Carcinoma, Non-Small Cell Lung, Non-Small-Cell Lung Carcinoma
Conditions
Keywords
lung cancer, NSCLC, lung neoplasms, respiratory
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).
Interventions
DRUGEntinostat
Entinostat tablets on Days 1 and 15 of a 28-day cycle.
DRUGPlacebo
Placebo-matching entinostat tablets on Days 1 and 15 of a 28-day cycle.
DRUGErlotinib
Erlotinib 150 mg tablets once daily.
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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) | — |
| 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) | — |
| 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) | — |
| 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) | — |
| 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. |
| 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) | — |
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
| 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) | — |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 6 |
| 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. | 65 |
| 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. | 67 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Crossover Phase | Adverse Event | 0 | 0 | 0 | 0 | 3 |
| Crossover Phase | Consent withdrawal | 0 | 0 | 0 | 0 | 2 |
| Crossover Phase | Disease Progression | 0 | 0 | 0 | 0 | 11 |
| Double-blind Phase | Administrative decision | 0 | 0 | 0 | 2 | 0 |
| Double-blind Phase | Adverse Event | 0 | 0 | 9 | 18 | 0 |
| Double-blind Phase | Consent withdrawal | 0 | 0 | 4 | 3 | 0 |
| Double-blind Phase | Death | 0 | 0 | 3 | 3 | 0 |
| Double-blind Phase | Disease progression | 0 | 0 | 33 | 30 | 0 |
| Double-blind Phase | Ineligibility | 0 | 0 | 0 | 1 | 0 |
| Double-blind Phase | Protocol deviation/noncompliance | 0 | 0 | 1 | 0 | 0 |
| Double-blind Phase | Reason not specified | 0 | 0 | 4 | 2 | 0 |
| Lead-in Phase | Adverse Event | 0 | 2 | 0 | 0 | 0 |
| Lead-in Phase | Disease Progression | 2 | 3 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Continuous | 72 years | 63.5 years | 67.0 years | 66.0 years | 67.1 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 1 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 6 Participants | 55 Participants | 55 Participants | 119 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 22 Participants | 28 Participants | 53 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 43 Participants | 39 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 63 / 63 | 64 / 65 | 14 / 16 |
| serious Total, serious adverse events | 2 / 3 | 3 / 6 | 29 / 63 | 32 / 65 | 5 / 16 |
Outcome results
Primary
4-Month Progression-free Survival (PFS) Rate in the Double-blind Phase
PFS rate at 4 months was defined as the percentage of participants who are progression-free at 4 months.
Time frame: Month 4
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | 4-Month Progression-free Survival (PFS) Rate in the Double-blind Phase | 24.0 percentage of participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | 4-Month Progression-free Survival (PFS) Rate in the Double-blind Phase | 20.8 percentage of participants |
p-value: 0.50595% CI: [0.27, 1.89]Cochran-Mantel-Haenszel
Primary
Identification of Safe-dose for the Phase 2 Double-blind Phase in the 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.
Time frame: Cycle 1 of Lead-in Phase
Population: Lead-in Safety Analysis Set included all participant who received at least one dose of study drug in the Lead-in Phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Identification of Safe-dose for the Phase 2 Double-blind Phase in the Lead-in Phase | 10 milligrams (mg) |
Secondary
6-Month PFS Rate in the Double-blind Phase
PFS rate at 6 months is defined as the percentage of participants who are progression-free at 6 months.
