatment with an histone deacetylase (HDAC) inhibitor or an epidermal growth factor receptor (EGFR) inhibitor

• Currently taking known inhibitors of CYPA4, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, ≥ 10 mg prednisone, and voriconazole

• Currently taking medication(s) on the prohibited medication list

• Prior exposure to SNDX-275

• Systemic chemotherapy, radiotherapy, or treatment with an investigational agent without recovery to at least grade 1 or baseline before study drug administration

• Daily treatment with ≥ 10 mg prednisone within 28 days before study drug administration

• Local or whole brain palliative radiotherapy within 14 days before study drug administration

• Currently active second malignancy, or any malignancy within the last 5 years other than cured basal or squamous cell skin carcinoma, cervical carcinoma in situ, carcinoma in situ of the bladder, or papillary thyroid cancer

• Inability to swallow oral medications or a gastrointestinal malabsorption condition

• Acute infection requiring intravenous (IV) antibiotics, antivirals, or antifungals within 14 days before study drug administration

• Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection

• Another serious or uncontrolled medical condition within 90 days before study drug administration such as acute myocardial infarction, angina, ventricular arrhythmias, hypertension, diabetes mellitus, or renal or hepatic insufficiency

• Known hypersensitivity to benzamides

• Women who are currently pregnant or breast-feeding

• Patient currently is enrolled in (or completed within 28 days before study drug administration) another investigational drug study

• Patient has any kind of medical, psychiatric, or behavioral disorder that places the patient at increased risk for study participation or compromises the ability of the patient to give written informed consent and/or to comply with study procedures and requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HOPE (Hematology Oncology Physicians & Extenders)	Tucson	Arizona	United States
2	Rocky Mountain Cancer Center	Denver	Colorado	United States
3	Advanced Medical Specialties	Miami	Florida	United States
4	Ocala Oncology Center	Ocala	Florida	United States
5	Cancer Centers of Florida	Ocoee	Florida	United States
6	Hematology Oncology Associates of Illinois	Chicago	Illinois	United States
7	Central Indiana Cancer Centers	Indianapolis	Indiana	United States
8	Kansas City Cancer Centers	Overland Park	Kansas	United States
9	Alliance Hematology Oncology	Westminster	Maryland	United States
10	St Joseph Oncology	Saint Joseph	Missouri	United States
11	The Center for Cancer Care & Research	Saint Louis	Missouri	United States
12	Mahonig Valley Hematology Oncology Associates	Boardman	Ohio	United States
13	Dayton Oncology & Hematology	Kettering	Ohio	United States
14	Oncology Associates of Oregon	Eugene	Oregon	United States
15	Texas Oncology	Amarillo	Texas	United States
16	Texas Oncology	Austin	Texas	United States
17	Texas Oncology	Bedford	Texas	United States
18	Texas Oncology, Sammons Cancer Center	Dallas	Texas	United States
19	Texas Oncology	Dallas	Texas	United States
20	Texas Oncology	Fort Worth	Texas	United States
21	Texas Oncology	Garland	Texas	United States
22	Texas Oncology	Longview	Texas	United States
23	Texas Oncology	Midland	Texas	United States
24	Texas Oncology	Odessa	Texas	United States
25	Texas Oncology	Tyler	Texas	United States
26	Fairfax Northern Virginia Hematology-Oncology	Fairfax	Virginia	United States
27	Virginia Oncology Associates	Norfolk	Virginia	United States
28	Highline Medical Oncology	Burien	Washington	United States
29	Cancer Care Northwest	Spokane	Washington	United States
30	Yakima Valley Memorial Hospital/North Star Lodge	Yakima	Washington	United States

Sponsors and Collaborators

• Syndax Pharmaceuticals

Investigators

• Principal Investigator: Samir Witta, MD, Rocky Mountain Cancer Centers
• Principal Investigator: Kartik Konduri, MD, Texas Oncology - Sammons Cancer Center
• Principal Investigator: Robert Raju, MD, Dayton Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Syndax Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00602030
• Other Study ID Numbers: SNDX-275-0401
• First Posted: Jan 28, 2008
• Last Update Posted: Aug 22, 2022
• Last Verified: Aug 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Syndax Pharmaceuticals: lung cancer; NSCLC; lung neoplasms; respiratory
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Entinostat

