Safety and Efficacy Study of Abraxane as Maintenance Treatment After Abraxane Plus Carboplatin in 1st Line Stage IIIB / IV Squamous Cell Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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Maintenance treatment of advanced stage squamous cell NSCLC. Phase III, randomized, open-label, multi-center study of nab-paclitaxel with best supportive care (BSC) or BSC alone as maintenance treatment after response or stable disease (SD) with nab-paclitaxel plus carboplatin as induction in subjects with stage IIIB/IV squamous cell NSCLC. Subjects who discontinued treatment from the maintenance part for any reason other than withdrawal of consent, lost to follow-up, or death, were entered into a Follow-up period that had a visit 28 days after progression or discontinuation. Those who entered Follow-up without progression continued with follow-up scans according to standard of care (SOC) until documentation of progression of disease. Additionally, subjects were followed for OS by phone approximately every 90 days for a minimum of 18 months, for up to approximately 5 years after the last subject was randomized.

Detailed Description
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The sponsor used 15 Sep 2017 as the database cut-off date.

Official Title
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A Phase III, Randomized, Open-Label, Multi-Center, Safety and Efficacy Study to Evaluate Nab-Paclitaxel (Abraxane®) as Maintenance Treatment After Induction With Nab-Paclitaxel Plus Carboplatin in Subjects With Squamous Cell Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Squamous Cell Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Abraxane (Induction)
* Drug: Carboplatin (Induction)
* Drug: Abraxane (Maintenance)
* Other: Best Supportive Care (Maintenance)
* Drug: Abraxane (Induction)
* Drug: Carboplatin (Induction)
* Other: Best Supportive Care (Maintenance)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 squamous cell Non Small Cell Lung Cancer at study entry. No other current active malignancy requiring anticancer therapy. Radiographically documented measurable disease at study entry (as defined by the Response Evaluation Criteria In Solid Tumors [RECIST] v1.1 criteria). No prior chemotherapy for the treatment of metastatic disease at study entry. Adjuvant chemotherapy is permitted providing cytotoxic chemotherapy was completed 12 months prior to starting the study and without disease recurrence. Absolute neutrophil count ≥ 1500 cells/mm^3. Platelets ≥ 100,000 cells/mm^3. Hemoglobin ≥ 9 g/dL. Aspartate transaminase/serum glutamic oxaloacetic transaminase, alanine transaminase/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal range or ≤ 5.0 × upper limit of normal range if liver metastases. Total bilirubin ≤ 1.5 × upper limit of normal range except in cases of Gilbert's disease and liver metastases. Creatinine ≤ 1.5 mg/dL. Expected survival of > 12 weeks for the Induction part of the study. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. For Maintenance part of the study, subjects must have received at least one dose of nab-paclitaxel in each of the 4 cycles during Induction Pregnancy 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 (i.e., has had menses at any time during the preceding 24 consecutive months)] must: agree to take a pregnancy test prior to starting study medication and throughout the study participation. commit to complete abstinence from heterosexual contact, or agree to use medical doctor-approved contraception throughout the study without interruption, and while receiving study medication or for a longer period if required by local regulations. Male subjects must: c. agree to complete abstinence from heterosexual contact or use a condom during sexual contact with a female of child bearing potential while receiving study medication and within 6 months after last dose of study medication, even if he has undergone a successful vasectomy. Females must abstain from breastfeeding during study participation and 3 months after IP discontinuation. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment into the Induction and Maintenance parts of the study (except if specified at study entry only): Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for ≥ 4 weeks prior to first dose of study drug). Only evidence of disease is non-measurable at study entry. Preexisting peripheral neuropathy of Grade 2, 3, or 4 (per Common Terminology Criteria for Adverse Events v4.0). Venous thromboembolism within 6 months prior to signing Informed Consent Form. Current congestive heart failure (New York Heart Association class II-IV). History of the following within 6 months prior to first administration of a study drug: 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 electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder. Treatment with any investigational product within 28 days prior to signing Informed Consent Form. History of allergy or hypersensitivity to nab-paclitaxel or carboplatin. Currently enrolled in any other clinical protocol or investigational trial that involved administration of experimental therapy and/or therapeutic devices. Any other clinically significant medical condition and/or organ dysfunction that will interfere with the administration of the therapy according to this protocol. Subject has any other malignancy within 5 years prior to randomization. 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 (TNM stage of T1a or T1b) - all treatments that should have been completed 6 months prior to signing informed consent form (ICF). 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. Pregnant and nursing females.

