A Phase I/II Study of ABI-007 (Abraxane®, Nab®-Paclitaxel)and Vinorelbine in Patients With Stage IV (Metastatic) Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to: 1) determine the optimal tolerated dose of ABI-007 and vinorelbine, given concurrently on a weekly basis, in the absence of planned growth factor support with granulocyte colony-stimulating factor (G-CSF) (Patients with HER-2/neu positive disease may receive Herceptin, and 2) determine the optimal tolerated dose of ABI-007 and vinorelbine, given concurrently on a weekly basis, in the presence of planned growth factor support with G-CSF.

Official Title
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An Open-Label Phase I/II Study of Weekly ABI-007 and Vinorelbine With or Without G-CSF in Patients With Stage IV (Metastatic) Breast Cancer

Conditions
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Stage IV (Metastatic) Breast Cancer

Intervention / Treatment
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* Drug: ABI-007
* Drug: vinorelbine
* Drug: Trastuzumab
* Biological: G-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has microscopically confirmed invasive breast carcinoma with clinical and/or radiographic evidence of stage 4 disease. If diagnosis is based on pleural effusion, positive cytology must be confirmed. Patient has had no prior chemotherapy for Stage 4 disease (hormone therapy is permitted). Prior adjuvant paclitaxel by 3-hour infusion is permitted, if there is no residual neuropathy. Prior adjuvant docetaxel on an every 3 week schedule is permitted. Disease must be measurable (unidimensional by Response Evaluation Criteria In Solid Tumors (RECIST) criteria) or evaluable (e.g., malignant effusion, marrow involvement). Elevated tumor markers alone are insufficient. Age >18. Southwest Oncology Group (SWOG)/Eastern Oncology Group (ECOG) performance status must be < or =2 at screen and on treatment day one. Life expectancy must be estimated at >16 weeks. Prior irradiation is permitted, provided: Does not exceed 25% of the estimated bone marrow volume Measurable/evaluable disease exists outside the radiation field, or progressive disease is documented within the radiation field. Informed consent must be obtained prior to registration. Patients must be > 2 weeks from prior surgery; > 3 weeks from radiation therapy to the pelvis, spine or long bones; > 3 weeks from prior chemotherapy (> 6 weeks for mitomycin C or nitrosureas), or > 2 weeks from prior hormonal therapy. All patients must have placement of appropriate central venous access device. Tumor HER2/neu expression must be determined prior to study enrollment. Assessment may be by fluorescence in situ hybridization (FISH) assay or by immunohistochemistry (ICC). If determination is intermediate by ICC, FISH must be performed. For enrollment purposes, this phase I study will not discriminate based on HER2 status. However, documentation of patients' HER2 status will be maintained and Herceptin will be prescribed for all HER2 positive patients. Exclusion Criteria: Granulocytes < 1,500/mm^3. Platelets < 100,000/mm^3. Hemoglobin < 9 gm/dl. Creatinine > 2.0 mg/dl. Total bilirubin > 2 mg/dl. Visceral crisis characterized by rapidly progressive hepatic or lymphangitic lung metastases. Medically unstable as judged by the patient's physician. Pregnancy or lactation; failure to employ adequate contraception. Uncontrolled central nervous system (CNS) disease. Pre-existing Grade ≥ 2 peripheral neuropathy except for abnormalities due to cancer. Psychological, familial, sociological or geographical conditions which do not permit weekly medical follow-up and compliance with the study protocol. Prior therapy with vinorelbine or prior therapy with a taxane that resulted in neuropathy.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: 80 mg ABI-007 + 15 mg vinorelbine<br>Weekly intravenous infusion of 80 mg/m^2 ABI-007, followed by an infusion of 15 mg/m^2 vinorelbine. Participants with human epidermal growth factor receptor 2-positive (HER2+) and who met cardiac safety requirements were also administered weekly Herceptin® (trastuzumab) following completion of ABI-007 and vinorelbine infusions. No G-CSF support was planned. | Drug: ABI-007<br>* Weekly intravenous infusions over 30 minutes.<br>* Other names: paclitaxel protein-bound particles for injectable suspension;Drug: vinorelbine<br>* Weekly intravenous infusions over 10-30 minutes, immediately after ABI-007. Vinorelbine is commercially available and was not supplied by the Sponsor.<br>* Other names: 5'noranhydrovinblastine;Drug: Trastuzumab<br>* Trastuzumab was administered to participants who had HER-2-neu positive tumors. Participants received trastuzumab by IV infusion via a vascular access device following dosing with ABI-007 and vinorelbine. During their first cycle, 4 mg/kg was administered on day 1 of that cycle as a loading dose. During subsequent weekly treatments, 2 mg/kg was administered. Trastuzumab is commercially available and was not supplied by the Sponsor.<br>* Other names: Herceptin;|