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 23 investigative sites in the United States from 8 January 2008 to 1 February 2012.
Pre-assignment Detail	Participants with a diagnosis of non-small cell lung carcinoma (NSCLC) were enrolled in 5 or 10 mg entinostat plus erlotinib arms to determine the Phase 2 dose. Participants were enrolled 1:1 in treatment arms: erlotinib 150 mg + entinostat 10 mg or erlotinib 150 mg + placebo. Placebo arm could receive entinostat 10 mg in the Crossover Phase.

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg	Crossover Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Participants in the Double-blind Phase Erlotinib + Placebo arm who experienced disease progression crossed over to receive open-label erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities.
Period Title: Lead-in Phase
STARTED	3	6	0	0	0
COMPLETED	1	1	0	0	0
NOT COMPLETED	2	5	0	0	0
Period Title: Lead-in Phase
STARTED	0	0	65	67	0
Received Treatment	0	0	63	65	0
COMPLETED	0	0	11	8	0
NOT COMPLETED	0	0	54	59	0
Period Title: Lead-in Phase
STARTED	0	0	0	0	16
COMPLETED	0	0	0	0	0
NOT COMPLETED	0	0	0	0	16

Baseline Characteristics

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg	Total
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Total of all reporting groups
Overall Participants	3	6	65	67	141
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72	63.5	67.0	66.0	67.1
Sex: Female, Male (Count of Participants)
Female	1 33.3%	2 33.3%	22 33.8%	28 41.8%	53 37.6%
Male	2 66.7%	4 66.7%	43 66.2%	39 58.2%	88 62.4%
Race/Ethnicity, Customized (Count of Participants)
White	3 100%	6 100%	55 84.6%	55 82.1%	119 84.4%
Black or African American	0 0%	0 0%	6 9.2%	5 7.5%	11 7.8%
Asian	0 0%	0 0%	2 3.1%	1 1.5%	3 2.1%
Hispanic	0 0%	0 0%	1 1.5%	6 9%	7 5%
Other	0 0%	0 0%	1 1.5%	0 0%	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Identification of Safe-dose for the Phase 2 Double-blind Phase in the Lead-in Phase
Description	Safe recommended Phase 2 dose was determined based on dose-limiting toxicities (DLT) in Cycle 1. A DLT was defined as any of the following occurring in Cycle 1: Grade 3 or greater nonhematologic toxicity that was considered related to either entinostat or erlotinib or a Grade 4 hematologic toxicity lasting more than 7 days and/or resulting in a dose delay. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale was used where Grade 1=mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=life-threatening and 5=death. The dose that was found to be safe is reported.
Time Frame	Cycle 1 of Lead-in Phase

Outcome Measure Data

Analysis Population Description

Lead-in Safety Analysis Set included all participant who received at least one dose of study drug in the Lead-in Phase.

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat
Arm/Group Description	Participants received erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg or 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle for up to 6 cycles in the Open-label Lead-in Phase 1 dose-finding study to identify a safe dose of entinostat in combination with erlotinib for further evaluation.
Measure Participants	9
Number [milligrams (mg)]	10

2. Primary Outcome

Title	4-Month Progression-free Survival (PFS) Rate in the Double-blind Phase
Description	PFS rate at 4 months was defined as the percentage of participants who are progression-free at 4 months.
Time Frame	Month 4

Outcome Measure Data

Analysis Population Description

Double-blind Per-protocol Analysis Set included all randomized participants who met key eligibility criteria, received an adequate course of treatment and who had baseline and postbaseline tumor measurements.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	50	53
Number (95% Confidence Interval) [percentage of participants]	24.0 800%	20.8 346.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lead-in Phase: Erlotinib + Entinostat, Double-blind Phase: Erlotinib + Entinostat 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.505
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.27 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cochran-Mantel-Haenszel estimation of odds ratio adjusted for the smoking history stratification factor, using placebo as reference group.

