Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Advanced Or Metastatic Breast Cancer

NCT ID: NCT00347919

Last Updated: 2016-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 189 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-07-31
• Study Completion Date: 2015-03-31

Brief Summary

This study is being conducted to compare the efficacy and safety of pazopanib in combination with lapatinib with that of lapatinib alone in subjects with locally advanced or metastatic breast cancer whose tumors overexpress the ErbB2 protein.

Conditions

Neoplasms, Breast

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

monotherapy arm

1500 mg (6 x 250 mg tablets) oral lapatinib once daily

Group Type: EXPERIMENTAL

lapatinib (GW572016) 1500 mg

Intervention Type: DRUG

1500 mg administered orally once daily.

Cohort 1 combination arm

1000 mg (4 x 250 mg tablets) of oral lapatinib and 400 mg (4 x 100 mg tablets) of oral pazopanib taken together once daily

Group Type: EXPERIMENTAL

pazopanib (GW786034) 400 mg

Intervention Type: DRUG

400 mg administered orally once daily

lapatinib (GW572016) 1000 mg

Intervention Type: DRUG

1000 mg administered orally once daily

Cohort 2 combination arm

1500 mg (6 x 250 mg tablets) of oral lapatinib and 800 mg (1 x 500 mg tablets plus 3 x 100 mg tablets) of oral pazopanib taken together once daily

Group Type: EXPERIMENTAL

lapatinib (GW572016) 1500 mg

Intervention Type: DRUG

1500 mg administered orally once daily.

pazopanib (GW786034) 800 mg

Intervention Type: DRUG

800 mg administered orally once daily

Interventions

pazopanib (GW786034) 400 mg

400 mg administered orally once daily

Intervention Type: DRUG

lapatinib (GW572016) 1500 mg

1500 mg administered orally once daily.

Intervention Type: DRUG

lapatinib (GW572016) 1000 mg

1000 mg administered orally once daily

Intervention Type: DRUG

pazopanib (GW786034) 800 mg

800 mg administered orally once daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• A subject will be eligible for inclusion in this study only if all of the following criteria apply:
• Women ≥ 18 years of age with a life expectancy of ≥ 12 weeks.
• Note: National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA).)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Histologically confirmed invasive breast cancer with incurable stage IIIb, stage IIIc with T4 lesion, or stage IV disease at primary diagnosis or at relapse after curative-intent surgery.
• No prior chemotherapy, immunotherapy, biologic therapy or anti-ErbB1/ErbB2 therapy for metastatic or recurrent disease (other than neoadjuvant or adjuvant therapy). Prior hormonal therapy (e.g., tamoxifen, raloxifen or an aromatase inhibitor) for advanced or metastatic disease is permitted provided at least 2 weeks have elapsed between the completion of the prior therapy and start of study drugs.
• Note: Subjects must have documented progressive disease (PD) or be intolerant to hormonal therapy. This must be documented in the source documentation.
• Prior neoadjuvant therapy and/or adjuvant therapy is permitted.
• Note:
• (a) Subjects who have received both neoadjuvant and adjuvant therapies must have at least 6 months between completion of the chemotherapy-component of adjuvant therapy and start of study drug(s)
• (b) Subjects who have received only adjuvant therapy must have at least 6 months between completion of the chemotherapy-component of adjuvant therapy and start of study drug(s)
• (c) Subjects who have received only neoadjuvant therapy must have at least 6 months between completion of neoadjuvant therapy and start of study drug(s)
• (d) Subjects who have received trastuzumab or hormonal agents as all or part of adjuvant therapy are eligible provided: (1) 2 weeks have elapsed since last dose (2) 6 months have elapsed between the start of trastuzumab or hormonal therapy and start of study drugs.
• Radiotherapy prior to initiation of randomized therapy to a limited area (e.g., palliative treatment for painful disease) other than the sole site of measurable and assessable disease is allowed however, subjects must have completed treatment at least 4 weeks prior to starting study drugs, and must have recovered from all treatment-related toxicities prior to starting pazopanib and/or lapatinib.
• Documented amplification of ErbB2 by Fluorescence In Situ Hybridization (FISH) in either the primary or metastatic tumor tissue. Archived tumor tissue must be provided for ErbB2 FISH testing by the central laboratory, which will be used to determine eligibility.
• Note: Subjects that have documented ErbB2 amplification based on prior FISH testing or documented ErbB2 overexpression based on prior immunohistochemistry (IHC) with a value of 3+ are eligible, however, archived tumor tissue must be provided for confirmation by the central laboratory. If the results from prior testing are not confirmed by the central laboratory, then the subject can continue to receive study drug(s) at the discretion of the investigator, but will be excluded from the statistical analysis.
• Archived tumor tissue (paraffin-embedded) must be available to correlate tumor response with intra-tumoral genetic changes as well as expression levels of relevant biomarkers. Results of biomarkers will not be used to determine subject eligibility for the study.
• Ability to swallow and retain oral medication.
• Disease must be measurable according to Response Evaluation Criteria in Solid Tumors (RECIST).
• Subjects must have chosen treatment with lapatinib and/or pazopanib as initial treatment over other initial treatments (such as cytotoxic chemotherapy regimens or trastuzumab as a single agent) for locally advanced or metastatic disease.
• Adequate organ function as defined below:
• System (Laboratory Values)
• Hematologic:Absolute neutrophil count (ANC) (≥1.5 X 109/L) Platelets (≥100 X 109/L)
• Hepatic:Albumin(≥2.5 g/dL)Serum bilirubin(≤1.5 X upper limit of normal (ULN) unless due to Gilbert's syndrome) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (≤2.0 X ULN)
• Renal:Calculated creatinine clearance1 (≥50 mL/min) Urine Protein2
• (Negative, trace or +1 by dipstick urinalysis or <1.0 gram determined by 24 hour urine protein analysis).
• A patient should first be screened with dipstick urinalysis. If urine protein by dipstick analysis is≥2+, then a 24-hour urine protein must be assessed and 24 hour urine protein must be <1 g protein to be eligible.
• Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram. Multigated acquisition (MUGA) scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive or where MUGA scans are the accepted standard. Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are not eligible.
• 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 (total cessation of menses for ≥1 year)
• Childbearing potential, has a negative serum pregnancy test within 2 weeks of the first dose of study medication, and agrees to use adequate contraception during study participation and for a minimum of 2 menstrual cycles after the last dose of study medication. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:
• An intrauterine device with a documented failure rate of less than 1% per year.
• Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.
• Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, through the clinical trial, and for at least 2 menstrual cycles 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).
• Oral contraceptives are not reliable due to the potential drug-drug interactions.
• Subjects must complete all screening assessments as outlined in the protocol.
• Subjects must provide written informed consent prior to performance of any study-specific procedures or assessments and are willing to comply with treatment and follow-up.

