Neurotoxicity Characterization Study of Nab-paclitaxel Versus Conventional Paclitaxel in Metastatic Breast Cancer

Study Overview
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Brief Summary
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Nanomedicines are currently being developed in the treatment of cancer due to their pharmacological advantages over traditional formulations; they provide a shorter infusion time and lower risks of hypersensitivity reactions associated with commonly used solvents. Nab-paclitaxel is a nanoparticle albumin-bound particle form of paclitaxel that is thought to exploit natural albumin pathways to enhance the selective uptake and accumulation of paclitaxel at the site of the tumour, thus reducing its diffusion to normal tissues. Nab-paclitaxel has been approved for the treatment of metastatic breast cancer patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. SPARC is a cysteine rich acid protein that is overexpressed in a broad proportion of solid tumours. Expression of this protein could sensitize tumour cells to antitumor activity of Nab-paclitaxel, due to its union through albumin-binding to this protein. First-line clinical trials have been developed with different Nab-paclitaxel regimens and also in combination with different chemotherapies and trastuzumab, showing a high level of efficacy. Toxicity profile of Nab-paclitaxel is well characterized with significantly less haematological toxicities compared with conventional paclitaxel. Nab-paclitaxel derived grade III neuropathy is short-lasting and more reversible than conventional paclitaxel-derived neuropathy, probably due to absence of Cremophor solvent, or due to paclitaxel itself. However there is still a lack of clinical and physiological characterisation of Nab-paclitaxel induced neuropathy. The current used tools for early detection and continuous evaluation of neurotoxicity are not optimal. Most used toxicity scales are limited, as they do not provide a detailed information of the severity of the neuropathy, its impact on quality of life, or physiopathology mechanisms. In addition, an inter-individual variability exists in terms of neurotoxicity predisposition when taxanes are used; it could be related to polymorphic differences in genes implicated in transport and metabolism of these drugs.

Official Title
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Neurotoxicity Characterization Phase II Randomized Study of Nab-paclitaxel Versus Conventional Paclitaxel as First-line Therapy of Metastatic HER2-negative Breast Cancer.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel 80 mg/m2
* Drug: Nab-paclitaxel 100 mg/m2 days 1, 8 and 15
* Drug: Nab-paclitaxel 150 mg/m2 days 1, 8 and 15
* Drug: Nab-paclitaxel 150 mg/m2 days 1 and 15


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with histologically or cytologically of stage IV breast cancer. Non-candidate patient to trastuzumab or lapatinib treatment as not presenting HER2 oncogene amplification. Metastatic disease not previously treated with chemotherapy. It is allowed pre-treatment hormone with anti-target or bisphosphonates for advanced disease. Measurable or evaluable disease by RECIST criteria. Previous sensory neuropathy <= grade 1, according to NCI-CTCAE criteria, due to any reason. Age> 18 years. Performance status <2 (ECOG). At least 12 months after the completion of adjuvant chemotherapy with taxanes to diagnosis of metastatic disease. Creatinine <= 1.5mg/dL, AST (SGOT), ALT (SGPT) and alkaline phosphatase <= 2.5 x ULN (hepatic metastases absent) in the 14 days prior to study entry. Hemoglobin> 10g/dl, WBC> 3000/mm3, platelets> 100000/mm3 and bilirubin <1.5 mg / dL in the 14 days prior to study entry. Women of childbearing potential with negative pregnancy test within 14 days prior to study treatment. Patients using adequate contraception throughout the entire duration of the study and until 4 weeks after completion of treatment. At least 4 weeks after radiotherapy or major surgery, with complete recovery. Life expectancy greater than 12 weeks. Patients who are able to meet the requirements of the protocol. Patients able to provide with two plasma samples (each sample 5cc) for analyzing polymorphisms. Written informed consent. Exclusion Criteria: Prior chemotherapy treatment for metastatic disease. Brain metastases. Concomitant treatment with hormone therapy or immunotherapy for breast cancer, or during the two weeks prior to inclusion in the study. Any concomitant medical or psychiatric illness including active infection. History of any malignancy other than breast cancer in the past 5 years except carcinoma or basal cell skin carcinoma or carcinoma in situ of cervix. Prior treatment with an investigational drug within the last 2 weeks. Known hypersensitivity to paclitaxel or Cremophor. Pregnant or breastfeeding. Have any acute, subacute or chronic peripheral nerve or spinal cord in grade, at the time of inclusion, greater than or equal to 2 (NCI CTCAE v4.0).

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Paclitaxel 80 mg/m2 days 1, 8 and 15 | Drug: Paclitaxel 80 mg/m2<br>* Paclitaxel 80 mg/m2 days 1, 8 and 15<br>|
| Experimental: Arm B<br>Nab-paclitaxel 100 mg/m2 days 1, 8 and 15 | Drug: Nab-paclitaxel 100 mg/m2 days 1, 8 and 15<br>* Nab-paclitaxel 100 mg/m2 days 1, 8 and 15<br>|
| Experimental: Arm C<br>Nab-paclitaxel 150 mg/m2 days 1, 8 and 15 | Drug: Nab-paclitaxel 150 mg/m2 days 1, 8 and 15<br>* Nab-paclitaxel 150 mg/m2 days 1, 8 and 15<br>|
| Experimental: Arm D<br>Nab-paclitaxel 150 mg/m2 days 1 and 15 | Drug: Nab-paclitaxel 150 mg/m2 days 1 and 15<br>* Nab-paclitaxel 150 mg/m2 days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TNS - Total Neuropathy Score |  | Every 3 months up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the incidence of neuropathy induced by study treatment (conventional paclitaxel vs nab-paclitaxel) |  | Every 3 weeks up to 24 weeks | 
| Evaluate the electromyographic abnormalities and the correlation of these alterations with the assessment of the TNS scale and NCI-CTCAE (Common Toxicity Criteria for Adverse Effects) v4.0 |  | Every 12 weeks up to 24 weeks | 
| Determine the predictive value of genetic variants (SNPs) for the development of neuropathy |  | In the two weeks before start treatment | 
| Determine the clinical activity of both treatments (response rate, time to progression) |  | Every 8-12 weeks up to 24 weeks | 
| Determine toxicity profile and safety of study treatments (NCI-CTCAE v4.0) |  | Every 2 weeks up to 24 weeks | 
| Determine time to neurotoxicity onset |  | Every 2 weeks up to 24 weeks | 
| Determine time to recovery from neurotoxicity |  | Every 2 weeks up to 24 weeks | 
| Determine time to progression |  | Every 8-12 weeks up to 24 weeks | 
| Assess quality of live (EORTC QLQ-C30 and EORTC QLQ-CIPN20) |  | Every 4 weeks up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Neurotoxicity