3. Secondary Outcome

Title	Objective Response Rate (ORR) in the Double-blind Phase
Description	ORR was defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) as assessed by the investigator. CR=disappearance of all target lesions; disappearance of non-target lesions and normalization of tumor marker level. PR=At least a 30% decrease in the sum of the longest diameter of target lesions, taking at reference the baseline sum longest diameter.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Double-blind Full Analysis Set included all randomized participants.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	65	67
Number (95% Confidence Interval) [percentage of participants]	9.2 306.7%	3.0 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lead-in Phase: Erlotinib + Entinostat, Double-blind Phase: Erlotinib + Entinostat 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; 0.06 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation of odds ratio was adjusted for the smoking history stratification factor, using placebo as reference group .

4. Secondary Outcome

Title	6-Month PFS Rate in the Double-blind Phase
Description	PFS rate at 6 months is defined as the percentage of participants who are progression-free at 6 months.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	65	67
Number (95% Confidence Interval) [percentage of participants]	10.8 360%	11.9 198.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lead-in Phase: Erlotinib + Entinostat, Double-blind Phase: Erlotinib + Entinostat 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.918
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.34 to 3.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation of odds ratio was adjusted for the smoking history stratification factor, using placebo as reference group.

5. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase
Description	An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Worsening of a pre-existing medical condition was considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. A TEAE is an AE that starts after the administration of study drug. A SAE is any AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth effect or other significant medical hazard. TEAE severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=Life-threatening and 5=Death.
Time Frame	First dose of study drug to within 30 days past last dose (Up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least one dose of study drug.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Any SAE	29 966.7%	32 533.3%
Any TEAE	63 2100%	65 1083.3%
Grade 1 TEAE	7 233.3%	1 16.7%
Grade 2 TEAE	16 533.3%	12 200%
Grade 3 TEAE	20 666.7%	34 566.7%
Grade 4 TEAE	5 166.7%	6 100%
Grade 5 TEAE	15 500%	12 200%

6. Secondary Outcome

Title	Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase
Description	Laboratory tests included tests of Hematology and Chemistry. The individual laboratory values were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=Life-threatening and 5=Death.
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
White Blood Count decreased	1 33.3%	1 16.7%
Absolute Neutrophil Count decreased	1 33.3%	2 33.3%
Lymphocytes decreased	9 300%	18 300%
Platelets decreased	1 33.3%	2 33.3%
Phosphorus decreased	4 133.3%	6 100%
Alanine aminotransferase increased	1 33.3%	6 100%
Sodium decreased	5 166.7%	4 66.7%
Glucose increased	2 66.7%	3 50%
Albumin decreased	4 133.3%	2 33.3%
Potassium decreased	2 66.7%	2 33.3%
Aspartate aminotransferase increased	0 0%	2 33.3%
Bilirubin increased	3 100%	0 0%
Creatinine abnormal	1 33.3%	1 16.7%
Magnesium decreased	0 0%	1 16.7%
Potassium increased	0 0%	1 16.7%
Calcium increased	2 66.7%	0 0%
Calcium decreased	1 33.3%	0 0%

7. Secondary Outcome

Title	Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	125.3 (17.41)	126.0 (18.93)
Minimum Post-Baseline Value	112.4 (13.95)	105.0 (15.14)
Maximum Post-Baseline Value	135.5 (15.74)	132.5 (20.64)

8. Secondary Outcome

Title	Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	72.5 (10.06)	72.1 (10.38)
Minimum Post-Baseline Value	64.7 (9.31)	61.3 (9.70)
Maximum Post-Baseline Value	78.8 (9.92)	78.5 (10.09)

9. Secondary Outcome

Title	Vital Sign Values: Heart Rate in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	87.5 (15.96)	85.6 (17.41)
Minimum Post-Baseline Value	78.5 (16.75)	79.7 (15.19)
Maximum Post-Baseline Value	98.2 (15.24)	102.1 (17.12)

10. Secondary Outcome

Title	Vital Sign Values: Respiration Rate in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	18.5 (2.56)	17.9 (2.46)
Minimum Post-Baseline Value	17.2 (2.62)	16.6 (2.34)
Maximum Post-Baseline Value	20.2 (3.14)	20.1 (2.66)

11. Secondary Outcome

Title	Vital Sign Values: Temperature in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	97.5 (0.84)	97.6 (0.90)
Minimum Post-Baseline Value	96.9 (1.15)	97.0 (0.91)
Maximum Post-Baseline Value	98.2 (0.90)	98.5 (1.12)

12. Secondary Outcome

Title	Vital Sign Values: Weight in the Double-blind Phase
Time Frame	Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug. Number analyzed is the number of participants with data available.