Exclusion Criteria

• A subject will not be eligible for inclusion in this study if any of the following criteria apply:
• Subjects with bilateral breast cancer or bone metastases as the only disease site.
• Patients with high disease burden defined as >30% replacement of hepatic parenchyma with metastases, symptomatic pulmonary metastases (e.g., clinically significant dyspnea, cough, or chest pain attributable to pulmonary metastases), or >3 visceral organs with tumor involvement.
• History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
• Sarcoma histology.
• Concurrent disease or condition that would make the subject inappropriate for study participation including (1) any unresolved or unstable, serious toxicity from prior administration of another investigational drug, (2) any serious medical disorder that would interfere with the subject's safety, obtaining informed consent or compliance to the study.
• 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 antiseizure medication for ³ 2 months prior to study enrollment. Routine 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.
• Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel.
• Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to beginning therapy.
• Presence of uncontrolled infection.
• Concurrent cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, and tumor embolization).
• Concurrent treatment with an investigational agent or participation in another clinical trial.
• Use of an investigational anti-cancer drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of pazopanib and/or lapatinib.
• Prior use of an investigational or licensed drug that targets either vascular endothelial growth factor (VEGF) or VEGF receptors, or ErbB2 (except for trastuzumab when used in the neo-adjuvant/adjuvant setting).
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or lapatinib.
• Has taken/is taking prohibited medications, Lapatinib-related, orPazopanib-related.
• Corrected QT interval (QTc) prolongation defined as QTc interval > 480 msecs.
• History of any one of the following cardiac conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• History of cerebrovascular accident within the past 6 months.
• Poorly controlled hypertension (systolic blood pressure (SBP) of ≥140mmHg, or diastolic blood pressure (DBP) of ≥90mmHg).
• Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. The blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP/DBP values from both BP assessments must be < 140/90mmHg in order for a subject to be eligible for the study.
• Presence of any non-healing wound, fracture, or ulcer, or the presence of symptomatic peripheral vascular disease.
• Evidence of bleeding diathesis or coagulopathy.
• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.
• Pregnant or lactating female.
• Has Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf vein thrombosis).

