BIO 300 Non-Small Cell Lung Cancer Study

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and effectiveness of BIO 300 Oral Suspension when used in combination with standard dose radiation therapy and chemotherapy in patients with non-small cell lung cancer. Based on preclinical data the investigators hypothesize that BIO 300 Oral Suspension will reduce the incidence of radiation-induced pneumonitis and pulmonary fibrosis.

Detailed Description
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This is an open-label, single-arm, ascending dose Phase I/II study of BIO 300 Oral Suspension given in combination with paclitaxel/carboplatin and radiotherapy in subjects with stage II, III, or IV NSCLC who are candidates for combined chemoradiotherapy. A minimum of 6 subjects will be accrued sequentially at each dose level of BIO 300. BIO 300 will be administered daily for the entire course of concurrent chemoradiotherapy, a minimum of 6 weeks; in combination with standard paclitaxel / carboplatin chemotherapy and radiotherapy. The initial dose of BIO 300 will be administered on Day 1, Visit 2 in which safety data (adverse events, electrocardiograms (ECGs), results of safety laboratory determinations), pharmacokinetic (PK) and pharmacodynamic (PD) data will be collected. PK data will be collected from a minimum of six (6) study subjects from each cohort. PD data will be collected from all subjects in each study cohort. Day 1 of chemotherapy will be scheduled at the discretion of the investigator provided the subject has completed a minimum of 1 day of BIO 300 dosing. BIO 300 will be administered in combination with the chemotherapy components of the protocol (paclitaxel and carboplatin). During the first or second chemotherapy infusion, additional safety, PK and PD data will be collected. Day 1 of radiation therapy (RT) may be scheduled at the discretion of the investigator provided the subject has completed a minimum of 2 days of BIO 300 dosing. BIO 300 will continue to be administered daily; paclitaxel and carboplatin will be administered weekly and radiotherapy will be administered daily until a total dose of 60-70 Gy has been administered. During the period of combined BIO 300 and chemoradiotherapy (6-7 weeks), additional safety, PK and PD data will be collected weekly. An interim data analysis will be completed once the highest dose cohort concludes chemoradiation therapy, in an effort to determine the optimal biological dose. Following analysis, there will be an option to enroll up to an additional 12 subjects at the optimal biological dose. At the conclusion of the study, primary and secondary outcome measures will be evaluated. Data will be analyzed from all cohorts to determine the oncologic response, safety of BIO 300, and a recommended BIO 300 dose.

Official Title
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A Phase I/II Clinical Study Evaluating the Safety and Effectiveness of BIO 300 Oral Suspension in Patients Receiving Chemoradiation Therapy for Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIO 300 Oral Suspension
* Drug: Paclitaxel
* Drug: Carboplatin
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of NSCLC Stage II, III, or IV NSCLC for whom radiation therapy of 60 Gy and concurrent weekly paclitaxel/carboplatin is recommended Up to three small (≤ 3 cm each) lung oligometastases will be allowed and/or one oligometastasis at any other site in the body Eastern Cooperative Oncology Group Performance Scale (ECOG PS) of 0 or 1 Forced expiratory volume at one second (FEV1): best value obtained pre- or post-bronchodilator must be ≥ 1.0 liters/second or > 50% predicted value Adequate bone marrow reserve Adequate hepatic reserve Adequate renal function Female subjects of childbearing potential must have a negative pregnancy test Female subjects of childbearing potential and male subjects with female sexual partners of childbearing potential must agree to use an effective method of contraception Ability to read and provide written informed consent Exclusion Criteria: Weight loss greater than 10% in prior 4 weeks Prior malignancy in which they received any thoracic radiotherapy unless the treating physician considers it unlikely to impact the clinical outcome of the patient Patients with concurrent invasive malignancy other than non-melanoma skin cancer or cervical intraepithelial neoplasia unless the treating physician considers it unlikely to impact the clinical outcome of the patient An active infection or with a fever ≥ 38.5°C Poorly controlled intercurrent illnesses Patients with a prior thoracotomy within 1 week of study registration Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration Patients