Arm/Group Title	Double-blind Phase: Erlotinib + Placebo	Double-blind Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.	Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.
Measure Participants	63	65
Baseline	77.9 (16.83)	74.3 (17.48)
Minimum Post-Baseline Value	73.5 (16.98)	70.0 (15.71)
Maximum Post-Baseline Value	77.6 (16.97)	74.3 (16.93)

13. Secondary Outcome

Title	Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase
Time Frame	Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population included all participants who had blood collected for PK parameters in the Lead-in Phase. Number analyzed is the number of participants with data available at the give timepoint.

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.
Measure Participants	3	6
Day 1 (entinostat alone)	19.6 (20.6)	123.1 (136.4)
Day 15 (entinostat + erlotinib)	30.2 (41.0)	99.4 (132.5)

14. Secondary Outcome

Title	Tmax: Time to Cmax of Entinostat in the Lead-in Phase
Time Frame	Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose

Outcome Measure Data

Analysis Population Description

PK Population included all participants who had PK samples collected in the Lead-in Phase. Number analyzed is the number of participants with data available at the give time point.

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.
Measure Participants	3	6
Day 1 (entinostat alone)	0.83 (0.29)	0.50 (0.00)
Day 15 (entinostat + erlotinib)	1.0 (0.9)	1.3 (1.5)

15. Secondary Outcome

Title	AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase
Time Frame	Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose

Outcome Measure Data

Analysis Population Description

PK Population included all participants who had PK samples collected in the Lead-in Phase. Number analyzed is the number of participants with data available at the given timepoint

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.
Measure Participants	3	6
Day 1 (entinostat alone)	46.5 (12.2)	133.3 (84.8)
Day 15 (entinostat + erlotinib)	51.7 (24.6)	110.2 (92.3)

16. Secondary Outcome

Title	AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase
Time Frame	Day 1 predose and 0.5, 1, 2, 4 and 6 hours after dose; Days 2 and 8 predose (entinostat alone); Day 15 predose and 0.5, 1, 2, 4, 6 and 24 hours after dose

Outcome Measure Data

Analysis Population Description

PK Population included all participants who had PK samples collected during the Lead-in Phase. Number analyzed is the number of participants with data available at the given timepoint.

Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg	Lead-in Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.	Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.
Measure Participants	3	6
Day 1 (entinostat alone)	152.1 (26.3)	325.8 (193.1)
Day 15 (entinostat + erlotinib)	51.7 (24.6)	106.4 (96.8)