Time frame: Month 6
Population: Full Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | 6-Month PFS Rate in the Double-blind Phase | 10.8 percentage of participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | 6-Month PFS Rate in the Double-blind Phase | 11.9 percentage of participants |
p-value: 0.91895% CI: [0.34, 3.27]Cochran-Mantel-Haenszel
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase | Day 1 (entinostat alone) | 46.5 ng*hr/mL | Standard Deviation 12.2 |
| Lead-in Phase: Erlotinib + Entinostat | AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 51.7 ng*hr/mL | Standard Deviation 24.6 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase | Day 1 (entinostat alone) | 133.3 ng*hr/mL | Standard Deviation 84.8 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | AUC(0-24): Area Under the Concentration-time Curve From Time 0 to 24 Hours in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 110.2 ng*hr/mL | Standard Deviation 92.3 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase | Day 1 (entinostat alone) | 152.1 ng*hr/mL | Standard Deviation 26.3 |
| Lead-in Phase: Erlotinib + Entinostat | AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 51.7 ng*hr/mL | Standard Deviation 24.6 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase | Day 1 (entinostat alone) | 325.8 ng*hr/mL | Standard Deviation 193.1 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 106.4 ng*hr/mL | Standard Deviation 96.8 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase | Day 1 (entinostat alone) | 19.6 ng/mL | Standard Deviation 20.6 |
| Lead-in Phase: Erlotinib + Entinostat | Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 30.2 ng/mL | Standard Deviation 41 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase | Day 1 (entinostat alone) | 123.1 ng/mL | Standard Deviation 136.4 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Cmax: Maximum Plasma Concentration of Entinostat in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 99.4 ng/mL | Standard Deviation 132.5 |
Secondary
Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase
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)
Population: Safety Population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Calcium decreased | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | White Blood Count decreased | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Absolute Neutrophil Count decreased | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Lymphocytes decreased | 9 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Platelets decreased | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Phosphorus decreased | 4 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Alanine aminotransferase increased | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Sodium decreased | 5 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Glucose increased | 2 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Albumin decreased | 4 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Potassium decreased | 2 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Aspartate aminotransferase increased | 0 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Bilirubin increased | 3 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Creatinine abnormal | 1 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Magnesium decreased | 0 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Potassium increased | 0 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Calcium increased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Creatinine abnormal | 1 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Albumin decreased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | White Blood Count decreased | 1 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Calcium decreased | 0 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Absolute Neutrophil Count decreased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Potassium decreased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Lymphocytes decreased | 18 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Magnesium decreased | 1 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Platelets decreased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Aspartate aminotransferase increased | 2 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Phosphorus decreased | 6 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Calcium increased | 0 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Alanine aminotransferase increased | 6 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Bilirubin increased | 0 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Sodium decreased | 4 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Potassium increased | 1 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Grade 3 or 4 Laboratory Variables in the Double-blind Phase | Glucose increased | 3 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase
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)
Population: Safety Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 2 TEAE | 16 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 4 TEAE | 5 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 1 TEAE | 7 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 5 TEAE | 15 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 3 TEAE | 20 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Any SAE | 29 Participants |
| Lead-in Phase: Erlotinib + Entinostat | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Any TEAE | 63 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Any SAE | 32 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Any TEAE | 65 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 1 TEAE | 1 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 2 TEAE | 12 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 3 TEAE | 34 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 4 TEAE | 6 Participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) by Severity in the Double-blind Phase | Grade 5 TEAE | 12 Participants |
Secondary
Objective Response Rate (ORR) in the Double-blind Phase
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
Population: Double-blind Full Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Objective Response Rate (ORR) in the Double-blind Phase | 9.2 percentage of participants |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Objective Response Rate (ORR) in the Double-blind Phase | 3.0 percentage of participants |
