Clinical trial NCT00272987: ErbB2 Over-expressing Metastatic Breast Cancer Study Using Paclitaxel, Trastuzumab, and Lapatinib
Official title: A Randomized, Double Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing the Activity of Paclitaxel Plus Trastuzumab Plus Lapatinib to Paclitaxel Plus Trastuzumab Plus Placebo in Women With ErbB2 Overexpressing Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Neoplasms, Breast
Keywords: trastuzumab
ErbB2
paclitaxel
Herceptin
Taxol
ErbB1
metastatic breast cancer
Stage IV breast cancer
lapatinib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-01-09
Enrollment: 63
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study was originally designed as a Phase III randomized, double blind, placebo controlled study to assess the safety and tolerability, and efficacy of paclitaxel plus trastuzumab plus lapatinib compared with paclitaxel plus trastuzumab plus placebo in women with ErbB2 overexpressing metastatic breast cancer. The planned study was a two stage design with an initial open-label safety stage to be conducted in approximately 65 subjects followed by a randomized phase conducted in a further 700 subjects. The open-label part of the study sequentially enrolled three cohorts with patients receiving a different dose combination of paclitaxel, trastuzumab and lapatinib. Following poor recruitment rate in the open label stage, the randomized stage of the study was terminated, thus no subjects were enrolled into the randomization stage.

Detailed description: The primary objective of this study was to evaluate and compare time to progression (TTP). The Primary objective for open label phase was to determine the safety and tolerability of lapatinib when administered in combination with both paclitaxel and trastuzumab. The study first enrolled an open label safety cohort of 20 patients to assess the tolerability of the triplet combination. This was a 1 arm, 3 cohort study stage.

Open-label Phase: Patients were sequentially enrolled into three cohorts and received an open-label combination of paclitaxel, trastuzumab and lapatinib: Cohort 1 received paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 2 received paclitaxel 70mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 3 paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 750 mg PO daily.

Randomized Phase: was terminated following the poor recruitment rate in the open-label safety stage. No subjects were enrolled into the randomization stage.

In summary, at approximately 3.5 years the primary analysis which included demographics, efficacy and safety were conducted; at approximately 7 years protocol amendment 7 cancelled collection of efficacy endpoints, and only key safety endpoints were to be collected; the final analysis was performed at approximately 14 years.

Eligibility criteria: Inclusion criteria:

* Histologically confirmed invasive breast cancer with stage IV disease
* If trastuzumab was administered in the adjuvant setting, \>12 months must have elapsed since discontinuation of trastuzumab therapy
* If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred ≥12 months after completion of this treatment
* Had tumors that overexpress ErbB2 defined as either: 3+ by IHC OR c-erbB2 gene amplification by FISH OR 0, 1+, 2+ by IHC and c-erbB2 gene amplification by FISH.
* Patients must have tumor tissue available for central testing, and must have Measurable lesion(s) according to RECIST
* Subjects must be females of at least 18 years Non-childbearing potential or Childbearing potential but using adequate contraception
* Radiotherapy to a limited area other than the sole site of measurable and assessable disease is allowed; however, patients must have completed treatment and recovered from all acute treatment-related toxicities prior to administration of the first dose of study medication
* Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
* For those patients whose disease is estrogen receptor positive+ and/or progesterone receptor + one the following criteria should be met: Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) or Rapidly progressing/life threatening disease, as determined by the investigator or Patients who received hormonal therapy and are no longer benefiting from this therapy;
* Able to swallow and retain oral medication
* Cardiac ejection fraction within institutional range of normal
* Patient must have adequate organ function

Exclusion criteria:

* Pregnant or lactating females;
* Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease, prior hormonal therapy is permitted but must be discontinued a minimum of 7 days prior to randomization;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Patients with ulcerative colitis are also excluded;
* History of other malignancy; however, patients who have been disease-free for five years, or patients 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 patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient's safety;
* 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;
* Active or 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, conduction abnormalities or congestive heart failure;
* Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis;
* Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy);
* Concurrent treatment with an investigational agent or participation in another clinical trial;
* Concurrent treatment with any medication on the prohibited medications list.
* Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of treatment. Hormonal therapy needs to be discontinued at least 7 days before the first dose of treatment.
* Prior therapy with an ErbB2 inhibitor, other than trastuzumab in the adjuvant setting;
* A known immediate or delayed hypersensitivity reaction to drugs chemically related to lapatinib or excipients;
* A known immediate or delayed hypersensitivity reaction to drugs chemically related to paclitaxel or excipients;
* A known immediate or delayed hypersensitivity reaction to drugs chemically related to trastuzumab or excipients;
* Non compliance with any of the screening procedures

Primary outcomes:
measure: Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation
timeFrame: From the date of the first dose of the investigational product to end of study, up to approx. 14 years
measure: Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Median/Min-Max
timeFrame: From the date of the first dose of the investigational product to end of study, up to approx. 14 years
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 14 years
measure: Number of Participants Who Died Due to Any Cause
timeFrame: From the date of the first dose of investigational product until last patient last visit, up to approximately 14 years
measure: Number of Events of Diarrhea With the Indicated Characteristics
timeFrame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
measure: Number of Events of Rash With the Indicated Characteristics
timeFrame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
measure: Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Hematology Parameters
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Number of Events of Hepatotoxicity With the Indicated Characteristics
timeFrame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
measure: Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Change From Baseline in Heart Rate at the Indicated Time Points
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Change From Baseline in Body Temperature at the Indicated Time Points
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Number of Participants With at Least 1 Event of Left Ventricular Ejection Fraction Decrease With the Indicated Characteristics
timeFrame: Baseline and every 8 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value
timeFrame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
measure: Number of Participants Who Received Any Concomitant Medications During the Study Period
timeFrame: withdrawal/study completion, up to approx. 3.5 years
measure: Overall Response (OR): Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator
timeFrame: From the date of the first dose of investigational product to end of study, up to approx. 7 years
Secondary outcomes:
measure: Time to Response as Assessed by the Investigator
timeFrame: From the date of the first dose of investigational product until the first documented evidence of a PR or CR, up to approx. 7 years
measure: Duration of Response (DoR), as Assessed by the Investigator
timeFrame: From the first documented evidence of a PR or CR until the earlier of the date of disease progression or the date of death due to breast cancer, up to approx. 7 years
measure: Percentage of Participants With Clinical Benefit (Complete Response (CR), Partial Response (PR), and Stable Disease [SD] for at Least 24 Weeks) as Assessed by Investigator
timeFrame: From the date of the first dose of investigational product until the first documented evidence of a PR or CR or SD until the earlier of the date of disease progression or the date of death due to breast cancer, up to approx. 7 years
measure: Progression-free Survival as Assessed by the Investigator
timeFrame: From the date of the first dose of investigational product until the earlier of the date of disease progression or death due to any cause, up to approx. 7 years
Other outcomes:
Locations:
city: Roswell
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Joliet
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Jackson
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Voorhees
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Winston-Salem
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Canton
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Middletown
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Charleston
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Amarillo
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Arlon
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Esteva FJ, Franco SX, Hagan MK, Brewster AM, Somer RA, Williams W, Florance AM, Turner S, Stein S, Perez A. An open-label safety study of lapatinib plus trastuzumab plus paclitaxel in first-line HER2-positive metastatic breast cancer. Oncologist. 2013 Jun;18(6):661-6. doi: 10.1634/theoncologist.2012-0129. Epub 2013 May 22.