Adverse Events

Time Frame	First dose of study drug to 30 days past last dose (up to 7 months)
Adverse Event Reporting Description	Number of participants at risk for Serious and Other Adverse events was based on the Safety Population that included all participants who received at least one dose of study drug.
Arm/Group Title	Lead-in Phase: Erlotinib + Entinostat 5 mg		Lead-in Phase: Erlotinib + Entinostat 10 mg		Double-blind Phase: Erlotinib + Placebo		Double-blind Phase: Erlotinib + Entinostat 10 mg		Crossover Phase: Erlotinib + Entinostat 10 mg
Arm/Group Description	Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.		Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase.		Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.		Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase.		Participants in the Double-blind Phase Erlotinib + Placebo arm who experienced disease progression crossed over to receive open-label erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities.
All Cause Mortality
	Lead-in Phase: Erlotinib + Entinostat 5 mg		Lead-in Phase: Erlotinib + Entinostat 10 mg		Double-blind Phase: Erlotinib + Placebo		Double-blind Phase: Erlotinib + Entinostat 10 mg		Crossover Phase: Erlotinib + Entinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lead-in Phase: Erlotinib + Entinostat 5 mg		Lead-in Phase: Erlotinib + Entinostat 10 mg		Double-blind Phase: Erlotinib + Placebo		Double-blind Phase: Erlotinib + Entinostat 10 mg		Crossover Phase: Erlotinib + Entinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/6 (50%)		29/63 (46%)		32/65 (49.2%)		5/16 (31.3%)
Blood and lymphatic system disorders
Anemia Group	0/3 (0%)		0/6 (0%)		0/63 (0%)		2/65 (3.1%)		0/16 (0%)
Thrombocytopenia Group	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Anemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Cardiac disorders
Cardiac failure congestive	0/3 (0%)		0/6 (0%)		0/63 (0%)		2/65 (3.1%)		0/16 (0%)
Acute myocardial infarction	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Atrial fibrillation	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		1/65 (1.5%)		1/16 (6.3%)
Cardia disorder	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Pericardial effusion	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		1/65 (1.5%)		0/16 (0%)
Supraventricular tachycardia	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Congestive cardiac failure	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Diarrhoea	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		2/65 (3.1%)		0/16 (0%)
Constipation	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Dehydration	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Gastritis	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Hernia obstructive	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Pancreatitis	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Vomiting	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Abdominal pain	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Duodenal obstruction	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Duodenal ulcer haemorrhage	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Pancreatitis acute	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Gastroenteritis	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
General disorders
Disease progression	2/3 (66.7%)		2/6 (33.3%)		16/63 (25.4%)		7/65 (10.8%)		0/16 (0%)
Pain in extremity	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Asthenia	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Chest pain	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Death	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		1/65 (1.5%)		0/16 (0%)
Hepatobiliary disorders
Hepatotoxicity	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Infections and infestations
Pneumonia	0/3 (0%)		0/6 (0%)		2/63 (3.2%)		3/65 (4.6%)		1/16 (6.3%)
Injury, poisoning and procedural complications
Accidental overdose	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Pelvic fracture	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Hip fracture	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Metabolism and nutrition disorders
Hypoalbuminaemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Hypovolaemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Hypercalcaemia	0/3 (0%)		0/6 (0%)		2/63 (3.2%)		0/65 (0%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Monoarthritis	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Metastases to spine	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Non-small cell lung cancer	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Nervous system disorders
Hypotension	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Syncope	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Renal and urinary disorders
Renal failure acute	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Haematuria	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Reproductive system and breast disorders