p-value: 0.1395% CI: [0.06, 1.54]Cochran-Mantel-Haenszel
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Tmax: Time to Cmax of Entinostat in the Lead-in Phase | Day 1 (entinostat alone) | 0.83 hour | Standard Deviation 0.29 |
| Lead-in Phase: Erlotinib + Entinostat | Tmax: Time to Cmax of Entinostat in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 1.0 hour | Standard Deviation 0.9 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Tmax: Time to Cmax of Entinostat in the Lead-in Phase | Day 1 (entinostat alone) | 0.50 hour | Standard Deviation 0 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Tmax: Time to Cmax of Entinostat in the Lead-in Phase | Day 15 (entinostat + erlotinib) | 1.3 hour | Standard Deviation 1.5 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Baseline | 72.5 mm Hg | Standard Deviation 10.06 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Minimum Post-Baseline Value | 64.7 mm Hg | Standard Deviation 9.31 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Maximum Post-Baseline Value | 78.8 mm Hg | Standard Deviation 9.92 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Baseline | 72.1 mm Hg | Standard Deviation 10.38 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Minimum Post-Baseline Value | 61.3 mm Hg | Standard Deviation 9.7 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Diastolic Blood Pressure in the Double-blind Phase | Maximum Post-Baseline Value | 78.5 mm Hg | Standard Deviation 10.09 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Heart Rate in the Double-blind Phase | Baseline | 87.5 beats per minute (bpm) | Standard Deviation 15.96 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Heart Rate in the Double-blind Phase | Minimum Post-Baseline Value | 78.5 beats per minute (bpm) | Standard Deviation 16.75 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Heart Rate in the Double-blind Phase | Maximum Post-Baseline Value | 98.2 beats per minute (bpm) | Standard Deviation 15.24 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Heart Rate in the Double-blind Phase | Baseline | 85.6 beats per minute (bpm) | Standard Deviation 17.41 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Heart Rate in the Double-blind Phase | Minimum Post-Baseline Value | 79.7 beats per minute (bpm) | Standard Deviation 15.19 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Heart Rate in the Double-blind Phase | Maximum Post-Baseline Value | 102.1 beats per minute (bpm) | Standard Deviation 17.12 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Respiration Rate in the Double-blind Phase | Baseline | 18.5 breaths per minute | Standard Deviation 2.56 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Respiration Rate in the Double-blind Phase | Minimum Post-Baseline Value | 17.2 breaths per minute | Standard Deviation 2.62 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Respiration Rate in the Double-blind Phase | Maximum Post-Baseline Value | 20.2 breaths per minute | Standard Deviation 3.14 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Respiration Rate in the Double-blind Phase | Baseline | 17.9 breaths per minute | Standard Deviation 2.46 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Respiration Rate in the Double-blind Phase | Minimum Post-Baseline Value | 16.6 breaths per minute | Standard Deviation 2.34 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Respiration Rate in the Double-blind Phase | Maximum Post-Baseline Value | 20.1 breaths per minute | Standard Deviation 2.66 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Baseline | 125.3 mm Hg | Standard Deviation 17.41 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Minimum Post-Baseline Value | 112.4 mm Hg | Standard Deviation 13.95 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Maximum Post-Baseline Value | 135.5 mm Hg | Standard Deviation 15.74 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Baseline | 126.0 mm Hg | Standard Deviation 18.93 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Minimum Post-Baseline Value | 105.0 mm Hg | Standard Deviation 15.14 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Systolic Blood Pressure in the Double-blind Phase | Maximum Post-Baseline Value | 132.5 mm Hg | Standard Deviation 20.64 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Temperature in the Double-blind Phase | Baseline | 97.5 degrees Celsius (C) | Standard Deviation 0.84 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Temperature in the Double-blind Phase | Minimum Post-Baseline Value | 96.9 degrees Celsius (C) | Standard Deviation 1.15 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Temperature in the Double-blind Phase | Maximum Post-Baseline Value | 98.2 degrees Celsius (C) | Standard Deviation 0.9 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Temperature in the Double-blind Phase | Baseline | 97.6 degrees Celsius (C) | Standard Deviation 0.9 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Temperature in the Double-blind Phase | Minimum Post-Baseline Value | 97.0 degrees Celsius (C) | Standard Deviation 0.91 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Temperature in the Double-blind Phase | Maximum Post-Baseline Value | 98.5 degrees Celsius (C) | Standard Deviation 1.12 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Weight in the Double-blind Phase | Baseline | 77.9 kilograms (kg) | Standard Deviation 16.83 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Weight in the Double-blind Phase | Minimum Post-Baseline Value | 73.5 kilograms (kg) | Standard Deviation 16.98 |
| Lead-in Phase: Erlotinib + Entinostat | Vital Sign Values: Weight in the Double-blind Phase | Maximum Post-Baseline Value | 77.6 kilograms (kg) | Standard Deviation 16.97 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Weight in the Double-blind Phase | Baseline | 74.3 kilograms (kg) | Standard Deviation 17.48 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Weight in the Double-blind Phase | Minimum Post-Baseline Value | 70.0 kilograms (kg) | Standard Deviation 15.71 |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | Vital Sign Values: Weight in the Double-blind Phase | Maximum Post-Baseline Value | 74.3 kilograms (kg) | Standard Deviation 16.93 |