with any of the following are not eligible: Previous history of Corrected QT Interval (QTc ) prolongation resulting from medication that required discontinuation of that medication Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age; Presence of left bundle branch block (LBBB); QTc with Fridericia's correction that is unmeasurable, or ≥ 480 msec on screening ECG. The average QTc from the screening ECG (completed in triplicate) must be < 480 msec in order for the patient to be eligible for the study; Subjects taking any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes are not eligible if QTc ≥ 460 msec. Patients must not have had a clinically significant cardiac event within 6 months before entry; or the presence of any other uncontrolled cardiovascular conditions that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. Patients with a history of arrhythmia or asymptomatic sustained ventricular tachycardia are not eligible. Patients with atrial fibrillation with well-controlled ventricular rate on medication, are eligible. Psychiatric conditions, social situations or substance abuse that precludes the ability of the subject to cooperate with the requirements of the trial and protocol therapy Grade 2 or higher peripheral neuropathy Known history of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), hepatitis B or C. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception Women who are breastfeeding are not eligible for this study.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-arm<br>Ascending dose evaluation of BIO 300 Oral Suspension (3 dose levels) given in combination with paclitaxel/carboplatin and radiotherapy. | Drug: BIO 300 Oral Suspension<br>* Cohort 1: BIO 300 500 mg Cohort 2: BIO 300 1,000 mg Cohort 3: BIO 300 1,500 mg Cohort 4: BIO 300 Optimal dose (TBD) BIO 300 dose will be given daily, 7 days/week (Week 1, day 1 through week 6) The 2nd and 3rd dosing cohort (1,000 and 1,500 mg/day) will begin following the accrual of a minimum of 6 subjects at the previous dose level, dose escalation to the next BIO 300 dose level will be allowed to occur when a cohort has completed concurrent chemoradiotherapy with fewer than 33% Dose Limiting Toxicities (DLTs) attributed to BIO 300 Oral Suspension.<br>* Other names: genistein, 5, 7-dihydroxy-3-(4-hydroxyphenyl)-chromen-4-one;Drug: Paclitaxel<br>* During the Concurrent Therapy period, paclitaxel 45 mg/m2 will be administered by intravenous drip weekly during weeks 1-6. During the Consolidation Therapy period, paclitaxel 200 mg/m2 will be administered by intravenous drip two times, 21 days apart.<br>* Other names: Taxol;Drug: Carboplatin<br>* During the Concurrent Therapy period, area under the curve (AUC) = 2mg* min/mL will be administered by intravenous drip weekly during weeks 1-6. During the Consolidation Therapy period, carboplatin AUC = 6mg*min/mL will be administered by intravenous drip two times, 21 days apart.<br>* Other names: CARBOplatin Novaplus;Radiation: Radiotherapy<br>* Radiation treatment will be scheduled at the discretion of the investigator provided the subject has completed a minimum of 2 days of BIO 300 dosing. Subjects will receive radiation therapy 5 days per week, once daily fractions, 1.8-2.0 Gy per fraction, for 6-7 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With BIO 300 Oral Suspension-related Dose Limiting Toxicity | Adverse events of CTCAE v4.0 grade 3 or higher that were possibly, probably or definitely related to BIO 300 Oral Suspension and have occurred before or during concurrent chemoradiotherapy were considered dose limiting toxicities. | Day 1 up to 6 weeks or maximum tolerated dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events Throughout the Study |  | Day 1 up to month 13 post radiation or 12 months post chemotherapy consolidation for surgical participants. | 
| Mean Maximum Serum Concentration (Cmax) of BIO 300 Administered in the Absence of Chemotherapy |  | Day 1, prior to 1st dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post dose | 
| Mean Area Under the Serum Concentration Curve (AUC) of BIO 300 Administered in the Absence of Chemotherapy |  | Day 1, prior to 1st dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post dose | 
| Mean Maximum Serum Concentration (Cmax) of BIO 300 When Administered in Combination With Paclitaxel and Carboplatin |  | Week 1 or 2, during the 1st or 2nd chemotherapy infusion, prior to 1st dose then 0.5, 1, 2, 3, 4, 8, and 24 hours post dose | 
| Mean Area Under the Serum Concentration Curve (AUC) of BIO 300 When Administered in Combination With Paclitaxel and Carboplatin |  | Week 1 or 2, during the 1st or 2nd chemotherapy infusion, prior to 1st dose then 0.5, 1, 2, 3, 4, 8, and 24 hours post dose | 