Genital rash	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	0/3 (0%)		1/6 (16.7%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Pleural effusion	0/3 (0%)		0/6 (0%)		2/63 (3.2%)		3/65 (4.6%)		0/16 (0%)
Haemoptysis	0/3 (0%)		0/6 (0%)		0/63 (0%)		2/65 (3.1%)		0/16 (0%)
Pulmonary embolism	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		2/65 (3.1%)		1/16 (6.3%)
Diaphragmatic paralysis	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Lung infiltration	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Respiratory disorder	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Chronic obstructive pulmonary disease	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Hemoptysis	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Vascular disorders
Peripheral artery aneurysm	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Vena cava thrombosis	0/3 (0%)		0/6 (0%)		0/63 (0%)		1/65 (1.5%)		0/16 (0%)
Orthostatic hypotension	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Superior vena caval occlusion	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		0/65 (0%)		0/16 (0%)
Hypertension	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Lead-in Phase: Erlotinib + Entinostat 5 mg		Lead-in Phase: Erlotinib + Entinostat 10 mg		Double-blind Phase: Erlotinib + Placebo		Double-blind Phase: Erlotinib + Entinostat 10 mg		Crossover Phase: Erlotinib + Entinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)		63/63 (100%)		64/65 (98.5%)		14/16 (87.5%)
Blood and lymphatic system disorders
Thrombocytopenia group	0/3 (0%)		2/6 (33.3%)		2/63 (3.2%)		10/65 (15.4%)		1/16 (6.3%)
Anemia group	2/3 (66.7%)		1/6 (16.7%)		7/63 (11.1%)		15/65 (23.1%)		3/16 (18.8%)
Neutropenia group	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Cardiac disorders
Tachycardia	1/3 (33.3%)		0/6 (0%)		2/63 (3.2%)		8/65 (12.3%)		0/16 (0%)
Eye disorders
Dry eye	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Photophobia	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Eye discharge	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Diarrhoea	1/3 (33.3%)		6/6 (100%)		30/63 (47.6%)		37/65 (56.9%)		3/16 (18.8%)
Nausea	1/3 (33.3%)		3/6 (50%)		16/63 (25.4%)		32/65 (49.2%)		4/16 (25%)
Vomiting	1/3 (33.3%)		2/6 (33.3%)		8/63 (12.7%)		20/65 (30.8%)		1/16 (6.3%)
Abdominal pain	0/3 (0%)		1/6 (16.7%)		6/63 (9.5%)		2/65 (3.1%)		0/16 (0%)
Dry mouth	1/3 (33.3%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Dyspepsia	1/3 (33.3%)		1/6 (16.7%)		4/63 (6.3%)		5/65 (7.7%)		0/16 (0%)
Dysphagia	0/3 (0%)		1/6 (16.7%)		4/63 (6.3%)		3/65 (4.6%)		0/16 (0%)
Gingival bleeding	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Abdominal pain upper	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Constipation	1/3 (33.3%)		0/6 (0%)		6/63 (9.5%)		9/65 (13.8%)		1/16 (6.3%)
Stomatitis	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		8/65 (12.3%)		0/16 (0%)
Gastrooesophageal reflux disease	0/3 (0%)		0/6 (0%)		2/63 (3.2%)		4/65 (6.2%)		1/16 (6.3%)
General disorders
Fatigue	3/3 (100%)		5/6 (83.3%)		32/63 (50.8%)		38/65 (58.5%)		5/16 (31.3%)
Asthenia	0/3 (0%)		2/6 (33.3%)		7/63 (11.1%)		11/65 (16.9%)		2/16 (12.5%)
Oedema peripheral	0/3 (0%)		2/6 (33.3%)		8/63 (12.7%)		18/65 (27.7%)		5/16 (31.3%)
Pyrexia	0/3 (0%)		1/6 (16.7%)		5/63 (7.9%)		4/65 (6.2%)		0/16 (0%)
Chest pain	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Xerosis	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Oedema	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		2/16 (12.5%)
Malaise	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Pain	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Infections and infestations
Urinary tract infection	0/3 (0%)		2/6 (33.3%)		7/63 (11.1%)		11/65 (16.9%)		2/16 (12.5%)
Herpes zoster	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Upper respiratory tract infection	0/3 (0%)		0/6 (0%)		4/63 (6.3%)		4/65 (6.2%)		0/16 (0%)
Eye infection	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Fungal infection	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Localised infection	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Investigations
Weight decreased	0/3 (0%)		0/6 (0%)		11/63 (17.5%)		21/65 (32.3%)		3/16 (18.8%)
Blood albumin decreased	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Protein total decreased	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)		2/6 (33.3%)		7/63 (11.1%)		4/65 (6.2%)		1/16 (6.3%)
Anorexia	0/3 (0%)		1/6 (16.7%)		10/63 (15.9%)		26/65 (40%)		2/16 (12.5%)
Hyperglycaemia	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Hypokalaemia	1/3 (33.3%)		1/6 (16.7%)		7/63 (11.1%)		6/65 (9.2%)		3/16 (18.8%)
Hypomagnesaemia	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Dehydration	0/3 (0%)		0/6 (0%)		5/63 (7.9%)		10/65 (15.4%)		1/16 (6.3%)
Hypophosphataemia	0/3 (0%)		0/6 (0%)		3/63 (4.8%)		9/65 (13.8%)		4/16 (25%)
