Phase 2 Study of AMG 386 Plus Paclitaxel With or Without Bevacizumab as First Line Therapy in Her2-Negative Breast Cancer Patients

Sponsor

Amgen (Industry)

Overall Status

Completed

CT.gov ID

NCT00511459

Collaborator

(none)

228

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 2, randomized, placebo controlled, multi-center study to estimate the treatment effect and evaluate the safety and tolerability of AMG 386 in combination with paclitaxel and paclitaxel/bevacizumab in the treatment of subjects with Her2-negative metastatic or locally recurrent breast cancer.

AMG 386 is a man-made medication that is designed to stop the development of blood vessels in cancer tissues. Cancer tissues rely on the development of new blood vessels, a process called angiogenesis, to obtain a supply of oxygen and nutrients to grow.

Condition or Disease	Intervention/Treatment	Phase
Locally Recurrent and Metastatic Breast Cancer	Drug: AMG 386 Placebo Drug: AMG 386 Drug: Bevacizumab Drug: AMG 386 Drug: AMG 386 Drug: Paclitaxel	Phase 2

Detailed Description

Primary Objective: To estimate the treatment effect as measured by progression free survival (PFS) of subjects receiving AMG 386 (at 2 doses) in combination with paclitaxel + bevacizumab relative to paclitaxel + bevacizumab + placebo.

Secondary Objective(s):

To compare the treatment effect as measured by PFS of subjects receiving open-label AMG 386 in combination with paclitaxel relative to paclitaxel + bevacizumab + placebo
To compare the treatment effect as measured by PFS of subjects receiving AMG 386 in combination with paclitaxel and bevacizumab relative to paclitaxel + AMG 386
To evaluate the safety and tolerability of the combination and non-bevacizumab regimens
To estimate other measures (RR, DOR, TTR, TTP) of treatment effect
To evaluate the pharmacokinetics (PK) of AMG 386 and bevacizumab when used in combination
To estimate the incidence of anti-AMG386 antibody formation

Exploratory Objective(s):

To explore the pharmacodynamic (PD) response as assessed by changes in blood levels of angiogenic cytokines, tumor apoptosis, and other markers
To explore the association of histological features and selected immunologic, biochemical, pharmacogenetic, or angiogenic markers in tumor biopsies, plasma, or serum samples with safety and/or efficacy outcomes

Study Design:

Two hundred twenty subjects will be randomized 1:1:1:1 to each of the following arms:

Arm A: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 10 mg/kg IV QW Arm B: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 3 mg/kg IV QW Arm C: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W

AMG 386 placebo IV QW Arm D: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + Open Label AMG 386 10 mg/kg IV QW To maintain the double-blind in arms A, B, and C, each subject will be infused weekly with a volume of investigational product equivalent to 10 mg/kg AMG 386 IV. Arm D will receive open label AMG 386 and will not receive a placebo for bevacizumab.

Subjects will be discontinued from study treatment at any time for radiographic disease progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or death.

Subjects alive at the time of discontinuation of all study medications will be followed for up to 48 months from the date of the last subject enrolled into the trial to evaluate overall survival.

Radiological imaging to assess disease status will be performed every 8 weeks ± 7 days (2 cycles) for 2 years and then every 4 months ± 1 month thereafter during the study until subjects develop radiographic disease progression per the modified RECIST criteria. In addition, any subject who discontinues study drug treatment prior to disease progression will continue to have radiological imaging performed every 8 weeks ± 7 days during the long term follow up period if the subject has not been in the study for 2 years until the subject develops radiographic disease progression or begins a new treatment. If the subject has been on study for 2 years, radiological imaging every 4 months ± 1 month will be performed during long term follow-up period until the subject develops radiographic disease progression or begins a new treatment.

The overall study design is described by a study schema immediately following this synopsis. Amgen Global Safety (AGS) will charter a data review team (DRT) that is independent of the team conducting the study and will review unblinded safety data after 20, 40, and 80 subjects have been randomized and have had the opportunity to receive at least 1 cycle (4 weeks) of study treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

228 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination With Bevacizumab and Paclitaxel or AMG 386 Plus Paclitaxel as First-Line Therapy in Subjects With Her2-Negative, Metastatic or Locally Recurrent Breast Cancer

Study Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Aug 1, 2010

Actual Study Completion Date :

