Phase II Safety and Tolerability Trial With Nab-Paclitaxel Plus Carboplatin Followed by Nab-Paclitaxel for First Line Treatment of NSCLC Subjects With ECOG PS 2

Study Overview
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Brief Summary
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4 cycles of induction treatment with nab-paclitaxel and carboplatin followed by nab-paclitaxel monotherapy for those subjects who are progression free at the end of 4 cycles.

Official Title
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A Phase II, Single Arm, Open-Label, Multicenter, Safety and Tolerability Trial With Nab-Paclitaxel (ABRAXANE®) Plus Carboplatin Followed by Nab-Paclitaxel Monotherapy as First-Line Treatment for Subjects With Locally Advanced or Metastatic Nonsmall Cell Lung Cancer (NSCLC) and an Eastern Cooperative Oncology Group Performance Status of 2 (ABOUND.PS2)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: nab-Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General and Demographics Age ≥ 18 years of age at the time of signing the Informed Consent Form. Understand and voluntarily provide written consent to the Informed Consent Form prior to conducting any study related assessments/procedures. Able to adhere to the study visit schedule and other protocol requirements. Disease Specific Histologically or cytologically confirmed Stage IIIB or IV Non-Small Cell Lung Cancer. Radiographically documented measurable disease at study entry per response evaluation criteria in solid tumours ( RECIST) v1.1. No prior anti-cancer therapy for the treatment of metastatic disease at the time of signing the ICF. Adjuvant treatment is permitted providing cytotoxic chemotherapy was completed 12 months prior to signing the ICF and without disease recurrence. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3. Platelets ≥ 100,000 cells/mm3. Hemoglobin (Hgb) ≥ 9 g/dL. Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]), alanine transaminase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × upper limit of normal range (ULN) or ≤ 5.0 × ULN if liver metastases. Total bilirubin ≤ 1.5 × ULN except in cases of Gilbert's disease and liver metastases. Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance ≥ 40 mL/min (if renal impairment is suspected 24-hour urine collection for measurement is required). Eastern Cooperative Oncology Group Performance Status 2. Females of childbearing potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months)] must: Have a negative pregnancy test Beta Human Chorionic Gonaditrophin(ß-hCG) as verified by the study doctor within 72 hours prior to starting study therapy. You must commit to complete abstinence from heterosexual contact, or agree to use medical doctor-approved contraception throughout the study without interruption; while receiving study medication or for a longer period if required by local regulations. Male subjects must: practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following study drug discontinuation, even if he has undergone a successful vasectomy. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for at least 21days prior to signing ICF). MRI of the brain (or CT scan w/contrast) is preferred for diagnosis. History of leptomeningeal disease. Only evidence of disease is non-measurable. Pre-existing peripheral neuropathy of Grade 2, 3, or 4 (per Criteria for Adverse Events (CTCAE) v4.0). Subject has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting investigational product (IP), and/or from whom ≥ 30% of the bone marrow was irradiated. Prior radiation therapy to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed. Venous thromboembolism within 1 month prior to signing ICF. Current congestive heart failure (New York Heart Association Class II-IV). History of the following within 6 months prior to first administration of investigational product: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder. Subject has a known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subject receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications. Subject has an active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. History of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis. Treatment with any investigational product within 28 days prior to signing the ICF. History of or suspected allergy to nab-paclitaxel, carboplatin and human albumin or any other platinum-based therapy. Currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices. Any other clinically significant medical condition, psychiatric illness, and/or organ dysfunction that will interfere with the administration of the therapy according to this protocol or which, in the views of investigator, preclude combination chemotherapy. Subject has any other malignancy within 5 years prior to signing the ICF. Exceptions include the following: squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer (Tumor, node and metastasis (TNM) stage of T1a or T1b). All treatment should have been completed 6 months prior to signing ICF. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Any medical condition that confounds the ability to interpret data from the study. This includes subjects with known psychiatric disorders. Pregnant or breast-feeding females. Subjects with an ECOG PS other than 2

