Navelbine, Taxol, Herceptin and Neupogen in Stage IV Breast Cancer: A Phase I - II Trial

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00041470
• Collaborator: Amgen (Industry), Bristol-Myers Squibb (Industry), GlaxoSmithKline (Industry)
• Enrollment: 38
• Location: 1
• Arm: 1
• Duration (Months): 89
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purposes of this are:

• To determine the highest doses of Taxol and Navelbine that we can safely give to patients;

• To determine what kind of side effects are caused by the combination of Taxol, Navelbine and G-CSF;

• To determine whether the combination of Taxol, Navelbine and G-CSF is more effective than standard therapy in treating metastatic breast cancer and prolonging life;

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Paclitaxel; Drug: Vinorelbine; Drug: Herceptin; Drug: Filgrastim	Phase 1/Phase 2

Detailed Description

Complete response (CR) in advanced breast cancer is an important predictor of improved survival. The largest experience reported with long-term follow-up in this regard is from M.D. Anderson Hospital, with a median survival of 33 months and 5-year survival of 19% among patients who achieved a CR with doxorubicin-based chemotherapy.19 We believe that our institutional experience to date indicates that CR rates in excess of 20% can be achieved in second-line chemotherapy from the combination of vinorelbine and a taxane, provided that G-CSF is given. For the reasons outlined, we believe that dose density is likely to be important for both classes of agents, but dose intensity may be most important for vinorelbine. Both paclitaxel and docetaxel can be given on a weekly schedule with some success, but it appears that myelosuppression is a more frequent dose-limiting toxicity on this schedule for docetaxel. For the current trial, we therefore propose to study weekly paclitaxel in combination with dose-intensive vinorelbine, utilizing continuous G-CSF support as in our prior studies. We believe that starting doses of 60 mg/m2 for paclitaxel and 20 mg/m2 for vinorelbine will be well tolerated, but our experience to date, treating 3 patients off study at these doses without G-CSF support, indicates that some will require G-CSF even at this dose level: we observed grade 4 neutropenia in 2 of the 3. Our intention in this trial is to determine the optimal dose of these two agents when continuous growth factor support is provided. We will be starting at a ratio of 0.8 for vinorelbine and 0.75 for paclitaxel (assuming 80 mg/m2/week as a "full" dose for the later agent).

It is now widely appreciated that patients with metastatic breast cancer whose tumors over express HER-2-neu demonstrate benefit from the addition of trastuzumab (Herceptin) to a chemotherapy program with paclitaxel as a single agent.20 Such patients will be allowed to receive trastuzumab in the standard dose and schedule (4 mg/kg loading dose, then 2 mg/kg/week) given IV, in addition to paclitaxel and vinorelbine. Since trastuzumab does not produce myelosuppression or neuropathy (the anticipated dose-limiting toxicities for vinorelbine and paclitaxel, respectively), and neither of these agents combined separately with trastuzumab produces unusual or severe new side effects, this should not affect the dose escalation scheme for the chemotherapeutic agents.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Navelbine, Taxol, Herceptin and Neupogen in Stage IV Breast Cancer: A Phase I - II Trial
• Study Start Date: Mar 1, 2001
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Weekly paclitaxel, vinorelbine and GCSF Weekly paclitaxel (50 mg/m2 IV) and weekly vinorelbine (20 mg/m2 IV) with daily G-CSF support and Herceptin for patients with HER-2/neu positive disease. Paclitaxel weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) administered one hour after paclitaxel, weekly. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients who are HER-2+ and IV infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., administered daily

Drug: Paclitaxel; 50 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment.; Other Names: Taxol ; Drug: Vinorelbine; 20 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment.; Other Names: Navelbine ; Drug: Herceptin; 4 mg/kg IV loading dose day 1 of first week followed by 2 mg/kg IV maintenance dose on each subsequent week. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment.; Other Names: Trastuzumab ; Drug: Filgrastim; 5 mcg/kg daily including the day of IV chemotherapy. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment.; Other Names: G-CSF Neupogen

Outcome Measures

Primary Outcome Measures

1. To Measure Response Rates, Time to Progression and Survival in Patients so Treated. [1 year]

Secondary Outcome Measures

1. To Measure the Qualitative and Quantitative Toxicity of This Regimen. [<=18 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

PATIENT ELIGIBILITY

Inclusion Criteria:

• Patient has stage IV, microscopically-confirmed carcinoma of the breast with histologic slides and/or blocks available for review.