| Experimental: Part 2: 80 mg ABI-007 + 15 mg vinorelbine<br>Weekly intravenous infusion of 80 mg/m^2 ABI-007, followed by an infusion of 15 mg/m^2 vinorelbine. Participants with human epidermal growth factor receptor 2-positive (HER2+) and who met cardiac safety requirements were also administered weekly Herceptin® (trastuzumab) following completion of ABI-007 and vinorelbine infusions. G-CSF support was given. | Drug: ABI-007<br>* Weekly intravenous infusions over 30 minutes.<br>* Other names: paclitaxel protein-bound particles for injectable suspension;Drug: vinorelbine<br>* Weekly intravenous infusions over 10-30 minutes, immediately after ABI-007. Vinorelbine is commercially available and was not supplied by the Sponsor.<br>* Other names: 5'noranhydrovinblastine;Drug: Trastuzumab<br>* Trastuzumab was administered to participants who had HER-2-neu positive tumors. Participants received trastuzumab by IV infusion via a vascular access device following dosing with ABI-007 and vinorelbine. During their first cycle, 4 mg/kg was administered on day 1 of that cycle as a loading dose. During subsequent weekly treatments, 2 mg/kg was administered. Trastuzumab is commercially available and was not supplied by the Sponsor.<br>* Other names: Herceptin;Biological: G-CSF<br>* During Part 1, participants followed a dosing regimen with ABI-007 and vinorelbine without G-CSF treatment. However, G-CSF was allowed for administration as necessary in accordance with commonly accepted clinical guidelines. In Part 2, participants started G-CSF treatment in concurrence with their ABI-007 and vinorelbine treatments. G-CSF was administered to all participants on Days 2-7 of each cycle, at a dose of 5 mcg/kg. If the participant's absolute neutrophil (ANC) count was >20,000/mm^3 on the day of anticipated chemotherapy, the site staff reduced the daily dose of G-CSF by 50% to 2.5 mcg/kg. G-CSF is commercially available and was not supplied by the Sponsor.<br>* Other names: granulocyte-colony stimulating factor;|
| Experimental: Part 2: 90 mg ABI-007 + 20 mg vinorelbine<br>Weekly intravenous infusion of 90 mg/m^2 ABI-007, followed by an infusion of 20 mg/m^2 vinorelbine. Participants with human epidermal growth factor receptor 2-positive (HER2+) and who met cardiac safety requirements were also administered weekly Herceptin® (trastuzumab) following completion of ABI-007 and vinorelbine infusions. G-CSF support was given. | Drug: ABI-007<br>* Weekly intravenous infusions over 30 minutes.<br>* Other names: paclitaxel protein-bound particles for injectable suspension;Drug: vinorelbine<br>* Weekly intravenous infusions over 10-30 minutes, immediately after ABI-007. Vinorelbine is commercially available and was not supplied by the Sponsor.<br>* Other names: 5'noranhydrovinblastine;Drug: Trastuzumab<br>* Trastuzumab was administered to participants who had HER-2-neu positive tumors. Participants received trastuzumab by IV infusion via a vascular access device following dosing with ABI-007 and vinorelbine. During their first cycle, 4 mg/kg was administered on day 1 of that cycle as a loading dose. During subsequent weekly treatments, 2 mg/kg was administered. Trastuzumab is commercially available and was not supplied by the Sponsor.<br>* Other names: Herceptin;Biological: G-CSF<br>* During Part 1, participants followed a dosing regimen with ABI-007 and vinorelbine without G-CSF treatment. However, G-CSF was allowed for administration as necessary in accordance with commonly accepted clinical guidelines. In Part 2, participants started G-CSF treatment in concurrence with their ABI-007 and vinorelbine treatments. G-CSF was administered to all participants on Days 2-7 of each cycle, at a dose of 5 mcg/kg. If the participant's absolute neutrophil (ANC) count was >20,000/mm^3 on the day of anticipated chemotherapy, the site staff reduced the daily dose of G-CSF by 50% to 2.5 mcg/kg. G-CSF is commercially available and was not supplied by the Sponsor.<br>* Other names: granulocyte-colony stimulating factor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Confirmed Complete or Partial Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | Overall response rate (ORR) is complete response (CR) + partial response (PR). Complete response (CR): The disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. Disappearance of all non-target lesions. The normalization of tumor marker level confirmed at least 4 weeks after initial documentation. Partial response (PR): At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. | up to month 30 | 
| Participants With Dose Limiting Toxicities | Toxicities were evaluated based on the U.S. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Any drug-related toxicities CTC Grade 3 or higher were considered dose limiting. Grade 3=severe AE, Grade 4=life-threatening or disabling AE, Grade 5=death. Other conditions considered dose-limiting toxicities include: requirement of a dose adjustment during the first 4 weeks a dose delay of >3 weeks during the first 4 weeks Grade 3 or greater toxicities attributed to the use of Herceptin were not considered dose-limiting toxicities. The optimal tolerated dose of ABI-007 and vinorelbine given concurrently was defined as the dose administered in the absence of DLTs. | up to month 1 | 
| Percentage of Participants With Discontinued, Delayed or Interrupted Therapy | Percentage of participants who had discontinued therapy or had a delayed dose or an interrupted (omitted) dose due to toxicities/adverse events. | up to week 129 | 
| Participant Counts of the Most Severe Grade for Absolute Neutrophil (ANC), White Blood Cell (WBC), Platelet, and Hemoglobin Counts as Graded by the National Cancer Institute Common Terminology Criteria for Adverse Experience (NCI CTCAE v3) | Myelosuppression is a decrease in the ability of the bone marrow to produce blood cells. The lowest measured (nadir) blood counts were graded using NCI CTCAE version 3. ANC: Grade 0 = within normal limits; Grade 1 = < lower limit of normal - 1.5*10^9/L; Grade 2 = <1.5 - 1.0*10^9/L; Grade 3 = <1.0 - 0.5*10^9/L; Grade 4 = <0.5*10^9/L WBC: Grade 0 = within normal limits; Grade 1 = < lower limit of normal - 3.0*10^9/L; Grade 2 = <3.0 - 2.0*10^9/L; Grade 3 = <2.0 - 1.0*10^9/L; Grade 4 = <1.0*10^9/L Platelets: Grade 0 = within normal limits; Grade 1 = < lower limit of normal - 75.0*10^9/L; Grade 2 = <75.0 - 50.0*10^9/L; Grade 3 = <50.0 - 25.0*10^9/L; Grade 4 = <25.0*10^9/L Hemoglobin: Grade 0 = within normal limits; Grade 1 = < lower limit of normal - 100 g/L ; Grade 2 = <100 - 80 g/L; Grade 3 = <80 - 65 g/L; Grade 4 = <65 g/L | up to week 129 (longest treatment) | 
| Nadir Measurement for Absolute Neutrophil (ANC), White Blood Cell (WBC) and Platelet Count | Myelosuppression is a decrease in the ability of the bone marrow to produce blood cells. The lowest observed measurement is the nadir. Blood counts were performed each week of treatment. | up to week 129 (longest treatment) | 
| Nadir Measurement for Hemoglobin (Hgb) | Myelosuppression is a decrease in the ability of the bone marrow to produce blood cells. The lowest observed measurement is the nadir. Blood counts were performed each week of treatment. | up to week 129 (longest treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Stable Disease for >= 16 Weeks, or Complete or Partial Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | Disease control is stable disease (SD) for >=16 weeks + complete response (CR) + partial response (PR). See Outcome #1 for definitions of CR and PR. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions. | up to month 30 | 
| Kaplan Meier Estimate for Time to Disease Progression (TTP) | Time to progression was defined as the time from the first dose of study drug to the start of progression. Participants that did not have progression were censored at the last known time the patient was evaluated for progression. Participants that initiate other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. | up to month 30 | 
| Kaplan-Meier Estimate for Duration of Response | Duration of response is defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or patient death from any cause, whichever occurred first. Patients that did not have progression or have not died were censored at the last known time the patient was progression free. Patients that initiate other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Complete response (CR) and partial response (PR) are defined in outcome #1. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. | up to month 30 | 
| Kaplan Meier Estimate for Progression-Free Survival (PFS) | PFS was defined as the time from the first dose of study drug to the start of progression or patient death (any cause) whichever occurred first. Participants that did not have progression or have not died were censored at the last known time the participant was progression free. Participants that initiate other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Because no patients died as a result of a non-disease progression event, the analysis of PFS was identical to the analysis for TTP. | up to month 30 | 
| Kaplan-Meier Estimates for Participant Survival | Participant survival is the time from the first dose of study drug to participant death from any cause. Participants that did not die were censored at the last known time the participant was alive. | up to 39 months | 

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