Hypomagnesaemia	0/3 (0%)		0/6 (0%)		5/63 (7.9%)		2/65 (3.1%)		0/16 (0%)
Hypoalbuminaemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		2/16 (12.5%)
Hypocalcaemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Hyponatraemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Hypovolaemia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Appetite disorder	0/3 (0%)		0/6 (0%)		4/63 (6.3%)		0/65 (0%)		3/16 (18.8%)
Musculoskeletal and connective tissue disorders
Monarthritis	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Neck pain	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Pain in extremity	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Back pain	0/3 (0%)		0/6 (0%)		6/63 (9.5%)		7/65 (10.8%)		2/16 (12.5%)
Muscle spasms	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		5/65 (7.7%)		0/16 (0%)
Arthralgia	0/3 (0%)		0/6 (0%)		6/63 (9.5%)		1/65 (1.5%)		0/16 (0%)
Back pain	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		2/16 (12.5%)
Myalgia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		2/16 (12.5%)
Flank pain	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Limb discomfort	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Sensation of heaviness	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Musculoskeletal chest pain	0/3 (0%)		1/6 (16.7%)		3/63 (4.8%)		4/65 (6.2%)		1/16 (6.3%)
Nervous system disorders
Balance disorder	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Dizziness	0/3 (0%)		1/6 (16.7%)		6/63 (9.5%)		9/65 (13.8%)		3/16 (18.8%)
Headache	1/3 (33.3%)		0/6 (0%)		6/63 (9.5%)		3/65 (4.6%)		1/16 (6.3%)
Neuropathy peripheral	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		2/16 (12.5%)
Dysgeusia	0/3 (0%)		0/6 (0%)		3/63 (4.8%)		4/65 (6.2%)		1/16 (6.3%)
Hypersomnia	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Neuropathy	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Peripheral sensory neuropathy	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Peroneal nerve palsy	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Psychiatric disorders
Anxiety	0/3 (0%)		0/6 (0%)		2/63 (3.2%)		5/65 (7.7%)		0/16 (0%)
Depression	0/3 (0%)		0/6 (0%)		3/63 (4.8%)		5/65 (7.7%)		0/16 (0%)
Insomnia	0/3 (0%)		0/6 (0%)		5/63 (7.9%)		2/65 (3.1%)		1/16 (6.3%)
Renal and urinary disorders
Proteinuria	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Vulvovaginal dryness	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		2/6 (33.3%)		9/63 (14.3%)		8/65 (12.3%)		1/16 (6.3%)
Dyspnoea	0/3 (0%)		2/6 (33.3%)		11/63 (17.5%)		20/65 (30.8%)		4/16 (25%)
Dry throat	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Dysphonia	1/3 (33.3%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Hiccups	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Pharyngolaryngeal pain	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Pleural effusion	0/3 (0%)		1/6 (16.7%)		2/63 (3.2%)		4/65 (6.2%)		1/16 (6.3%)
Sinus congestion	0/3 (0%)		1/6 (16.7%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Epistaxis	0/3 (0%)		0/6 (0%)		4/63 (6.3%)		8/65 (12.3%)		1/16 (6.3%)
Hypoxia	0/3 (0%)		0/6 (0%)		4/63 (6.3%)		3/65 (4.6%)		1/16 (6.3%)
Haemoptysis	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Lung disorder	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Nasal congestion	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Nasal dryness	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	2/3 (66.7%)		3/6 (50%)		35/63 (55.6%)		33/65 (50.8%)		1/16 (6.3%)
Hair growth abnormal	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Nail disorder	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Rash maculo-papular	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Dermatitis acneiform	0/3 (0%)		0/6 (0%)		12/63 (19%)		10/65 (15.4%)		0/16 (0%)
Dry skin	0/3 (0%)		0/6 (0%)		3/63 (4.8%)		4/65 (6.2%)		2/16 (12.5%)
Pruritus	0/3 (0%)		0/6 (0%)		5/63 (7.9%)		3/65 (4.6%)		0/16 (0%)
Cellulitis	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		3/16 (18.8%)
Decubitus ulcer	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Erythema	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Skin lesion	0/3 (0%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		1/16 (6.3%)
Vascular disorders
Flushing	1/3 (33.3%)		0/6 (0%)		0/63 (0%)		0/65 (0%)		0/16 (0%)
Hypotension	0/3 (0%)		0/6 (0%)		1/63 (1.6%)		8/65 (12.3%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Publication of the results of the multi-center Study shall not be made before the first multi-site publication by Sponsor or Publications Committee. No Public Presentation by Institution or Investigator will be made until Study Documentation/Results from all sites are received and analyzed by Sponsor. Separate publication by Investigator will be delayed for a period of 18 months until the initial publication by Committee or Sponsor, or a determination is made not to make such publication.