Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory Breast Cancer

Neoplasms, Breast Clinical Trial

Official title:

A Randomized, Multicenter, Phase III Study Comparing the Combination of Pazopanib and Lapatinib Versus Lapatinib Monotherapy in Patients With ErbB2 Over-expressing Inflammatory Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00558103
• Other study ID #: VEG108838
• Status: Completed
• Phase: Phase 2
• First received: November 9, 2007
• Last updated: January 31, 2013
• Start date: December 2007
• Est. completion date: December 2011

Study information

• Verified date: January 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The double blind part of the study is being conducted to compare the efficacy and safety of pazopanib in combination with lapatinib with that of lapatinib alone in subjects with inflammatory breast cancer whose tumors overexpress the ErbB2 protein. There is also an Open-label pazopanib arm to this study designed to test whether pazopanib given alone and lapatinib given alone would be safe and effective to treat patients with inflammatory breast cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 163
• Est. completion date: December 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact patient eligibility is provided in the pazopanib IB and lapatinib prescribing information (or the lapatinib IB).

For Cohort 1 of this study, eligible patients met inclusion criteria outlined in the original version of the protocol and protocol amendment 1.

For Cohort 2 of this study, eligible patients must meet all of the following criteria:

• Patients must have evaluable Inflammatory Breast Cancer (IBC) substantiated by all of the following prior to randomization:

• History of invasive breast cancer documented by a biopsy and accompanying pathology report

• Current photographs* (global view and close-up views of all skin lesions) submitted at screening demonstrating unequivocal evidence of IBC as determined by either the medical monitor alone or in consultation with one or more of the study Principal Investigators.

• All patients must have photography at screening. Canfield Scientific Inc. will provide centralized monitoring, tracking, and collection of patients' photographs throughout the study. Screening photographs must be uploaded to the Canfield Scientific Inc website and approved by Canfield Scientific Inc, as the central photography vendor. The photographs, along with the completed Inflammatory Breast Cancer Skin Assessment Tool (IBSAT), must be reviewed and approved by GSK before a patient can be randomized. Sites should allow a minimum of 3 business days for this process. Sites submitting quality photographs and IBSATs on a regular basis will receive an exemption from this requirement for future patients.

• Patients with secondary IBC are eligible.

• Measurable lesions (cutaneous or radiographic) may be in the field of prior standard or palliative radiation therapy; however, there must be at least a 4 week period between the last radiation treatment and the baseline scan documenting disease status for the lesion to be measurable. If the irradiated lesion is the only site of disease, documented progression of the irradiated lesion is required.

• Disease progression or relapse following treatment for invasive breast cancer, which must have included a chemotherapy regimen. In regions where trastuzumab is available with no barriers to access*, patients must have received prior trastuzumab in addition to chemotherapy in order to be eligible. * (Barriers to access may include financial considerations.)

• Unequivocal ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH/CISH, or ErbB2 gene amplification by FISH/CISH alone (in subjects whose tumor blocks were not assessed by IHC). ErbB2 gene amplification is defined by: > six (6) ErbB2 gene copies/nucleus for test systems without an internal control probe or an ErbB2/CEP 17 ratio of more than 2.2.

Sites must submit a copy of the laboratory report demonstrating unequivocal ErbB2 overexpression, if testing performed at a local laboratory, with the screening worksheet. Archived tumor must be provided for all patients for ErbB2 FISH testing by the central laboratory. Patients will remain on study based on local ErbB2 expression results. If archived tumor is not available, a biopsy must be obtained at screening and sent to TMD Laboratories for ErbB2 FISH testing.

• Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the patient's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.

Note: Informed consent may be obtained prior to the protocol-specified screening window (i.e. Day -14 to Day -1).

• Females age = 18 years, except in Tunisia. In Tunisia, patients must be = 20 years to be eligible for this study.

• Adequate organ function as defined below:

• System (Laboratory Values)

• Hematologic:Absolute neutrophil count (ANC)(= 1.5 X 10^9/L)Hemoglobin1(=9 g/dL)Platelets(=100 X 10^9/L)International normalized ratio (INR)(= 1.2 X upper limit of normal (ULN))Partial thromboplastin time (PTT)(=1.2 X ULN)

• Hepatic:Total bilirubin2 (= 1.5 X upper limit of normal (ULN))AST and ALT(= 2.5 X ULN)

• Renal:Serum Creatinine (= 1.5 mg/dL)Or, if serum creatinine >1.5 mg/dL,

• Calculated creatinine clearance(=50 mL/min)

• Urine Protein to Creatinine Ratio(<1)

• Patients may not have had a transfusion within 7 days of screening assessment.

• Exception: Patients with elevated bilirubin levels due to Gilberts syndrome are eligible.

• Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive or where MUGA scans are the accepted standard. Patients with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are not eligible.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:

• A hysterectomy

• A bilateral oophorectomy (ovariectomy)

• A bilateral tubal ligation

• Is post-menopausal

• Patients not using hormone replacement therapy (HRT) must have experienced total cessation of menses for = 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).

Patients must discontinue HRT prior to study enrollment due to the potential for inhibition of CYP enzymes that metabolize estrogens and progestins (See Section 8). For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female patient is determined not to be post-menopausal, they must use adequate contraception, as defined immediately below.

Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, has used adequate contraception since the pregnancy test and agrees to use adequate contraception as described below. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:

• An intrauterine device with a documented failure rate of less than 1% per year.

• Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual partner for that female.

• Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product.

• Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

Note: Oral contraceptives are not reliable due to potential drug drug interactions.

Female patients who are lactating should discontinue nursing prior to the first dose of investigational product and should refrain from nursing throughout the treatment period and for 14 days following the last dose of investigational product.

• French patients: In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Patients meeting any of the following criteria must not be enrolled in the study:

• Treatment in the 14 days prior to randomization with any cancer therapy (tumor embolization, chemotherapy, immunotherapy, biological therapy, or hormonal therapy) or treatment with mitomycin within 6 weeks prior to randomization. Such treatment may not be resumed or begun after study entry. Note: Patients receiving LH-RH analogue therapy prior to the study may continue to receive LH-RH analogues for the duration of study participation. Bisphosphonates are permitted if started prior to Day 1.

• Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity (with the exception of alopecia).

• Prior lapatinib therapy or other Her2/ErbB2 targeted therapy (except trastuzumab).

• Prior therapy with an anti-VEGF antibody or other VEGF/VEGF-R targeted therapy.

• Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of investigational product.

• Use of any prohibited medication within the timeframes listed in Section 8.1.3

• History of another malignancy.

• Note: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. If subject previously had breast cancer, it must have been HER2+ with either 3+ overexpression by IHC or unequivocal HER2 gene amplification by FISH or CISH.

• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 2 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.

• Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding including, but not limited to:

• Active peptic ulcer disease

• Known intraluminal metastatic lesion/s with suspected bleeding

• Inflammatory bowel disease

• Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation

• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.

• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but limited to:

• Malabsorption syndrome

• Major resection of the stomach or small bowel.

• Presence of uncontrolled infection.

• Prolongation of corrected QT interval (QTc) > 480 msecs.

• History of any one or more of the following cardiovascular conditions within the past 6 months:

• Cardiac angioplasty or stenting

• Myocardial infarction

• Unstable angina

• Arterial thrombosis

• Symptomatic peripheral vascular disease

• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (see Section 15.9 Appendix 9 for description).

• Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140mmHg or diastolic blood pressure (DBP) of = 90mmHg].

Note: Initiation or adjustment of antihypertensive medication(s) is permitted during the screening period, in order to control a patient's BP prior to randomization. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from each blood pressure assessment must be < 140/90mmHg in order for a patient to be eligible for the study. See Section 6.2 and Section 6.4.2 for details on blood pressure control and reassessment prior to study enrollment.

• History of cerebrovascular accident, including TIA, pulmonary embolism or deep venous thrombosis (DVT).

• Prior major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (other than ulcers due to inflammatory breast cancer).

• Evidence of active bleeding or bleeding diathesis.

• Hemoptysis within 6 weeks prior to first dose of investigational product.

• Known endobronchial lesions or involvement of large pulmonary vessels by tumor.

• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient's safety, provision of informed consent, or compliance to study procedures.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or lapatinib.

• Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• lapatinib
Oral administration
• Pazopanib
Oral administration

