Clinical trial NCT00281658: Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2
Official title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Study of Lapatinib (GW572016) in Combination With Paclitaxel Versus Paclitaxel Plus Placebo in Subjects With ErbB2 Amplified Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasms, Breast
Keywords: ErbB2 positive
human epidermal growth factor receptor 2 positive (Her2+)
metastatic breast cancer
Fluorescence in situ hybridization (FISH) positive
Stage IV
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-01-25
Enrollment: 444
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study to evaluate and compare the efficacy and safety of Lapatinib + Paclitaxel versus Placebo + Paclitaxel in men and women with ErbB2 amplified metastatic (Stage IV) breast cancer who had not received prior therapy for metastatic disease.

Detailed description: Subjects were randomized to receive either Lapatinib (1500 mg once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks) or Placebo (once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks).

Subjects who progressed while on study and were on the placebo+paclitaxel arm were permitted to enter an extension phase of open label monotherapy therapy with lapatinib or open label combination therapy with lapatinib+paclitaxel and followed for response, progression and survival.

Based on the positive results in the primary analysis, Protocol Amendment 02 (dated 09 May 2011) discontinued further entry into the lapatinib monotherapy extension phase, and ongoing subjects taking placebo were permitted to replace it with open label lapatinib therapy (with or without continued paclitaxel therapy).

Following the primary Overall Survival (OS) analysis and subsequent implementation of Protocol Amendment 03, subjects who were still receiving active treatment entered the Long-term follow-up (LTFU) phase of the study. Reporting requirements in the LTFU phase were limited to Adverse events of special interest (AESI), Serious adverse events (SAEs) and pregnancy, and the subjects continued to receive treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator) or permanent withdrawal from treatment for any reason. Subjects who were no longer receiving active treatment were withdrawn from the study.

Eligibility criteria: Inclusion criteria:

* Signed informed consent;
* Male or female ≥18 years;
* Histologically confirmed invasive breast cancer with stage IV disease; If the disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology.
* Documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue by the central laboratory for randomization into the study;
* If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred \>12 months after completion of this treatment and the patient recovered from all associated toxicities;
* Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors);
* Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment. All subjects must have recovered from all radiotherapy related toxicities prior to initiation of any investigational treatment. The site of radiotherapy must not be used as a site of measurable disease;
* Bisphosphonate therapy for bone metastases and is allowed; however, treatment must be initiated prior to the first dose of investigational treatment. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis;
* For those patients whose disease is ER+ and/or PR+ the following criteria should be met:

Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) Rapidly progressing or life threatening disease, as determined by the investigator Patients who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment;

* Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive;
* ECOG Performance Status of 0 to 1;
* Life expectancy of ≥ 12 weeks;
* Able to swallow and retain oral medication;
* Archived tumor tissue available for testing;
* Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study;
* Willing to complete all screening assessments as outlined in the protocol;
* Adequate organ function as defined in Table 1 Baseline Laboratory Values;

Exclusion Criteria:

* Pregnant or lactating females at anytime during the study
* Subjects with only non-measurable metastatic sites of disease per RECIST, (e.g. bone metastases, pleural effusion, or ascites, etc. (Refer to Section 5.3 Efficacy for list sites considered to be non-measurable disease.);
* Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease.
* Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab in the adjuvant setting. If trastuzumab was administered in the adjuvant setting, then \> 12 months must have elapsed since completion of trastuzumab therapy;
* Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment;
* Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
* Peripheral neuropathy of Grade 2 or greater;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
* History of other malignancy. However, 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;
* Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety;
* Uncontrolled infection;
* Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
* Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;
* Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis;
* Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines;
* Concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents;
* Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational treatment;
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel or lapatinib or their excipients.

Primary outcomes:
measure: Overall Survival (OS) at 53 Months
timeFrame: From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Secondary outcomes:
measure: Overall Survival (OS) at 190 Months
timeFrame: From date of randomization until date of death from any cause, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021)
measure: Progression-free Survival (PFS) by Investigator Assessment
timeFrame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
measure: Overall Response Rate (ORR) by Investigator Assessment
timeFrame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
measure: Clinical Benefit Rate (CBR)
timeFrame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary analysis cut-off date = 18-Jun-2010)
measure: Duration of Response (DOR)
timeFrame: From date of confirmed CR or PR until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
measure: Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72
timeFrame: Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72
measure: Number of Tumors Evaluable for PIK3CA Mutations
timeFrame: Baseline
measure: Number of Participants With Tumors Evaluable for PTEN
timeFrame: Baseline
measure: Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR)
timeFrame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
measure: Predictive Effect of PTEN Low on Overall Response Rate (ORR)
timeFrame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
measure: Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR)
timeFrame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
measure: Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR)
timeFrame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Other outcomes:
Locations:
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: Bahía
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: Bahía
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Du Norte
city: Jau
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Dalian
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Xi'an
country: China
facility: Novartis Investigative Site
state: Shaanxi
city: Xi'an
country: China
facility: Novartis Investigative Site
state: Shaanxi
city: Jinan
country: China
facility: Novartis Investigative Site
state: Shandong
city: Jinan
country: China
facility: Novartis Investigative Site
state: Shandong
city: Jinan
country: China
facility: Novartis Investigative Site
state: Shandong
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Chengdu
country: China
facility: Novartis Investigative Site
city: Chongqing
country: China
facility: Novartis Investigative Site
city: Dalian
country: China
facility: Novartis Investigative Site
city: Fuzhou
country: China
facility: Novartis Investigative Site
city: Fuzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shenyang
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Kowloon
country: Hong Kong
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Tuen Mun
country: Hong Kong
facility: Novartis Investigative Site
city: Lahore
country: Pakistan
facility: Novartis Investigative Site
city: Lahore
country: Pakistan
facility: Novartis Investigative Site
city: Lahore
country: Pakistan
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov-na-Donu
country: Russian Federation
facility: Novartis Investigative Site
city: Samara
country: Russian Federation
facility: Novartis Investigative Site
city: Voronezh
country: Russian Federation
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiangmai
country: Thailand
facility: Novartis Investigative Site
city: Cherkasy
country: Ukraine
facility: Novartis Investigative Site
city: Chernihiv
country: Ukraine
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Zaporizhzhia
country: Ukraine
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Xu B, Guan Z, Shen Z, Tong Z, Jiang Z, Yang J, DeSilvio M, Russo M, Leigh M, Ellis C. Association of phosphatase and tensin homolog low and phosphatidylinositol 3-kinase catalytic subunit alpha gene mutations on outcome in human epidermal growth factor receptor 2-positive metastatic breast cancer patients treated with first-line lapatinib plus paclitaxel or paclitaxel alone. Breast Cancer Res. 2014 Jul 24;16(4):405. doi: 10.1186/s13058-014-0405-y.
citation: Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, Lorvidhaya V, Jiang Z, Yang J, Makhson A, Leung WL, Russo MW, Newstat B, Wang L, Chen G, Oliva C, Gomez H. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J Clin Oncol. 2013 Jun 1;31(16):1947-53. doi: 10.1200/JCO.2011.40.5241. Epub 2013 Mar 18.