Neoadjuvant Treatment With Nab-paclitaxel for Patients With Stage II and III Luminal Breast Cancer

Study Overview
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Brief Summary
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Multicenter, open label, non-randomized phase 2 trial to evaluate the efficacy and safety of nab-paclitaxel in the neoadjuvant treatment of ER positive human epidermal growth factor receptor 2 (HER2) negative patients amenable to receive neoadjuvant chemotherapy.

Detailed Description
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The primary objective of the trial is to determine the percentage of patients with poor response [residual cancer burden III (RCB-III) rate] in contrast to good response [residual cancer burden 0/I RCB-0/1] measured by the Symmans criteria [20] at surgery, in patients with stage II-III luminal breast cancer treated with neoadjuvant nab-paclitaxel. The primary endpoint of the study is to determine the residual cancer burden grade III (RCB-III) after surgery. The total number of patients to be included in this study is 78 patients. The duration of the study, from first patient visit to last patient visit will be approximately 90 months (Including follow-ups)

Official Title
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Phase II, Open-label, Non-randomized Study of Nab-paclitaxel for the Neoadjuvant Treatment of Patients With Stage II and III Luminal Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with histologically confirmed diagnosis of primary unilateral invasive early breast cancer with longest tumor size in breast ≥ 2cm, or < 2 cm with axillary involvement. In case of a multifocal tumor (tumor foci located in the same quadrant) the largest lesion must be ≥ 2cm (unless axillary involvement) and is designated as the target lesion for all subsequent tumor evaluations. The breast tumors must be ER positive: more than 1% of stained tumor cells by immuno-histochemistry (IHC), and HER2 negative: 0, or 1+ score by IHC, or 2+ with fluorescence in situ hybridization (FISH)/chromogenic in situ hybridization (CISH) negative for HER2 amplification (defined as a ratio of HER2/neu copies to chromosome 17 centromere (CEP17) signals <1.8), according to the local laboratory). Are clear candidates to receive chemotherapy by the investigator criteria. Are at least 18 years of age. Have at least one unidimensionally measurable lesion by RECIST [65] version 1.1, measured by mammogram. Have adequate performance status: Eastern Cooperative Oncology Group (ECOG) <2 Have adequate renal and liver function and bone marrow reserve as follows: Bone marrow: absolute neutrophil count (ANC) > or = 1.500/mm3 (1.5 x 109/L); platelet count > or = 100.000/mm3 (100.0 x 109/L); and hemoglobin > or = 9 g/dL. Hepatic: bilirubin < or = 1.5 times the upper limit of normal (x ULN); alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) < or = 2.5 * ULN and Albumin ≥ 2.5 g/dL. Renal: serum creatinine < 1.5 x ULN. Exhibit patient compliance and geographic proximity that allow for adequate follow-up Entry informed consent form signed by the patient. Exclusion Criteria: Inflammatory breast cancer (T4d) and supraclavicular lymph nodes (N3) Synchronous contralateral or multicentric breast cancer. Clinical or radiologic evidence of metastatic disease. Chest examination by x-ray or CT-scan, abdominal examination by CT-scan, bone examination by bone scan as well as other radiological methods in case of suspicion must be performed before enrollment in order to rule out metastasis. Second primary malignancy, except adequately treated carcinoma in situ of the cervix, stage I colon cancer, non-invasive melanoma, basal or squamous cell carcinomas of the skin, ipsilateral ductal carcinoma in-situ (DCIS) of the breast and lobular carcinoma in-situ (LCIS) of the breast; unless that prior malignancy was diagnosed and definitively treated more than 5 years ago with no subsequent evidence of recurrence. Prior or concurrent anti-cancer therapy for current disease (hormone therapy, chemotherapy, radiotherapy, immunotherapy, biological therapy other than the trial therapies). Concurrent treatment with any hormonal treatment either for osteoporosis or as replacement therapy. Patients with known hypersensitivity to nab-paclitaxel or any of its components. Previous neuropathy grade >1 according to the NCI-CTCAE vs 4.03 criteria Have received treatment within the last 4 weeks with a drug that has not received regulatory approval for any indication at the time of study entry. Have any serious concomitant systemic disorder incompatible with the study (at the discretion of investigator). Patient is pregnant or breast feeding or planning to become pregnant within the six months after the end of treatment. Women with child-bearing potential must be performed a pregnancy serum or urine testing within 7 days prior to study entry according to institutional standards and should use an adequate non-hormonal contraceptive method (intra-uterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterilized) during treatment with study drugs and within the six months after the end of treatment.