• Patient has had one or less prior regimens for metastatic disease. Prior paclitaxel by 3, 24 or 96-hour infusion is permitted as long as it did not result in any neuropathy. Prior docetaxel on an every 3-week schedule is permitted.

• Measurable (bidimensionally) or evaluable disease.

• Age > 18.

• Karnofsky Performance Status > 70% (ECOG, < 2) at screen and on the first day of treatment.

• Life expectancy > 16 weeks.

• Prior irradiation is permitted, provided:

• Prior irradiation does not exceed 25% of the estimated bone marrow volume. (See Appendix I)

• Measurable/evaluable disease must exist outside the radiation field OR there must be histologic proof of progressive disease within a 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 hydridization (FISH) assay or by immunohistochemistry (ICC). If determination is intermediate by ICC, FISH must be performed. For enrollment purposes, the phase I portion of the 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. The phase II portion of the study will enroll 30 patients who are documented HER2 overexpressors and 30 patients who are non-overexpressors.

Exclusion Criteria:

• Granulocytes < 1,500/mm3.

• Platelets < 100,000/mm3.

• 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 CNS disease.

• Pre-existing clinically significant 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.

• Known hypersensitivity to E. coli-derived proteins, Filgrastim, or any component of the product as Neupogen® is contraindicated in such subjects.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023

Sponsors and Collaborators

• University of Washington
• Amgen
• Bristol-Myers Squibb
• GlaxoSmithKline

Investigators

• Principal Investigator: Julie R. Gralow, M.D., University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Julie Ruth Gralow, Professor of Medicine, Medicine/Oncology, University of Washington
• ClinicalTrials.gov Identifier: NCT00041470
• Other Study ID Numbers: 18245
• First Posted: Jul 10, 2002
• Last Update Posted: Jul 17, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Vinorelbine; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Paclitaxel, Vinorelbine, G-CSF, Herceptin - no Placebo
Arm/Group Description	Weekly paclitaxel (50 mg/m2 IV) and weekly vinorelbine (20 mg/m2 IV) with daily G-CSF support and Herceptin for patients with HER-2/neu positive disease. Treatment continues until disease progression, toxicity or other reason to remove the patient from protocol treatment. Paclitaxel is administered weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) is administered one hour after paclitaxel, every week. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients whose tumors over express HER-2-neu and who meet the cardiac safety criteria will receive weekly Herceptin administered by intravenous infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., is administered daily including the day of chemotherapy. Paclitaxel: 50 mg/m2 IV weekly. Treatment continues until progression
Period Title: Overall Study
STARTED	38
COMPLETED	0
NOT COMPLETED	38

Baseline Characteristics

Arm/Group Title	Phase I/II
Arm/Group Description	Weekly paclitaxel (50 mg/m2 IV) and weekly vinorelbine (20 mg/m2 IV) with daily G-CSF support and Herceptin for patients with HER-2/neu positive disease. Treatment continues until disease progression, toxicity or other reason to remove the patient from protocol treatment. Paclitaxel is administered weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) is administered one hour after paclitaxel, every week. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients whose tumors over express HER-2-neu and who meet the cardiac safety criteria will receive weekly Herceptin administered by intravenous infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., is administered daily including the day of chemotherapy. Paclitaxel: 50 mg/m2 IV weekly. Treatment continues until disease pr
Overall Participants	38
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46.5
Sex: Female, Male (Count of Participants)
Female	38 100%
Male	0 0%
Baseline Participants (participants) [Number]
Number [participants]	38 100%

