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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Non-Small-Cell Lung Carcinoma, Carcinoma, Non-Small Cell Lung

Intervention / Treatment
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* Drug: Entinostat
* Drug: Placebo
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in Phase: Erlotinib + Entinostat 5 mg<br>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<br>* Entinostat tablets on Days 1 and 15 of a 28-day cycle.<br>* Other names: SNDX-275;Drug: Erlotinib<br>* Erlotinib 150 mg tablets once daily.<br>* Other names: Tarceva;|
| Experimental: Lead-in Phase: Erlotinib + Entinostat 10 mg<br>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<br>* Entinostat tablets on Days 1 and 15 of a 28-day cycle.<br>* Other names: SNDX-275;Drug: Erlotinib<br>* Erlotinib 150 mg tablets once daily.<br>* Other names: Tarceva;|
| Experimental: Double-blind Phase: Erlotinib + Entinostat 10 mg<br>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<br>* Entinostat tablets on Days 1 and 15 of a 28-day cycle.<br>* Other names: SNDX-275;Drug: Erlotinib<br>* Erlotinib 150 mg tablets once daily.<br>* Other names: Tarceva;|
| Placebo Comparator: Double-blind Phase: Erlotinib + Placebo<br>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<br>* Placebo-matching entinostat tablets on Days 1 and 15 of a 28-day cycle.<br>Drug: Erlotinib<br>* Erlotinib 150 mg tablets once daily.<br>* Other names: Tarceva;|
| Experimental: Crossover Phase: Erlotinib + Entinostat 10 mg<br>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<br>* Entinostat tablets on Days 1 and 15 of a 28-day cycle.<br>* Other names: SNDX-275;Drug: Erlotinib<br>* Erlotinib 150 mg tablets once daily.<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 of Lead-in Phase | 
| 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. | Month 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 6 | 
| 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. | Month 6 | 
| 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. | First dose of study drug to within 30 days past last dose (Up to 7 months) | 
| 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. | Day 1 and 15 of each cycle to safety follow-up 30 days past last dose (up to 7 months) | 
| 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) | 
| 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, NSCLC, lung neoplasms, respiratory