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nab-Paclitaxel<br>The patients will be included to receive 3 weekly nab-paclitaxel doses of 150 mg/m2 with one week of rest for 4 cycles. | Drug: Nab-paclitaxel<br> <br> * Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Residual Cancer Burden Grade III (RCB-III). | The RCB-III was reported, including a 95% confidence interval. The estimate of the RCB-III was calculated as follows: Overall Response Rate = Number of patients with RCB-III / Intent to treat (ITT) population | After surgery, up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) Rate | Objective Response was measured following the Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. For the purpose of this study a response is defined as the achievement of a complete or partial response measured by breast MRI. Pathological complete response (pCR) was evaluated following the Symmans method at the time of the definitive surgery. For the purpose of this study RCB-0 was considered a pCR. The pCR (RCB-0) rate (pCRR) was reported including a 95% confidence interval. The estimate of the pCR rate was calculated as follows by central laboratory: pCR Rate = Number of patients with pCR / ITT population. | After surgery, up to 4 months | 
| Objective Response Rate (ORR) by Magnetic Resonance Imaging (MRI) | The ORR was reported including a 95% confidence interval. The estimate of the ORR was determined according to RECIST 1.1 and measured by MRI and mammogram in patients treated with this regimen. ORR was calculated as follows: Overall Response Rate = Number of Complete Responses (CRs), Partial Responses (PRs) / ITT population | After surgery, up to 4 months | 
| Objective Response Rate (ORR) by Mammogram | The ORR was reported including a 95% confidence interval. The estimate of the ORR was determined according to RECIST 1.1 and measured by MRI and mammogram in patients treated with this regimen. ORR was calculated as follows: Overall Response Rate = Number of CRs, PRs / ITT population | After surgery, up to 4 months | 
| Invasive Disease Free Survival (IDFS) | IDFS was defined as the time (days) from the date of randomization until the date of objective recurrent disease (local, regional or distant), second primary invasive malignancy (breast or non-breast) or death from any cause. For patients not known to have died as of the data cut-off date and who do not have recurrent disease or second primary tumor, invasive disease-free survival will be censored at the last contact date. Ductal carcinoma in-situ (DCIS) will not be considered an event for the purpose of this analysis. | Up to 6 years | 
| Rate of Conversion to Breast Conserving Surgery (BCS) | The conversion from the initially planned mastectomy to BCS was reported including a 95% confidence interval. The estimate of the rate of conversion to BCS was calculated as follows: BCS rate = Number of patients with BCS / Number of patients with initially planned mastectomy. | After surgery, up to 4 months | 
| The Number of Participants Who Experienced Adverse Events (AE) | Incidence of adverse events by maximum CTCAE grade (v4.03; NCI 2010) that occur during the study treatment period or within 30 days of the last dose of study treatment, regardless of causality and according to the relationship to study drug as assessed by the investigator, were collected and evaluated. | During treatment and until 30 days after the last dose of each patient study treatment | 
| Ki67 in Pre-treatment Tumor Samples as Tumor Predictive Marker of Nab-paclitaxel Response | Ki67 was analysed by immunohistochemistry following the American Society of Clinical Oncology and the College of American Pathologists guidelines. The cut-off considered for Ki67 expression was 20% of positively stained tumor cells. | Baseline visit | 
| Caveolin-1 in Pre-treatment Tumor Samples as Tumor Predictive Marker of Nab-paclitaxel Response | Caveolin (Cav)-1 was evaluated in the stroma and its expression was categorized in low, moderate, or high (tertile). The high expression of Cav-1 was considered as positive. | Baseline visit | 
| Secreted Protein, Acidic, Cysteine-rich (SPARC) in Pre-treatment Tumor Samples as Tumor Predictive Marker of Nab-paclitaxel Response | SPARC was evaluated for both tumor and stroma. Its expression was categorized as negative when the intensity was absent-to-weak (1), or moderate (11)-to-strong (111) with a proportion of stained cells <10%. Immunolabeling was positive if the intensity was moderate (11)-to-strong (111) and the extent of staining was 10%. | Baseline visit | 
| Molecular Tumor Subtypes According to St. Gallen Criteria 2013 in Pre-treatment Tumor Samples as Predictive Marker of Nab-paclitaxel Response | Molecular subtypes were classified according to St. Gallen criteria 2013 and Prat et al. into Luminal A (ER+, Progesterone Receptor (PgR) >20%, Human Epidermal growth factor Receptor 2 - (HER2), Ki67 <14%), Luminal B1 (ER+, HER2-, PgR >20% and/or Ki67 <14%), Luminal B2 (ER+, HER2+, any PgR, any Ki67), TN (ER-, PgR-, HER2-), and HER2-enriched (ER-, PgR-, HER2+) subtypes. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant nab-paclitaxel luminal breast cancer