Schedules of Nab-Paclitaxel in Metastatic Breast Cancer

Study Overview
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Brief Summary
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Longer first line chemotherapy duration has recently been associated with a modest, but significant improvement in overall survival and a clinically meaningful and statistically significant improvement in progression-free survival, in metastatic breast cancer patients. Prolonging chemotherapy until disease progression, however, must be weighed against the detrimental effects of continuous chemotherapy delivery. The SNAP trial seeks to improve the tolerability of prolonged chemotherapy administration strategy by studying alternative treatment schedules, while preserving and possibly improving treatment efficacy in this disease setting. The availability of a new nanoparticle albumin-bound taxane, nab-Paclitaxel (Abraxane®), represents an opportunity to test this hypothesis. Nab-Paclitaxel has been developed in an attempt to reduce the toxicity associated with standard taxane administration (caused by the use of chemical solvents) while increasing antitumor efficacy. The SNAP randomized phase II trial evaluates three schedules of nab-Paclitaxel as prolonged chemotherapy administration strategy. Each of three arms will be compared to a historical reference of seven-month median progression-free survival (PFS) based on the most recent trial with docetaxel as control arm to determine whether any of the three arms are worthy of further investigation.

Official Title
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A Randomized Phase II Study Evaluating Different Schedules of Nab-Paclitaxel in Metastatic Breast Cancer (SNAP Trial)

Conditions
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Metastatic Breastcancer

Intervention / Treatment
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* Drug: nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer. Measurable or non-measurable, but radiologically evaluable, disease according to RECIST 1.1 criteria. Female aged 18 years or older. Life expectancy > 3 months. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Either ER-positive or ER-negative disease. Patients with ER-positive disease must be endocrine resistant, defined as having failed at least one prior endocrine therapy for breast cancer, or must be candidates for first-line chemotherapy. If previously treated with a taxane or anthracycline in the neoadjuvant or adjuvant setting, the period from end of treatment to disease recurrence must have been > 12 months (> 365 days). Radiation therapy, if given and regardless of site, must be completed at least 2 weeks prior to randomization. Normal hematologic status. Normal renal function. Normal liver function. Normal cardiac function. Women of childbearing potential: documented negative pregnancy test within 2 weeks prior to randomization, and acceptable birth control during the duration of the trial therapy and for a period of 6 months following the last administration of study drug. Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to randomization. Completed baseline Quality of Life Form. The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines. Availability of an formalin fixed paraffin embedded (FFPE) block from the primary tumor (breast lesion) for submission to central pathology review and for translational research. Written consent to pathology material submission, signed and dated by the patient and the Investigator prior to randomization. Exclusion Criteria: Any prior chemotherapy for metastatic breast cancer. Presence of central nervous system (CNS) metastasis. Peripheral neuropathy grade 2 or higher (CTCAE version 4). Significant uncontrolled cardiac disease (i.e. unstable angina, recent myocardial infarction within prior 6 months), patients classified as having a New York Heart Association (NYHA) class III or IV congestive heart failure. Pregnant or lactating. Prior history of non-breast malignancy (except for adequately controlled basal cell carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the bladder). Any concurrent condition which in the Investigator's opinion makes it inappropriate for the patient to participate in the trial or which would jeopardize compliance with the protocol. Contraindications or known hypersensitivity to the study medication or excipients. The use of any anti-cancer investigational agents within 30 days prior to expected start of trial treatment. Inability or unwillingness to abide by the study protocol or cooperate fully with the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: nab-Paclitaxel 150 mg/m2 days 1,15<br>Arm A: Induction* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 150 mg/m2 administered on days 1, 15 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity. *Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m². | Drug: nab-Paclitaxel<br>* Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations)<br>* Other names: Abraxane;|
| Experimental: B: nab-Paclitaxel 100 mg/m2 days 1,8,15<br>Arm B: Induction* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 100 mg/m2 administered on days 1, 8, 15 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity. *Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m². | Drug: nab-Paclitaxel<br>* Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations)<br>* Other names: Abraxane;|
| Experimental: C: nab-Paclitaxel 75 mg/m2 days 1,8,15,22<br>Arm C: Induction* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 75 mg/m2 administered on days 1, 8, 15, 22 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity. *Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m². | Drug: nab-Paclitaxel<br>* Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations)<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Time from randomization until objective disease progression [progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions] or death, whichever occurs first. For patients without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurred within a short period of time (12 weeks) following the date last known progression-free, in which case the death was counted as a PFS event. | Reported after 18.2 months median follow-up since randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks | Whether or not the patient completed treatment according to the protocol for at least 24 weeks. Patients who progressed within 24 weeks were considered as not completing. | Baseline to 24 weeks follow-up | 
| Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks | Overall response of stable disease (or non-CR/non-PD for patients with non-measurable disease) for a duration of ≥24 weeks, or better (i.e., partial or complete response) according to RECIST criteria [Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.] | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months | 
| Best Overall Response | Best response according to RECIST 1.1 criteria [assessed by MRI] recorded from the start of treatment across all time points until end of study treatment. Confirmation of partial or complete response by an additional scan was not requested in this trial. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months | 
| Overall Survival | Time from randomization until death from any cause, or censored at date last known alive | Reported after 18.2 months median follow-up since randomization | 
| Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6) | Primary quality of life=physical well being; endpoint based on the GLQ 8. The indicator was in Linear Analogue Self-Assessment (LASA) format ranging 0-100 (0=as bad as it can be, 100=as good as it can be). | Assessed from day 1 of cycle 4 through day 1 of cycle 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-negative Stage IV, No previous chemotherapy, Metastatic, Breast, Cancer