• Minimum Eligible Age: 21 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Jonesboro, Arkansas, United States

GSK Investigational Site

Alhambra, California, United States

GSK Investigational Site

Bakersfield, California, United States

GSK Investigational Site

Fullerton, California, United States

GSK Investigational Site

Long Beach, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Northridge, California, United States

GSK Investigational Site

Oxnard, California, United States

GSK Investigational Site

Redondo Beach, California, United States

GSK Investigational Site

Santa Barbara, California, United States

GSK Investigational Site

Santa Maria, California, United States

GSK Investigational Site

Indianapolis, Indiana, United States

GSK Investigational Site

Metairie, Louisiana, United States

GSK Investigational Site

Henderson, Nevada, United States

GSK Investigational Site

The Bronx, New York, United States

GSK Investigational Site

Akron, Ohio, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

Lubbock, Texas, United States

GSK Investigational Site

San Antonio, Texas, United States

GSK Investigational Site

Edmonton, Alberta, Canada

GSK Investigational Site

Halifax, Nova Scotia, Canada

GSK Investigational Site

Weston, Ontario, Canada

GSK Investigational Site

Besançon, , France

GSK Investigational Site

Hyères, , France

GSK Investigational Site

Lille, , France

GSK Investigational Site

Lyon, , France

GSK Investigational Site

Marseille Cedex BP 156, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Strasbourg, , France

GSK Investigational Site

Budapest, , Hungary

GSK Investigational Site

Budapest, , Hungary

GSK Investigational Site

Győr, , Hungary

GSK Investigational Site

Bangalore, , India

GSK Investigational Site

Delhi, , India

GSK Investigational Site

Jaipur, , India

GSK Investigational Site

Mumbai, , India

GSK Investigational Site

Pune, , India

GSK Investigational Site

Pune, , India

GSK Investigational Site

Trivandrum, , India

GSK Investigational Site

Haifa, , Israel

GSK Investigational Site

Jerusalem, , Israel

GSK Investigational Site

Petah Tikva, , Israel

GSK Investigational Site

Ramat Gan, , Israel

GSK Investigational Site

Rehovot, , Israel

GSK Investigational Site

Tel Aviv, , Israel

GSK Investigational Site

Bandar Tun Razak, Cheras, , Malaysia

GSK Investigational Site

Petaling Jaya, , Malaysia

GSK Investigational Site

Mérida, Yucatán, Mexico

GSK Investigational Site

Mexico City, , Mexico

GSK Investigational Site

Islamabad, , Pakistan

GSK Investigational Site

Karachi, , Pakistan

GSK Investigational Site

Lahore, , Pakistan

GSK Investigational Site

Lahore, , Pakistan

GSK Investigational Site

Multan, , Pakistan

GSK Investigational Site

Lima, Lima Province, Peru

GSK Investigational Site

Lima, Lima Province, Peru

GSK Investigational Site

Callao, , Peru

GSK Investigational Site

Elblag, , Poland

GSK Investigational Site

Kielce, , Poland

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Olsztyn, , Poland

GSK Investigational Site

Olsztyn, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Singapore, , Singapore

GSK Investigational Site

Incheon, , South Korea

GSK Investigational Site

Seodaemun-gu, Seoul, , South Korea

GSK Investigational Site

Songpa-gu, Seoul, , South Korea

GSK Investigational Site

Suwon, Kyonggi-do, , South Korea

GSK Investigational Site

Bangkok, , Thailand

GSK Investigational Site

Chelmsford, Essex, United Kingdom

GSK Investigational Site

Manchester, Lancashire, United Kingdom

GSK Investigational Site

Sutton, Surrey, United Kingdom

GSK Investigational Site

Birmingham, , United Kingdom

GSK Investigational Site

Glasgow, , United Kingdom

GSK Investigational Site

Ipswich, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Nottingham, , United Kingdom

GSK Investigational Site

Plymouth, , United Kingdom

Countries

United States; Canada; France; Hungary; India; Israel; Malaysia; Mexico; Pakistan; Peru; Poland; Russia; Singapore; South Korea; Thailand; United Kingdom

References

Johnston SR, Gomez H, Stemmer SM, Richie M, Durante M, Pandite L, Goodman V, Slamon D. A randomized and open-label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer. Breast Cancer Res Treat. 2013 Feb;137(3):755-66. doi: 10.1007/s10549-012-2399-4. Epub 2013 Jan 3.

Reference Type: BACKGROUND

PMID: 23283526 (View on PubMed)

de Jonge MJ, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, Arumugham T, Pandite LN, Hurwitz HI. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):751-9. doi: 10.1007/s10637-012-9885-8. Epub 2012 Oct 6.

Reference Type: DERIVED

PMID: 23054212 (View on PubMed)

Other Identifiers

VEG20007

Identifier Type: -

Identifier Source: org_study_id