May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 10 mg/kg IV QW	Drug: Bevacizumab Bevacizumab 10mg/kg IV Q2W Drug: AMG 386 AMG 386 10mg/kg IV QW [blinded] Drug: Paclitaxel Paclitaxel 90mg/m2 IV QW (3 on/1 0ff)
Experimental: D Paclitaxel 90 mg/m² IV QW (3 on/1 off) + Open Label AMG 386 10 mg/kg IV QW	Drug: AMG 386 AMG 386 10mg/kg IV QW [Open-Label] Drug: Paclitaxel Paclitaxel 90mg/m2 IV QW (3 on/1 0ff)
Experimental: B Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 3 mg/kg IV QW	Drug: AMG 386 AMG 386 3mg/kg IV QW [blinded] Drug: Bevacizumab Bevacizumab 10mg/kg IV Q2W Drug: Paclitaxel Paclitaxel 90mg/m2 IV QW (3 on/1 0ff)
Active Comparator: C Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 placebo IV QW	Drug: AMG 386 Placebo AMG 386 Placebo [blinded] Drug: Bevacizumab Bevacizumab 10mg/kg IV Q2W Drug: Paclitaxel Paclitaxel 90mg/m2 IV QW (3 on/1 0ff)

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [3 YEARS]

Secondary Outcome Measures

Objective Response (OR) [3 YEARS]
Duration of Response (DOR) [3 YEARS]
Time to response [3 YEARS]
Overall Survival [3 YEARS]
Time to progression (TTP) [3 YEARS]
Incidence of AEs and significant laboratory changes [3 YEARS]
AMG 386 Pharmakokinetic parameters [3 YEARS]
Incidence of the occurrence of anti-AMG 386 antibody formation [3 YEARS]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Subjects must have histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
Measurable or non-measurable disease per modified RECIST guidelines
ECOG of 0 or 1 (within 14 days prior to randomization)
Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to randomization:

• Cardiac function, as follows:

Normal sinus rhythm (no significant ECG changes)
Left ventricular ejection fraction ≥ LLN, as determined by echocardiogram or MUGA scan, according to institutional standards within 28 days prior to randomization

Exclusion Criteria:

Inflammatory Breast Cancer
Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral neuropathy > grade 1 at randomization
History of arterial or venous thrombosis, including transient ischemic attack (TIA), within 1 year prior to randomization
Adjuvant or neoadjuvant taxane treatment within 12 months of randomization. Any other adjuvant chemotherapy regimen must be discontinued at least 21 days prior to randomization
Prior chemotherapy, vaccine, or biological therapy for locally recurrent or metastatic breast cancer (prior endocrine therapy is permitted)
Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or hepatic chemoembolization on all sites of disease unless disease progression was subsequently documented 14 days prior to randomization.
Overexpression of HER-2 (gene amplification by FISH or 3+ over expression by immunohistochemistry).
Current or prior history of central nervous system metastasis
History of bleeding diathesis or clinically significant bleeding within 6 months prior to randomization
Major surgical procedure within 28 days prior to randomization
Open breast biopsy within 14 days prior to randomization
Minor surgical procedure, placement of access device, or fine needle aspiration within 7 days of first dose
Prior malignancy (other than thyroid cancer, in situ cervical cancer, or basal cell cancer of the skin, treated with curative intent and without evidence of disease for ≥ 3 years prior to randomization)
Clinically significant cardiac disease within 12 months prior to randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication
Non-healing wound, ulcer or fracture
Known hypersensitivity to paclitaxel or drugs using the vehicle cremophor
Known hypersensitivity to bacterial proteins, or any of the drugs required in this study
Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen
Known active or chronic hepatitis
Uncontrolled hypertension as defined as systolic blood pressure ≥ 150 mm Hg and diastolic blood pressure ≥ 90 mm Hg. Anti-hypertensive medications are allowed if the subject is stable on their current dose at the time of randomization
Currently or previously treated with any VEGF or VEGFr inhibitor, including but not limited to, bevacizumab, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788, BAY 43-9006 (sorafenib) and AMG 706.
Treatment with coumarin-type anticoagulants, (other than low dose prophylaxis for central venous catheters ≤ 1mg/day) within 7 days prior to randomization
Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2 including, but not limited to, AMG 386, XL880, XL820
Treatment with immune modulators such as cyclosporine and tacrolimus within 30 days prior to randomization
Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMS), given for breast cancer prevention or for osteoporosis. Subjects must have discontinued these agents 28 days prior to randomization
Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Litchfield Park	Arizona	United States	85340
2	Research Site	Tucson	Arizona	United States	85724
3	Research Site	Hot Springs	Arkansas	United States	71913
4	Research Site	Little Rock	Arkansas	United States	72205
5	Research Site	Campbell	California	United States	95008
6	Research Site	Los Angeles	California	United States	90095
7	Research Site	Murrieta	California	United States	92562
8	Research Site	Santa Maria	California	United States	93454
9	Research Site	New Haven	Connecticut	United States	06520
10	Research Site	Stamford	Connecticut	United States	06902
11	Research Site	Orlando	Florida	United States	32804
12	Research Site	Robbinsdale	Minnesota	United States	55422
13	Research Site	Henderson	Nevada	United States	89052
14	Research Site	Lebanon	New Hampshire	United States	03756
15	Research Site	Nashua	New Hampshire	United States	03061
16	Research Site	Edison	New Jersey	United States	08820
17	Research Site	Mountain Lakes	New Jersey	United States	07046
18	Research Site	Asheville	North Carolina	United States	28806
19	Research Site	Charlotte	North Carolina	United States	28203
20	Research Site	Hershey	Pennsylvania	United States	17033
21	Research Site	Philadelphia	Pennsylvania	United States	19106
22	Research Site	Columbia	South Carolina	United States	29210
23	Research Site	Richardson	Texas	United States	75080
24	Research Site	San Antonio	Texas	United States	78229
25	Research Site	Sugar Land	Texas	United States	77479
26	Research Site	Ogden	Utah	United States	84403
27	Research Site	Kurralta Park	South Australia	Australia	5037
28	Research Site	Epping	Victoria	Australia	3076
29	Research Site	Fitzroy	Victoria	Australia	3065
30	Research Site	Footscray	Victoria	Australia	3011
31	Research Site	Malvern	Victoria	Australia	3144
32	Research Site	Perth	Western Australia	Australia	6000
33	Research Site	Innsbruck		Austria	6020
34	Research Site	Wels		Austria	4600
35	Research Site	Wien		Austria	1090
36	Research Site	Leuven		Belgium	3000
37	Research Site	Liege		Belgium	4000
38	Research Site	Wilrijk		Belgium	2610
39	Research Site	Herlev		Denmark	2730
40	Research Site	Helsinki		Finland	00029
41	Research Site	La Roche Sur Yon Cedex 9		France	85925
42	Research Site	Lyon		France	69008
43	Research Site	Marseille		France	13009
44	Research Site	Montpellier Cedex 5		France	34298
45	Research Site	Paris Cedex 20		France	75020
46	Research Site	Paris Cedex 5		France	75248
47	Research Site	Toulouse Cedex		France	31052
48	Research Site	Vandoeuvre les Nancy		France	54511
49	Research Site	Gyula		Hungary	5700
50	Research Site	Kaposvar		Hungary	7400
51	Research Site	Szombathely		Hungary	9700
52	Research Site	Veszprem		Hungary	8200
53	Research Site	Bangalore	Karnataka	India	560 029
54	Research Site	Miraj	Maharashtra	India	416 410
55	Research Site	Mumbai	Maharashtra	India	400 012
56	Research Site	Nagpur	Maharashtra	India	440 012
57	Research Site	Pune	Maharashtra	India	411 001
58	Research Site	Jaipur	Rajasthan	India	302 004
59	Research Site	Jaipur	Rajasthan	India	302 013
60	Research Site	Maastricht		Netherlands	6229 HX
61	Research Site	Gdansk		Poland	80-952
62	Research Site	Lubin		Poland	59-300
63	Research Site	Poznan		Poland	61-485
64	Research Site	Warszawa		Poland	02-781
65	Research Site	Warszawa		Poland	04-141
66	Research Site	Wroclaw		Poland	53-413
67	Research Site	JaÃ©n	AndalucÃ-a	Spain	23007
68	Research Site	Sabadell	CataluÃ±a	Spain	08208
69	Research Site	Santiago de Compostela	Galicia	Spain	15706
70	Research Site	Madrid		Spain	28033
71	Research Site	Guildford		United Kingdom	GU2 7XX
72	Research Site	Leicester		United Kingdom	LE1 5WW
73	Research Site	London		United Kingdom	NW1 2PG
74	Research Site	London		United Kingdom	W6 8RF
75	Research Site	Manchester		United Kingdom	M20 4BX
76	Research Site	Northwood		United Kingdom	HA6 2RN
77	Research Site	Nottingham		United Kingdom	NG5 1PB