| Mean Maximum Serum Concentration (Cmax) of Paclitaxel When Administered in Combination With BIO 300 |  | Week 1 or 2, during the 1st or 2nd chemotherapy infusion, prior to BIO 300 dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post initial dose | 
| Mean Area Under the Serum Concentration Curve (AUC) of Paclitaxel When Administered in Combination With BIO 300 |  | Week 1 or 2, during the 1st or 2nd chemotherapy infusion, prior to BIO 300 dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post initial dose | 
| Mean Maximum Serum Concentration (Cmax) of Carboplatin When Administered in Combination With BIO 300 |  | Week 1 or 2, during the 1st or 2nd chemotherapy infusion, prior to BIO 300 dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post initial dose | 
| Mean Area Under the Serum Concentration Curve (AUC) of Carboplatin When Administered in Combination With BIO 300 |  | Week1 or 2, during the 1st or 2nd chemotherapy infusion, prior to BIO 300 dose then 0.5, 1, 2, 3, 4, 8 and 24 hours post initial dose | 
| Percent Change From Baseline in Expression Levels of Serum TGF-beta Isoform 1 (TGFB1) | Measuring change from baseline (screening visit) of TGF-beta isoform 1 (TGFB1) | Screening, once weekly during weeks 1-6 of concurrent chemoradiotherapy prior to BIO 300, paclitaxel, and carboplatin dose, and once at the end of consolidation, 3 months and 6 months after the completion of RT | 
| Rate of Progressive Disease Evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) (1.1) Criteria | Best Response Rate reported per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by chest CT imaging: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Screening, visits 20, 37, 38, 39, 40, 41 & 42 (through visit 41 for surgical participants) | 
| Change in Tumor Diameter as Measured by Diagnostic Computerized Tomography (CT) Scan | Tumor diameter was measured in centimeters. Mean change in tumor diameter from the baseline measurement at screening is reported. | Screening, visits 20 and 3, 6, 11 & 13 months post radiation therapy | 
| DLCO as Measured by Pulmonary Function Test (PFT) |  | Screening and months 6 & 13 post radiation therapy completion | 
| Number of Participants With Pulmonary Fibrosis Assessed by Four-dimensional Computerized Tomography (4D-CT) |  | Screening, visits 20 & 37 and 9 & 13 months post radiation therapy for non-surgical participants; screening only for surgical participants | 
| Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) Patient Reported Outcome Questionnaire. | The Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) questionnaire is a 36-item self-reporting instrument that measures quality of life specific to patients with cancer. Items are rated on a 5 item (point) Likert Scale, from 0 (not at all) to 4 (very much). Total scores range from 0 to 136 and higher scores indicate better quality of life. The FACT-TOI questionnaire was scored according to FACT-L Scoring Guidelines Version 4. | Screening and months 3, 6, & 13 post radiation therapy completion | 
| Quality of Life (QOL) as Measured by University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Patient Reported Outcome Questionnaire. | The UCSD-SOBQ is a 24-item patient self-reported questionnaire where items are scored on a 6-point scale (0, not at all to 5, maximal or unable to-do because of breathlessness). Total scores range from 0 to 120 and lower scores indicate better quality of life. | Screening and months 3, 6, & 13 post radiation therapy completion | 
| Extent of Esophagitis by Patient Reported Swallowing Diary | The assessment will provide a score (the swallowing questionnaire) from 0 to 5; 1 no problems swallowing; 2 mild soreness only; 3 some difficulty swallowing solids; 4 cannot swallow solids; and 5 cannot swallow liquids. | Screening, weeks 1, 2, 3, 4, 5, & 6 and months 3 & 6 post radiation therapy completion | 
| Mean Weekly BIO 300 Trough Levels, Serum Concentration of BIO 300 |  | Concurrent chemoradiotherapy weeks 1, 2, 3, 4, 5 and 6 | 
| Weekly Paclitaxel Trough Levels, Plasma Concentration of Paclitaxel and Carboplatin | Serum trough levels of paclitaxel and carboplatin were measured. Carboplatin trough levels were below the limit of quantification at all timepoints and are therefore reported as zero ng/mL. | Concurrent chemoradiotherapy weeks 1, 2, 3, 4, 5 and 6 | 
| FVC as Measured by Pulmonary Function Test (PFT) |  | Screening and months 6 & 13 post radiation therapy completion | 
| FEV1 as Measured by Pulmonary Function Test (PFT) |  | Screening and months 6 & 13 post radiation therapy completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Neoplasms