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Perth	Western Australia
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Jette
Belgium	GSK Investigational Site	Wilrijk
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Temuco	Región De La Araucania
Chile	GSK Investigational Site	Viña del Mar	Valparaíso
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Tianjin
Czech Republic	GSK Investigational Site	Brno
Czech Republic	GSK Investigational Site	Hradec Kralove
Czech Republic	GSK Investigational Site	Praha 8
Egypt	GSK Investigational Site	Cairo
France	GSK Investigational Site	Bayonne
France	GSK Investigational Site	Bordeaux
France	GSK Investigational Site	Clermont-Ferrand cedex
France	GSK Investigational Site	Lille
France	GSK Investigational Site	Lyon
France	GSK Investigational Site	Marseille Cedex BP 156
France	GSK Investigational Site	Mulhouse
France	GSK Investigational Site	Paris Cedex 20
France	GSK Investigational Site	Paris Cedex 5
France	GSK Investigational Site	Saint-Cloud
France	GSK Investigational Site	Saint-Herblain
France	GSK Investigational Site	Tours
France	GSK Investigational Site	Valenciennes
Germany	GSK Investigational Site	Aschaffenburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Duisburg	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Herne	Nordrhein-Westfalen
Germany	GSK Investigational Site	Lohsa	Sachsen
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Mannheim	Baden-Wuerttemberg
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Pinneberg	Schleswig-Holstein
Germany	GSK Investigational Site	Rosenheim	Bayern
Germany	GSK Investigational Site	Troisdorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Germany	GSK Investigational Site	Velbert	Nordrhein-Westfalen
Germany	GSK Investigational Site	Witten	Nordrhein-Westfalen
Germany	GSK Investigational Site	Zwickau	Sachsen
Greece	GSK Investigational Site	Athens
Hong Kong	GSK Investigational Site	Hong Kong
Hong Kong	GSK Investigational Site	Sheung Wan
Hong Kong	GSK Investigational Site	Tuen Mun
Israel	GSK Investigational Site	Petach Tikva
Israel	GSK Investigational Site	Ramat Gan
Israel	GSK Investigational Site	Rehovot
Israel	GSK Investigational Site	Zrifin
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Prato (PO)	Toscana
Italy	GSK Investigational Site	Sassari	Sardegna
Korea, Republic of	GSK Investigational Site	Incheon City
Korea, Republic of	GSK Investigational Site	seodaemun-gu, Seoul
Korea, Republic of	GSK Investigational Site	songpa-gu, Seoul
Morocco	GSK Investigational Site	Casablanca
Morocco	GSK Investigational Site	Hassan Rabat
Morocco	GSK Investigational Site	Rabat
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Multan
Peru	GSK Investigational Site	Lima
Philippines	GSK Investigational Site	Cebu
Philippines	GSK Investigational Site	Manila
Philippines	GSK Investigational Site	Quezon City
Philippines	GSK Investigational Site	Sampaloc Manila
Romania	GSK Investigational Site	Bucuresti
Romania	GSK Investigational Site	Cluj-Napoca
Romania	GSK Investigational Site	Iasi
Russian Federation	GSK Investigational Site	Chelyabinsk
Russian Federation	GSK Investigational Site	Kazan
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Ryazan
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Singapore	GSK Investigational Site	Singapore
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Málaga
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Taiwan	GSK Investigational Site	Changhua
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Tao-Yuan county
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Khon Kaen
Thailand	GSK Investigational Site	Lampang
Thailand	GSK Investigational Site	Phitsanulok
Tunisia	GSK Investigational Site	Ariana, Tunis
Tunisia	GSK Investigational Site	Sfax
Tunisia	GSK Investigational Site	Sousse
Turkey	GSK Investigational Site	Istanbul
Turkey	GSK Investigational Site	Izmir
United Kingdom	GSK Investigational Site	Bebington, Wirral
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Northwood	Middlesex
United Kingdom	GSK Investigational Site	Sutton
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Ogden	Utah
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Scarborough	Maine
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Voorhees	New Jersey
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Zion	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Chile,  China,  Czech Republic,  Egypt,  France,  Germany,  Greece,  Hong Kong,  Israel,  Italy,  Korea, Republic of,  Morocco,  Pakistan,  Peru,  Philippines,  Romania,  Russian Federation,  Singapore,  Spain,  Taiwan,  Thailand,  Tunisia,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Overall Response (OR), Defined as Those Participants Achieving Complete Response (CR) or Partial Response (PR), Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 and Cutaneous Lesions	RECIST-based response assessment was done at Weeks (Wks) 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, CR is the disappearance of all target and non-target lesions; PR is at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.	Baseline until disease progression/recurrence was documented, assessed for up to 66 weeks	No
Secondary	Median Duration of Response,Defined as the First Documented Evidence of CR or PR Until the First Documentation of Disease Progression	RECIST-based response assessment was done at Wks 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, PD is >=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment started or the appearance of >=1 new lesion and/or unequivocal progression of existing non-target lesions. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.	From the date of the first documented evidence of CR or PR until the date of the first documented disease progression or death, assessed for up to 62 weeks	No
Secondary	Progression-free Survival, Defined as the Interval Between the Date of Randomization and the Earliest Date of Disease Progression (PD) or Death Due to Any Cause (Defined by an Investigator Review of Lesions Based on RECIST and Cutaneous Disease)	RECIST-based response assessment was done at Wks 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, PD is >=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment started or the appearance of >=1 new lesion and/or unequivocal progression of existing non-target lesions. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.	From the date of the randomization until the earliest date of disease progression or death due to any cause, assessed for up to 66 weeks	No
Secondary	Overall Survival	Overall survival is defined as the time from randomization until death due to any cause. For participants who did not die, time to death was censored at the time of last contact.	From the date of randomization until the date of death due to any cause, assessed for up to 163 weeks	No