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nab-Paclitaxel<br>nab-Paclitaxel 100 mg/m2 intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle • Carboplatin AUC = 5 mg*min/mL IV on Day 1 of each 21-day cycle after completion of nab-paclitaxel infusion. | Drug: nab-Paclitaxel<br> <br> * Other names: Abraxane;Drug: Carboplatin<br> <br> * Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Discontinued Study Treatment During the Induction Period Due to Treatment Emergent Adverse Events (TEAEs). | Treatment-emergent adverse events were defined as any adverse event (AE) or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the investigational product through 28 days after the last dose of IP. In addition, any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. A participant met the primary endpoint if: an AE was the reason for discontinuation as recorded in the electronic Case Report Form (eCRF) and the participant had no doses administered beyond Cycle 4. 95% confidence interval for the percentage was calculated using the Clopper Pearson method. | From date of the first dose of IP until 28 days after the last dose of IP during induction and SAEs made known to the investigator any time thereafter that are suspected of being related to IP; maximum treatment duration during induction was 3.9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Discontinued Study Treatment During the Induction Period (Discontinuation Rate) | Discontinuation Rate was measured as Percentage of Participants who Discontinued Study Treatment During the Induction Period | From date of the first dose of IP until 28 days after the last dose of IP during induction and SAEs made known to the investigator any time thereafter that are suspected of being related to IP; maximum treatment duration during induction was 3.9 months | 
| Dose Intensity of Nab-Paclitaxel During the Entire Study | Dose intensity for nab-paclitaxel during the entire study period was (mg/m^2/week) = [cumulative dose for nab-paclitaxel in mg/m^2] / [nab-paclitaxel dosing period in weeks] | From Day 1 of study treatment to end of study treatment; maximum treatment duration on study was 14.1 months | 
| Dose Intensity of Carboplatin During the Entire Study | Dose intensity for carboplatin during the entire study period was (mg*min/mL/week) = [cumulative dose for carboplatin in mg*min/mL] / [carboplatin dosing period in weeks]. | From Day 1 of study treatment to end of study treatment; maximum treatment duration on study was 14.1 months | 
| Percentage of Participants With Dose Reductions During the Entire Study | A dose reduction occurs when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions are typically caused by clinically significant laboratory abnormalities and/or treatment emergent adverse events or toxicities. | From day 1 of IP until 28 days after the last dose of IP; maximum treatment duration was 14.1 months during the entire study | 
| Kaplan Meier Estimate of Progression-Free Survival (PFS) | Progression-free survival was defined as the time in months from day 1 of treatment to the date of disease progression based on the investigator's assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. RECIST V1.1 criteria includes: - Complete Response (CR) is the disappearance of all target lesions; - Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions from baseline; - Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease (PD); - Progressive Disease is at least a 20% increase in the sum of diameters of target lesions from nadir | From Day 1 of study drug treatment to the date of disease progression; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Percentage of Participants Who Achieved a Complete Response or Partial Response or Continued Stable Disease (Disease Control Rate) | Disease control rate was defined as the percentage of participants who had continued stable disease, complete or partial response during the course of the study, according to RECIST v1.1 guidelines, as evaluated by the investigator. RECIST V1.1 criteria includes: - Complete Response is the disappearance of all target lesions; - Partial Response is at least a 30% decrease in the sum of diameters of target lesions from baseline; - Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease; - Progressive Disease is at least a 20% increase in the sum of diameters of target lesions from nadir | Response assessments were evaluated every 6 weeks; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Kaplan Meier Estimate of Overall Survival (OS) | Overall survival was defined as the time in months between day 1 of treatment and death from any cause). Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact. | From Day 1 of study treatment to death from any cause; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST 1.1 Guidelines | Overall tumor response is defined as the percentage of participants who achieved an objective confirmed CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions from baseline) according to RECIST V1.1 guidelines, compared with baseline where baseline was the last computed tomography (CT) scan obtained prior to or on Day 1 of study treatment. | Response assessments were evaluated every 2 cycles; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Time to Response | Time to response was defined as the time from Day 1 of study treatment to the first occurrence of response (CR or PR) according to RECIST v1.1 guidelines. RECIST V1.1 criteria includes: - A Complete Response (CR) is the disappearance of all target lesions; - A Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions from baseline | From Day 1 of study drug treatment to the date of first occurrence of CR or PR; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Kaplan Meier Estimate of Duration of Response | Duration of overall response was measured from the time measurement criteria were first met for CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions from baseline), whichever was first recorded, until the first date that recurrent disease or PD (at least a 20% increase in the sum of diameters of target lesions from nadir) was radiologically documented (taking as reference for PD the smallest measurements recorded on study). Median and 95% CI were estimated based on the Kaplan-Meier method. | From Day 1 of study drug treatment to the date of first occurrence of CR or PR; up to the clinical cut-off date of 24 February 2017; maximum treatment duration on study was 14.1 months | 
| Number of Participants With TEAEs During the Induction and Monotherapy Periods | Treatment-emergent adverse events were defined as any adverse event or serious adverse event that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP. In addition, any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. The severity of AEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild l intervention/therapy required Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death. | From date of the first dose of IP until 28 days after the last IP dose and SAEs made known to the investigator any time thereafter that are suspected of being related to IP; up to cutoff date of 24 Feb 2017; maximum treatment duration was 14.1 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase II, LOCALLY ADVANCED OR METASTATIC NON SMALL, CELL LUNG CANCER (NSCLC) AND AN, EASTERN COOPERATIVE ONCOLOGY GROUP, PERFORMANCE STATUS OF 2, (ABOUND.PS2), LOCALLY ADVANCED OR METASTATIC NON SMALL, CELL LUNG CANCER (NSCLC) SUBJECTS THAT AE NOT CANDIDATES FOR RADIATION OR CURATIVE SURGERY