Outcome Measures

1. Primary Outcome

Title	To Measure Response Rates, Time to Progression and Survival in Patients so Treated.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Weekly Paclitaxel, Vinorelbine and GCSF
Arm/Group Description	Weekly paclitaxel (50 mg/m2 IV) and weekly vinorelbine (20 mg/m2 IV) with daily G-CSF support and Herceptin for patients with HER-2/neu positive disease. Paclitaxel weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) administered one hour after paclitaxel, weekly. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients who are HER-2+ and IV infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., administered daily Paclitaxel: 50 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment. Vinorelbine: 20 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment. Herceptin: 4 mg/kg IV loading dose day 1
Measure Participants	38
Complete Response	6 15.8%
Partial Response	14 36.8%
Stable Disease	9 23.7%
Progressive Disease	8 21.1%
Inevaluable	1 2.6%

2. Secondary Outcome

Title	To Measure the Qualitative and Quantitative Toxicity of This Regimen.
Time Frame	<=18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Weekly Paclitaxel, Vinorelbine and GCSF
Arm/Group Description	Weekly paclitaxel (50 mg/m2 IV) and weekly vinorelbine (20 mg/m2 IV) with daily G-CSF support and Herceptin for patients with HER-2/neu positive disease. Paclitaxel weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) administered one hour after paclitaxel, weekly. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients who are HER-2+ and IV infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., administered daily Paclitaxel: 50 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment. Vinorelbine: 20 mg/m2 IV weekly. Treatment continues until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment. Herceptin: 4 mg/kg IV loading dose day 1
Measure Participants	38
>=Grade 3 Toxicity	30 78.9%
serious adverse events	10 26.3%

Adverse Events

Time Frame	1 year
Arm/Group Title	Weekly Paclitaxel and Vinorelbine With GCSF Support
Arm/Group Description	Weekly paclitaxel (50 mg/m2 IV) and vinorelbine (20 mg/m2 IV) with daily G-CSF and Herceptin for patients with HER-2+ disease. Treatment until disease progression, excessive toxicity or other reason to remove the patient from protocol treatment. Paclitaxel administered weekly. Dose levels: 50 mg/m2, 60 mg/m2, 70 mg/m2, 80 mg/m2 Vinorelbine (Navelbine) administered one hour after paclitaxel, weekly. Dose levels: 20 mg/m2, 22.5 mg/m2, 25 mg/m2, 27.5 mg/m2 Patients who are HER-2+ and meet the cardiac safety criteria will receive weekly Herceptin administered by infusion. Herceptin 4 mg/kg IV given only on day 1 of the first cycle. Herceptin 2 mg/kg IV, maintenance dose will be given every week starting with week 2. G-CSF (filgrastim, Neupogen) 5 mg/kg/day s.c., is administered daily including the day of chemotherapy. Paclitaxel: 50 mg/m2 IV weekly. Treatment continues until disease pr
All Cause Mortality
	Weekly Paclitaxel and Vinorelbine With GCSF Support
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Weekly Paclitaxel and Vinorelbine With GCSF Support
	Affected / at Risk (%)	# Events
Total	10/38 (26.3%)
Blood and lymphatic system disorders
Leukopenia	4/38 (10.5%)	4
Cardiac disorders
Congestive Heart Failure	1/38 (2.6%)	1
Infections and infestations
Mucositis	2/38 (5.3%)	2
Febrile Neutropenia	2/38 (5.3%)	2
Respiratory, thoracic and mediastinal disorders
Aspiration Pneumonia	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Weekly Paclitaxel and Vinorelbine With GCSF Support
	Affected / at Risk (%)	# Events
Total	38/38 (100%)
Blood and lymphatic system disorders
Neutropenia	20/38 (52.6%)	20
Thrombocytopenia	16/38 (42.1%)	16
Gastrointestinal disorders
Vomiting	4/38 (10.5%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.