Ph I/II Nab-Paclitaxel & Carboplatin w/Concurrent Radiation Therapy for Unresectable Stg III NSCLC

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) may make tumor cells more sensitive to radiation therapy. Giving nab-paclitaxel together with radiation therapy and carboplatin may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving nab-paclitaxel together with carboplatin and radiation therapy and to see how well it works in treating patients with stage III non-small-cell lung cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose of nab-paclitaxel when combined concurrently with carboplatin and radiation followed by two courses of nab-paclitaxel carboplatin as consolidation. (Phase I) To evaluate the progression-free survival in patients with stage III unresectable non-small cell lung cancer treated with nab-paclitaxel, carboplatin, and radiotherapy followed by two courses of nab-paclitaxel with carboplatin as consolidation. (Phase II) Secondary To assess safety and tolerability and identify dose-limiting toxicities in patients receiving nab-paclitaxel combined concurrently with carboplatin and radiotherapy. (Phase I) To assess progression-free survival, response rates, and survival. (Phase I) To assess overall survival and response rates in all patients treated on this study. (Phase II) To assess the safety and tolerability of patients receiving nab-paclitaxel combined concurrently with carboplatin and radiotherapy followed by two courses of nab-paclitaxel/carboplatin as consolidation. (Phase II) OUTLINE: This is a multicenter study. Phase I: Concurrent chemoradiotherapy: Patients receive escalating doses of nab-paclitaxel IV over 30 minutes and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. They also receive conformal radiotherapy once daily 5 days a week on days 1-5 in weeks 1-7. Patients are evaluated between weeks 8-10. Patients with disease progression are removed from study. Patients with stable disease, partial response, or complete response proceed to consolidation chemotherapy 3 weeks after completion of chemoradiotherapy. Consolidation chemotherapy: Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats ever 21 days for up to 2 courses. Phase II: Patients receive concurrent chemoradiotherapy at the Maximum Tolerated Dose (MTD) of nab-paclitaxel followed by consolidation chemotherapy as in phase I. After completion of study treatment, patients are followed at 2 months, every 3 months for 2 years, every 4 months for 2 years, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 98 patients (15 patients for phase I and 83 patients for phase II) will be accrued for this study.

Official Title
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A Phase I/II Study of Nab-Paclitaxel and Carboplatin With Concurrent Radiation Therapy for Unresectable Stage III Non-Small-Cell Lung Cancer (NSCLC)

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: nab-paclitaxel
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Phase I and Phase II Patients: Patients must voluntarily sign and date an informed consent before the initiation of any study procedures Patients must have non-metastatic, inoperable, Stage IIIA or IIIB histologically or cytologically documented NSCLC without evidence of malignant pleural effusion Patients must not have received any prior systemic chemotherapy, thoracic radiotherapy or surgical resection for treatment of NSCLC Patients must have at least one site of unidirectionally measurable disease as defined by Response Evaluation in Solid Tumors (RECIST) criteria Patients must be ≥ 3 weeks from a formal exploratory thoracotomy Patients must have a Radiation Oncology and Medical Oncology consult and approval prior to study entry Patients must be ≥ 18 years of age Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Women of childbearing potential must have a negative baseline serum pregnancy or a negative urine pregnancy test within 7 days prior to Week 1, Day 1 and must not be breast feeding. Women of childbearing potential and men with a sexual partner of child bearing potential must use an effective method of contraception beginning prior to study entry, for the duration of the study participation and for a minimum of 3 months after the last dose of chemotherapy. Patients must have adequate hepatic, renal, lung and bone marrow function as defined below: Absolute neutrophil count (ANC) ≥1,500/mm3 Hemoglobin ≥ 9.0 gm/dL Serum Creatinine ≤1.5mg/dl Platelets > 100,000/mm3 Total bilirubin ≤ upper limit of normal AST and ALT < 2.5 X upper limit of normal Alkaline phosphatase < 2.5 X upper limit of normal Calculated CrCl > 45 ml/min (via Cockroft-Gault formula) Forced expiratory volume in 1 second (FEV 1) > 800 ml Exclusion Criteria for Phase I and Phase II Patients: Known hypersensitivity to carboplatin or nab-paclitaxel Peripheral neuropathy Grade ≥ 2 Wet stage IIIB (documented malignant pleural effusion) or stage IV NSCLC Previous chemotherapy or radiation therapy to the chest Any concomitant malignancy or brain metastasis Any uncontrolled, clinically significant medical or psychiatric disorder Pregnant or nursing women A greater than or equal to 10% weight loss over the past 3 months

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: Treatment<br>nab-paclitaxel+ carboplatin + radiation | Drug: carboplatin<br>* (AUC 2) through a vein over 30 minutes following nab-paclitaxel, once per week x 7 weeks<br>* Other names: Paraplatin;Drug: nab-paclitaxel<br>* Phase I: beginning at 40 mg/m2 through a vein over 30 minutes once per week x 7 weeks Phase II: Maximum tolerated dose through a vein over 30 minutes once per week x 7 weeks<br>* Other names: Abraxane;Radiation: Radiation therapy<br>* 3D conformal radiotherapy or Intensity-Modulated Radiation Therapy (IMRT), 2.0 Gy per day x 5 days per week for 33 days during Weeks 1-7 ; Total Dose = 66 Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Nab-paclitaxel When Combined Concurrently With Carboplatin and Radiation (Phase I) | The highest dose in milligrams per meter of body surface squared (mg/m2) of nab-paclitaxel in combination with carboplatin while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of nab-paclitaxel in combination with carboplatin until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs per Common Toxicity Criteria v 3.0: recurring non-hematological (except esophagitis) > Grade 2, non-hematological or esophagitis > Grade 3 toxicities that are symptomatically unacceptable to patient and result in treatment delay for > 2 weeks, persistent toxicity resulting in treatment delay for > 2 weeks. | 7 weeks | 
| Progression-free Survival (Phase II) | Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: >= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions | On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Phase I) | Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: >= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions | On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years) | 
| Overall Survival (Phase I) | Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details). | On-study date to date of death from any cause (assessed up to 2 years) | 
| Response (Phase I) | Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) >=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD. | On-treatment date to date of progressive disease (assessed up to 2 years) | 
| Number of Patients With Each Worst Grade Toxicity (Phase I) | Count of patients according to the worst-grade toxicity (WGT) experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening; Grade 5, death. | On-study date to 30 days following final dose of study drug | 
| Overall Survival (Phase II) | Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details. Too few patients were enrolled in the Phase II arm for an analysis of overall survival | Time Frame: date on study to date of death from any cause or last known date alive | 
| Number of Patients With Each Worst Grade Toxicity (Phase II) | The number of patients with worst-grade toxicity at each of five grades following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death | at 16 weeks | 
| Response (Phase II) | Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) >=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD. | On-treatment date to date of progressive disease (assessed up to 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV non-small cell lung cancer, stage IIIB non-small cell lung cancer