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abraxane + Best Supportive Care (BSC)<br>Dosing will occur in two phases - induction and maintenance. During induction, the subject will receive Abraxane plus carboplatin as standard of care. At the end of 4 cycles, if the subject has a complete response, partial response, or stable disease, he/she will continue on to the maintenance phase. Maintenance dosing on this arm includes Abraxane plus best supportive care. | Drug: Abraxane (Induction)<br>* 100 mg/m2 IV infusion over 30 minutes on Days 1 and 8 and 15 of each 21-day cycle, administered as standard of care<br>* Other names: nab-paclitaxel;Drug: Carboplatin (Induction)<br>* 6 mg/min/mL IV on Day 1 of each 21-day cycle after completion of nab-paclitaxel infusion<br>Drug: Abraxane (Maintenance)<br>* 100 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, administered as standard of care<br>Other: Best Supportive Care (Maintenance)<br>* The best palliative care per investigator (including but not limited to: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and/or focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis), excluding antineoplastic agents<br>|
| Other: Best Supportive Care (BSC)<br>Dosing will occur in two phases - induction and maintenance. During induction, the subject will receive Abraxane plus carboplatin as standard of care. At the end of 4 cycles, if the subject has a complete response, partial response, or stable disease, he/she will continue on to the maintenance phase. Maintenance dosing on this arm includes best supportive care only. | Drug: Abraxane (Induction)<br>* 100 mg/m2 IV infusion over 30 minutes on Days 1 and 8 and 15 of each 21-day cycle, administered as standard of care<br>* Other names: nab-paclitaxel;Drug: Carboplatin (Induction)<br>* 6 mg/min/mL IV on Day 1 of each 21-day cycle after completion of nab-paclitaxel infusion, administered as standard of care<br>Other: Best Supportive Care (Maintenance)<br>* The best palliative care per investigator (including but not limited to: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and/or focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis), excluding antineoplastic agents<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Progression-Free Survival (PFS) From Randomization Into Maintenance | Progression-free survival is defined as the time in months from the date of randomization 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 computerized axial tomography [CT scan], not including symptomatic deterioration) or death (any cause) on or prior to 01 Aug 2019. RECIST 1.1 Definition: - Complete response (CR) -disappearance of all target lesions; - Partial response (PR) -at least a 30% decrease in the sum of diameters of target lesions from baseline - Stable disease (SD) -neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase of lesions to qualify for progressive disease (PD) - Progressive Disease (PD) - At least a 20% increase in the sum of diameters of target lesions from nadir, and/or the appearance of new lesions. | From the date of randomization to the date of disease progression or death of any cause; up to data cut off date of 15 September 2017; up to 27.6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Overall Survival (OS) From Randomization Into Maintenance | Overall survival was defined as the duration in months between randomization 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 (01 August 2019 whichever was earlier. The last contact date was the date of the last record in the database, or if the subject was lost to follow-up, the last known date that the subject was alive. | From the date of randomization to death from any cause; up to 01 August 2019; survival follow up was 55.89 months | 
| Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) Over Entire Study | Overall response was defined as the percentage of participants with a confirmed assessment of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria and confirmed in no less than 28 days. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. RECIST 1.1 Definition: - Complete response-disappearance of all target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. - Partial response-at least a 30% decrease in the sum of diameters of target lesions from baseline. | Day 1 of treatment in the induction period and subsequent anticancer therapy, death or discontinuation up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study | 
| Kaplan-Meier Estimate of Progression-Free Survival (PFS) Over Entire Study | PFS was defined as the time in months from Day 1 of treatment for the Induction part to the date of disease progression according to RECIST 1.1 criteria (documented by CT-scan, not including symptomatic deterioration) or death (any cause) on or prior to 01 August 2019, whichever occurred earlier. RECIST 1.1 Definition: - Progressive Disease (PD) - At least a 20% increase in the sum of diameters of target lesions from nadir; the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of new lesions is also considered progression. | Between Day 1 of the Induction Part through to the date of disease progression or death; up to 01 August 2019; the maximum treatment duration was 234.1 weeks for entire study | 
| Kaplan-Meier Estimate of Overall Survival (OS) Over Entire Study | Overall survival was defined as the time in months from Day 1 of treatment for the Induction part to death from any cause. Subjects who were alive at the time of analysis had their OS censored at the date or last contact of 01 August 2019, whichever was earlier. The last contact date was the date of the last record in the database, or if the subject was lost to follow-up, the last known date that the subject was alive. | Between Day 1 of treatment in the Induction Part to death from any cause; up to 01 August 2019; survival follow up was 55.89 months | 
| Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) In Maintenance Beyond the Response in Induction | Overall response in the maintenance period was defined as the percentage of participants who showed an improvement in best overall response from stable disease (SD) or partial response (PR) during Induction to a Complete Response (CR) or PR during Maintenance according to RECIST 1.1 criteria and confirmed in no less than 28 days. Evaluation takes as reference the lesion measurement or status at the last tumor assessment before randomization to Maintenance. The 95% CI was calculated using Clopper-Pearson method. RECIST 1.1 Definition: - Complete response-disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - Partial response-at least a 30% decrease in the sum of diameters of target lesions from baseline. - Stable disease-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. | For the induction period the maximum treatment was 19 weeks for the maintenance period the maximum treatment was 150 weeks. | 
| Percentage of Participants Who Achieved Disease Control (Disease Control Rate) by Investigator Assessment During Induction and Over the Entire Study | Disease control rate was defined as the percentage of participants who had radiologic CR, PR or SD for >= 6 weeks according to RECIST 1.1 criteria as determined by the investigator. Only participants with a confirmed CR/PR are included in this summary. Two timeframes are offered: - Time to confirmed response within the Induction timeframe. - Time to Confirmed Response Over the Entire Study, i.e. the time from Day 1 of treatment in Induction to the first occurrence of confirmed CR/PR any time during the study. RECIST 1.1 Definition: - CR- disappearance of all target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. - PR- at least a 30% decrease in the sum of diameters of target lesions from baseline; - SD- neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for PD. The 95% CI was calculated using Clopper-Pearson method. | Induction is from Day 1 to a maximum treatment time of 19 weeks; entire study from Day 1 induction through maintenance up to PD; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study | 
| Time to Confirmed Response During Induction and Over the Entire Study | Time to confirmed complete or partial response (CR/PR) is defined as the time from day 1 of treatment in Induction to the first occurrence of confirmed CR/PR. Two timeframes are offered: - Time to confirmed response within the Induction timeframe. - Time to Confirmed Response Over the Entire Study, i.e. the time from Day 1 of treatment in Induction to the first occurrence of confirmed CR/PR any time during the study. Only participants with a confirmed CR or PR are included in this summary. | Induction is from Day 1 to a maximum treatment time of 19 weeks; entire study from Day 1 Induction through Maintenance up to PD; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study | 
| Kaplan-Meier Estimate for Duration of Response Over the Entire Study | Duration of overall response was measured from the time criteria were first met for CR/PR until the first date the recurrent or progressive disease (PD) was radiologically documented. Participants who did not have PD after the response were censored on the date of last tumor assessment. If a participant died before PD, the participant was censored on the date of death. | Between Day 1 of the Induction Period through to the date of disease progression or death; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study. | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) in the Induction Period | TEAE in the Induction part is defined as any adverse event (AE) with an onset on or after Day 1 of treatment for the Induction part, and on or before the day of randomization for subjects who entered into the Maintenance part, or, for subjects who did not enter into the Maintenance part, before the treatment discontinuation date plus 28 days or any serious AE which occurred thereafter but was determined to be related to any study drug by the investigator. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild, Grade 2 = Moderate Grade, 3 = Severe Grade, 4 = Life threatening, Grade 5 = Death. Relation to study drug was determined by the investigator. | Day 1 of Induction up to Week 23 (maximum treatment in Induction plus 4 weeks if not continuing into Maintenance) | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) Over the Entire Study | TEAE over entire study is defined as any adverse event (AE) with an onset on or after Day 1 of treatment for the Induction part, and before the treatment discontinuation date plus 28 days, or any serious AE which occurred thereafter but was determined to be related to any study drug by the investigator. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. Relation to study drug was determined by the investigator. | From Day 1 up to 01 August 2019; (maximum treatment length plus 28 days); the maximum treatment duration was 234.1 weeks for entire study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nab-paclitaxel, Albumin bound paclitaxel, Taxanes, Maintenance trials, Celgene, Abraxane, ABI-007, NSCLC, Non-Small Cell Lung Cancer, Cancer of the Lung, Carcinoma, Squamous Cell, Lung Neoplasms, Abound.sqm