Clinical trial NCT00558103: Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neoplasms, Breast
Keywords: GW572016
Breast Cancer
RECIST
Inflammatory Breast Cancer
Pazopanib
ErbB2
Cutaneous Disease
Tykerb
Inflammatory
Skin
Her2
Lapatinib
GW786034
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-11-14
Enrollment: 163
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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).

Primary outcomes:
measure: 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
timeFrame: Baseline until disease progression/recurrence was documented, assessed for up to 66 weeks
Secondary outcomes:
measure: Median Duration of Response,Defined as the First Documented Evidence of CR or PR Until the First Documentation of Disease Progression
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Overall Survival
timeFrame: From the date of randomization until the date of death due to any cause, assessed for up to 163 weeks
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Zion
country: United States
facility: GSK Investigational Site
state: Illinois
city: Scarborough
country: United States
facility: GSK Investigational Site
state: Maine
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Voorhees
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Ogden
country: United States
facility: GSK Investigational Site
state: Utah
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Jette
country: Belgium
facility: GSK Investigational Site
city: Wilrijk
country: Belgium
facility: GSK Investigational Site
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Temuco
country: Chile
facility: GSK Investigational Site
state: Región De La Araucania
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Viña del Mar
country: Chile
facility: GSK Investigational Site
state: Valparaíso
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Tianjin
country: China
facility: GSK Investigational Site
city: Brno
country: Czech Republic
facility: GSK Investigational Site
city: Hradec Kralove
country: Czech Republic
facility: GSK Investigational Site
city: Praha 8
country: Czech Republic
facility: GSK Investigational Site
city: Cairo
country: Egypt
facility: GSK Investigational Site
city: Bayonne
country: France
facility: GSK Investigational Site
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Clermont-Ferrand cedex
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Marseille Cedex BP 156
country: France
facility: GSK Investigational Site
city: Mulhouse
country: France
facility: GSK Investigational Site
city: Paris Cedex 20
country: France
facility: GSK Investigational Site
city: Paris Cedex 5
country: France
facility: GSK Investigational Site
city: Saint-Cloud
country: France
facility: GSK Investigational Site
city: Saint-Herblain
country: France
facility: GSK Investigational Site
city: Tours
country: France
facility: GSK Investigational Site
city: Valenciennes
country: France
facility: GSK Investigational Site
city: Mannheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Rosenheim
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Duisburg
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Herne
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Troisdorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Velbert
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Lohsa
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Zwickau
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Pinneberg
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Hong Kong
country: Hong Kong
facility: GSK Investigational Site
city: Sheung Wan
country: Hong Kong
facility: GSK Investigational Site
city: Tuen Mun
country: Hong Kong
facility: GSK Investigational Site
city: Petach Tikva
country: Israel
facility: GSK Investigational Site
city: Ramat Gan
country: Israel
facility: GSK Investigational Site
city: Rehovot
country: Israel
facility: GSK Investigational Site
city: Zrifin
country: Israel
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Sassari
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Prato (PO)
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Incheon City
country: Korea, Republic of
facility: GSK Investigational Site
city: seodaemun-gu, Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: songpa-gu, Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Casablanca
country: Morocco
facility: GSK Investigational Site
city: Hassan Rabat
country: Morocco
facility: GSK Investigational Site
city: Rabat
country: Morocco
facility: GSK Investigational Site
city: Lahore
country: Pakistan
facility: GSK Investigational Site
city: Lahore
country: Pakistan
facility: GSK Investigational Site
city: Multan
country: Pakistan
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Cebu
country: Philippines
facility: GSK Investigational Site
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Quezon City
country: Philippines
facility: GSK Investigational Site
city: Sampaloc Manila
country: Philippines
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Changhua
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Tao-Yuan county
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Khon Kaen
country: Thailand
facility: GSK Investigational Site
city: Lampang
country: Thailand
facility: GSK Investigational Site
city: Phitsanulok
country: Thailand
facility: GSK Investigational Site
city: Ariana, Tunis
country: Tunisia
facility: GSK Investigational Site
city: Sfax
country: Tunisia
facility: GSK Investigational Site
city: Sousse
country: Tunisia
facility: GSK Investigational Site
city: Istanbul
country: Turkey
facility: GSK Investigational Site
city: Izmir
country: Turkey
facility: GSK Investigational Site
city: Northwood
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: Bebington, Wirral
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: