A Study of Trastuzumab Emtansine Versus Taxane in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Gastric Cancer
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Terminated
CT.gov ID
NCT01641939
Collaborator
(none)
415
148
3
43.9
2.8
0.1
Study Details
Study Description
Brief Summary
This multicenter, randomized, adaptive Phase II/III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to standard taxane (docetaxel or paclitaxel) treatment in participants with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. At the start of the trial (stage 1), participants will be randomized with a ratio 2:2:1 to one of three treatment arms: Arm A: trastuzumab emtansine 3.6 milligram per kilogram (mg/kg) per intravenous injection (IV) every 3 weeks; Arm B: trastuzumab emtansine 2.4 mg/kg IV every week; Arm C: standard taxane therapy (docetaxel 75 milligram per meter square [mg/m2] IV every 3 weeks or paclitaxel 80 mg/m2 kg IV every week per investigator choice). At the end of the first stage of the study, the dose and schedule of trastuzumab emtansine that will be used in the second stage of the study will be selected by an Independent Data Monitoring Committee (IDMC). The regimen selection analysis will be made after approximately 100 participants across all three study arms have been treated for at least 12 weeks.
Once a trastuzumab emtansine regimen has been selected, Stage I participants who were assigned to the treatment arm which was selected for Stage II of the study and participants who were in the standard taxane group will continue to receive their assigned treatment regimen. Stage I participants who were assigned to the regimen that was not selected for further evaluation will continue to receive their assigned regimen and will continue to be followed for efficacy and safety. In Stage II of the study, additional participants will be recruited and randomized with a ratio 2:1 to either the selected regimen of trastuzumab emtansine or to the standard taxane therapy. Participants will receive study treatment until disease progression, unacceptable toxicity, initiation of another cancer therapy or withdrawal.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
415 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Multicenter, Adaptive Phase II/III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine (T-DM1) Versus Taxane (Docetaxel Or Paclitaxel) In Patients With Previously Treated Locally Advanced Or Metastatic HER2-Positive Gastric Cancer, Including Adenocarcinoma Of The Gastroesophageal Junction
Actual Study Start Date
:
Sep 3, 2012
Actual Primary Completion Date
:
Jun 30, 2015
Actual Study Completion Date
:
Apr 30, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Standard taxane therapy Docetaxel will be administered at 75 milligram per meter square (mg/m^2) intravenous (IV) on Day 1 of a 21-day cycle, or paclitaxel will administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) according to investigator choice until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
Drug: Taxane
Standard taxane (docetaxel 75 mg/m^2 IV every 3 weeks or paclitaxel 80 mg/m^2) IV once a week according to investigator choice.
|
| Experimental: trastuzumab emtansine 2.4 mg Trastuzumab emtansine will be administered on Day 1, 8, and 15 of a 21-day cycle at 2.4 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
Drug: trastuzumab emtansine
trastuzumab emtansine 2.4 mg/kg IV once a week
|
| Experimental: trastuzumab emtansine 3.6 mg Trastuzumab emtansine will be administered on Day 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
Drug: trastuzumab emtansine
trastuzumab emtansine 3.6 mg/kg IV every 3 weeks
|
Outcome Measures
Primary Outcome Measures
- Overall Survival (OS)- Phase 3 [Date of randomization until death (up to 2 years 3 months)]
Overall survival was defined as the time between the date of randomization and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Participants for whom no death was reported prior to an analysis cutoff (30 June 2015) was censored at the latest date before the cutoff in which they were known to be alive. All data from the standard taxane therapy and trastuzumab emtansine 2.4 mg (selected treatment arm) from phase 2 and phase 3 (Stage 2) are combined into phase 3 data, and thus cumulative data are provided within the results presented for phase 3. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg).
- Overall Survival (OS) - Phase 2 (Dose Selection Portion of the Study) [Date of randomization until death (up to 1 year)]
Overall survival was defined as the time between the date of randomization and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Participants for whom no death was reported prior to an analysis cutoff (10 August 2013) was censored at the latest date before the cutoff in which they were known to be alive.
Secondary Outcome Measures
- Percentage of Participants With Disease Progression or Death According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 [Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)]
Progressive disease could base on symptom deterioration or was defined as at least a 20 percent (%) increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Tumor assessment was performed using modified RECIST v1.1. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Progression Free Survival (PFS) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 [Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)]
Progression-free survival was defined as the time between the date of randomization and the first date of documented progression or date of death due to any cause, whichever occurred first. Tumor assessment was performed using modified RECIST v1.1. Progressive disease could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Kaplan-Meier estimates were used for analysis. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg).
- Percentage of Participants With Objective Response According to mRECIST v1.1 - Phase 3 [Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)]
Objective response referred to participants with complete response (CR) or partial response (PR). CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: greater than or equal to (>=) 30% decrease in sum of the longest diameter (LD) of all target lesions taking as reference the screening sum LD. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Duration of Objective Response (DOR) - Phase 3 [Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)]
DOR: time from the date when a clinical response [CR or PR] was first documented to the date of first documented progressive disease (PD) or death. CR:disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: >= 30% decrease in sum of the LD of all target lesions taking as reference the screening sum LD. PD: could base on symptom deterioration or at least a 20% increase in the sum of diameters of target or non-target lesions and new lesions, taking as reference the smallest sum on study (nadir), including baseline. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Percentage of Participants With Clinically Significant Improvement in European Organisation for Research and Treatment of Cancer Quality of Life Core Module 30 (EORTC QLQ-C30) Score - Phase 3 [Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at follow-up (up to 2 years 3 months)]
The EORTC QLQ-C30 is a validated, cancer-specific 30-item patient-reported measure, and contains 14 domains to assess the impact of cancer treatment on 5 aspects of participants functioning (physical, role, cognitive, emotional, and social), 9 aspects of disease/treatment-related symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) and a global QoL/overall health status scale. Questions used 4 point scale (1 'Not at all' to 4 'Very much'; with the exception of the QoL/health status scale which uses a 7-point scale (1 'very poor' to 7 'Excellent'). Each scale is transformed on a scale of 0-100; a higher score equals (=) a better level of functioning or greater degree of symptoms. Change of greater than or equal to (>=) 10-points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Percentage of Participants With Clinically Significant Improvement in Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) Score - Phase 3 [Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)]
The Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) supplements the EORTC QLQ-C30 to assess symptoms and treatment-related side effects commonly reported in participants. There are 22 questions which comprise 5 scales (dysphagia, pain, reflux symptom, dietary restrictions, and anxiety) and 4 single items (dry mouth, hair loss, taste, body image). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. Change of >=10 points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Percentage of Participants With Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 [Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)]
AGC symptomatic progression: a worsening of >=10-points in any 1 of the abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and/or weight loss scales of the EORTC QLQ-C30 and QLQ-STO22. QLQ-STO22 supplements EORTC QLQ-C30 to assess symptoms and commonly reported treatment-related side effects. There are 22 questions comprise 5 scales (dysphagia, pain, reflux symptom, diet restrictions, anxiety), 4 single items (dry mouth, hair loss, taste, body image), which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'). All scores and single-items transformed to a scale of 0-100; higher score=better level of functioning or greater degree of symptoms. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Time to Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 [Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)]
Time to AGC symptom were defined as the time from randomization to the first documentation of an increase in at least one of the pre-specified abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and weight loss subscales of the QLQ STO22 and EORTC QLQ-C30. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure.
- Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 1 [Day 1 (D1) of Cycle 1 (C1) and C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
Maximum observed plasma concentration of Trastuzumab Emtansine (T-DM1) and total trastuzumab were reported. Stage 1 consists of all participants recruited before the regimen selection, which was carried out after 12 weeks of randomization.
- Maximum Observed Plasma Concentration (Cmax) of N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) - Stage 1 [C1D1 and C1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
Maximum observed plasma concentration of DM1 were reported. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization.
- Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 2 [C1D1; C4D1]
Stage 2 consists of all participants recruited after the regimen selection decision up to primary data cut-off date 30-June-2015.
- Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] - Stage 1 [D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization.
- Plasma Decay Half-Life (t1/2) - Stage 1 [D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization.
- Volume of Distribution at Steady State (Vss) - Stage 1 [D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization.
- Systemic Clearance (CL) - Stage 1 [D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)]
CL is a quantitative measure of the rate at which a drug substance is removed from the body. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-
Life expectancy of at least 12 weeks from the first dose of study treatment
-
Measurable and/or evaluable disease based on Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
-
Adequate organ function as determined by the following laboratory results, within 28 days prior to randomization
-
Participants must have a history of advanced gastric cancer (AGC), defined as unresectable and locally advanced or metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (GEJ), and must have experienced disease progression during or after first-line therapy for their disease
-
HER2-positive tumor (primary tumor or metastatic lesion) as confirmed by central laboratory HER2 testing (immunohistochemistry and/or in-situ hybridization)
-
Participants must have received at least one prior chemotherapy regimen for AGC; prior therapy does not need to have included HER2-directed therapy.
-
First-line therapy for AGC, including adenocarcinoma of the GEJ, must have included a combination of at least a platinum- and a fluoropyrimidine-based treatment given concurrently; prior therapy does not need to have included a HER2-directed therapy.
-
Adjuvant or neoadjuvant therapy for AGC is allowed.
Exclusion Criteria:
-
An interval shorter than 21 days from the last dose of chemotherapy or HER2-directed therapy until the time of randomization
-
Prior treatment with trastuzumab emtansine, docetaxel, or paclitaxel either as single agents or as part of a treatment regimen.
-
Treatment with any investigational anticancer drug within 21 days of the first study treatment administration
-
More than one prior line of therapy for advanced gastric cancer
-
History of other malignancy within the previous 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome
-
Brain metastases that are untreated or symptomatic or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 1 month of randomization
-
Peripheral neuropathy Grade >/=2
-
Uncontrolled cardiopulmonary dysfunction (e.g., high blood pressure, serious cardiac arrhythmia)
-
Other current, severe, uncontrolled systemic disease (e.g., clinically significant metabolic disease, wound healing disorders, ulcers)
-
Clinically significant bleeding within 30 days before enrollment
-
For female participants, current pregnancy or lactation
-
Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
-
Infection with Human immunodeficiency virus (HIV) or hepatitis B virus, hepatitis C virus
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Comprehensive Blood/Cancer Ctr | Bakersfield | California | United States | 93309 |
| 2 | Stanford University School of Medicine | Stanford | California | United States | 94305-5151 |
| 3 | Yale Cancer Center | New Haven | Connecticut | United States | 06520 |
| 4 | University of Kansas; Medical Center & Medical pavilion | Westwood | Kansas | United States | 66205 |
| 5 | Norton Healthcare Inc. | Louisville | Kentucky | United States | 40202 |
| 6 | Massachusetts General Hospital. | Boston | Massachusetts | United States | 02114 |
| 7 | Dana Farber Can Ins | Boston | Massachusetts | United States | 02215 |
| 8 | Weill Cornell Medical College | New York | New York | United States | 10065 |
| 9 | Vanderbilt | Nashville | Tennessee | United States | 37232 |
| 10 | University of Texas M.D. Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 11 | Fundación Investigar | Buenos Aires | Argentina | 1025 | |
| 12 | Hospital de Gastroenterologia Dr. Bonorino Udaondo ; Servicio de Oncología | Buenos Aires | Argentina | C1264AAA | |
| 13 | Instituto de Oncología de Rosario | Rosario | Argentina | S2000KZE | |
| 14 | UZ Leuven Gasthuisberg | Leuven | Belgium | 3000 | |
| 15 | Instituto Nacional de Cancer - INCa; Oncologia | Rio de Janeiro | RJ | Brazil | 20560-120 |
| 16 | Clinica de Oncologia de Porto Alegre - CliniOnco | Porto Alegre | RS | Brazil | 90430-090 |
| 17 | Hospital Sao Lucas - PUCRS | Porto Alegre | RS | Brazil | 90610-000 |
| 18 | Hospital de Cancer de Barretos | Barretos | SP | Brazil | 14784-400 |
| 19 | Hospital Amaral Carvalho | Jau | SP | Brazil | 17210-080 |
| 20 | Instituto do Cancer do Estado de Sao Paulo - ICESP | Sao Paulo | SP | Brazil | 01246-000 |
| 21 | Instituto de Oncologia de Sorocaba - CEPOS | Sorocaba | SP | Brazil | 18030-245 |
| 22 | BCCA-Vancouver Cancer Centre | Vancouver | British Columbia | Canada | V5Z 4E6 |
| 23 | Brampton Memorial Hospital, William Osler Health Center | Brampton | Ontario | Canada | L6R 3J7 |
| 24 | Toronto East General Hospital; Haematology/Oncology | Toronto | Ontario | Canada | M4C 3E7 |
| 25 | St. Michael'S Hospital | Toronto | Ontario | Canada | M5B 1W8 |
| 26 | The Affiliated Hospital of Military Medical Sciences(The 307th Hospital of Chinese PLA) | Beijing | China | 100071 | |
| 27 | Beijing Cancer Hospital | Beijing | China | 100142 | |
| 28 | Jilin Cancer Hospital | Changchun | China | 130012 | |
| 29 | the First Hospital of Jilin University | Changchun | China | 130021 | |
| 30 | Changzhou First People's Hospital | Changzhou | China | 213003 | |
| 31 | Third Affiliated Hospital of Third Military Medical University | ChongQing | China | 400042 | |
| 32 | Fujian Cancer Hospital | Fuzhou | China | 350014 | |
| 33 | Sun Yet-sen University Cancer Center | Guangzhou | China | 510060 | |
| 34 | Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University | Hangzhou | China | 310016 | |
| 35 | Harbin Medical University Cancer Hospital | Harbin | China | 150081 | |
| 36 | Jiangsu Cancer Hospital | Nanjing | China | 210009 | |
| 37 | The 81st Hospital of P.L.A. | Nanjing | China | ||
| 38 | Affiliated Hospital of Nantong University | Nantong | China | 226001 | |
| 39 | Fudan University Shanghai Cancer Center | Shanghai | China | 200032 | |
| 40 | Zhongshan Hospital Fudan University | Shanghai | China | 200032 | |
| 41 | Shanghai First People's Hospital | Shanghai | China | 200080 | |
| 42 | General Hospital of Shenyang Military Command of PLA | Shenyang | China | 110016 | |
| 43 | Union Hospital of Tongji Medical College, Dept. of Cancer Center; Cancer Center | Wuhan | China | 430023 | |
| 44 | First Affiliated Hospital of Medical College of Xi'an Jiaotong University | Xi'an | China | 710061 | |
| 45 | The Affiliated Hospital of Xuzhou Medical College | Xuzhou | China | 221004 | |
| 46 | Fakultni Nemocnice Hradec Kralove; Dept of Radiotherapy & Oncology | Hradec Kralove | Czechia | 500 05 | |
| 47 | Fakultni nemocnice Olomouc; Onkologicka klinika | Olomouc | Czechia | 779 00 | |
| 48 | Fakultni Poliklinika Vseobecne Fakultni Niemocnice; Onkologicka Klinika | Praha 2 | Czechia | 128 08 | |
| 49 | Fakultní Nemocnice V Motole; Radioterapeuticko-Onkologicke Oddeleni | Praha 5 | Czechia | 150 06 | |
| 50 | Tampere University Hospital; Dept of Oncology | Tampere | Finland | 33520 | |
| 51 | Hopital Augustin Morvan; Federation De Cancerologie | Brest | France | 29200 | |
| 52 | Hopital Beaujon; Gastro Enterologie 1 | Clichy | France | 92118 | |
| 53 | Centre Val Aurelle Paul Lamarque; Medecine A1 A2 | Montpellier | France | 34298 | |
| 54 | Hopital Saint Antoine; Hepatologie-Gastr-Enterologie | Paris | France | 75571 | |
| 55 | Hop Europeen Georges Pompidou; Gastro Enterologie | Paris | France | 75908 | |
| 56 | Hopital Robert Debre; Gastro Enterologie | Reims | France | 51092 | |
| 57 | Hopital Purpan; Unite Onco Digestive | Toulouse | France | 31059 | |
| 58 | Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo. | Berlin | Germany | 10117 | |
| 59 | Universitätsklinikum "Carl Gustav Carus"; Med. Klinik & Poliklinik I, Arbeitsgr. intern. Onkologie | Dresden | Germany | 01307 | |
| 60 | Facharztzentrum Eppendorf, Studien GbR | Hamburg | Germany | 20249 | |
| 61 | Universitätsklinikum Köln | Köln | Germany | 50937 | |
| 62 | Tagesklinik Landshut; Hämatologie/Onkologie | Landshut | Germany | 84028 | |
| 63 | Onkologische Gemeinschaftspraxis | Magdeburg | Germany | 39104 | |
| 64 | Grupo Angeles | Guatemala City | Guatemala | 01015 | |
| 65 | Centro Oncológico Sixtino / Centro Oncológico SA | Guatemala | Guatemala | 01010 | |
| 66 | Fovarosi Szent Laszlo Korhaz-Rendelointezet; Onkologiai Osztaly X | Budapest | Hungary | 1097 | |
| 67 | Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika | Szeged | Hungary | 6720 | |
| 68 | Hetenyi Geza County Hospital; Onkologiai Kozpont | Szolnok | Hungary | 5004 | |
| 69 | Zala Megyei Kórház, Külsö Kórház, Pózva; Onkológiai Osztály | Zalaegerszeg | Hungary | 8900 | |
| 70 | Campus Universitario S.Venuta; Centro Oncologico T.Campanella | Catanzaro | Calabria | Italy | 88100 |
| 71 | AZ.Osp S. Orsola - Malpighi-Reparto di Oncologia Medica | Bologna | Emilia-Romagna | Italy | 40138 |
| 72 | A.O. Città della Salute e della Scienza - Presidio Molinette; divisione oncologia medica | Torino | Piemonte | Italy | 10126 |
| 73 | Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1 | Firenze | Toscana | Italy | 50139 |
| 74 | A.O. Universitaria Pisana; Oncologia | Pisa | Toscana | Italy | 56100 |
| 75 | Aichi Cancer Center Hospital; Clinical Oncology | Aichi | Japan | 464-8681 | |
| 76 | Chiba Cancer Center; Gastroenterology | Chiba | Japan | 260-8717 | |
| 77 | National Cancer Center Hospital East; Gastroenterology | Chiba | Japan | 277-8577 | |
| 78 | National Hospital Organization Shikoku Cancer Center; Gastroenterology | Ehime | Japan | 791-0280 | |
| 79 | Hokkaido University Hospital：Gastroenterology | Hokkaido | Japan | 060-8648 | |
| 80 | Hyogo College Of Medicine; Upper Gastroenterology | Hyogo | Japan | 663-8501 | |
| 81 | Hyogo Cancer Center; Gastroenterology | Hyogo | Japan | 673-8558 | |
| 82 | Ibaraki Prefectural Central Hospital; Gastroenterology | Ibaraki | Japan | 309-1793 | |
| 83 | Tohoku Uni Hospital; Clinical Oncology | Miyagi | Japan | 980-8574 | |
| 84 | Osaka University Hospital; Surgery | Osaka | Japan | 565-0871 | |
| 85 | Kindai University Hospital; Medical Oncology | Osaka | Japan | 589-8511 | |
| 86 | Saitama Cancer Center; Gastroenterology | Saitama | Japan | 362-0806 | |
| 87 | Shizuoka Cancer Center; Gastroenterology | Shizuoka | Japan | 411-8777 | |
| 88 | Shizuoka General Hospital; Clinical Oncology | Shizuoka | Japan | 420-8527 | |
| 89 | Tochigi Cancer Center; Medical Oncology | Tochigi | Japan | 320-0834 | |
| 90 | National Cancer Center Hospital; Gastrointestinal Oncology | Tokyo | Japan | 104-0045 | |
| 91 | Toranomon Hospital; Medical Oncology | Tokyo | Japan | 105-8470 | |
| 92 | Tokyo Metropolitan Komagome Hospital; Chemotherapy | Tokyo | Japan | 113-8677 | |
| 93 | The Cancer Institute Hospital, JFCR; Gastroenterology | Tokyo | Japan | 135-8550 | |
| 94 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 | |
| 95 | Asan Medical Center; Medical Oncology | Seoul | Korea, Republic of | 05505 | |
| 96 | Samsung Medical Center | Seoul | Korea, Republic of | 06351 | |
| 97 | Yonsei University Severance Hospital; Medical Oncology | Seoul | Korea, Republic of | 120-752 | |
| 98 | Korea University Anam Hospital; Oncology Haemotology | Seoul | Korea, Republic of | 136-705 | |
| 99 | Seoul St.Mary's Hospital; Medical Oncology | Seoul | Korea, Republic of | 137-807 | |
| 100 | University Malaya Medical Centre; Clinical Oncology Unit, | Kuala Lumpur | Malaysia | 59100 | |
| 101 | Hospital Wanita dan Kanak-Kanak Sabah | Sabah | Malaysia | 88996 | |
| 102 | Centenario Hospital Miguel Hidalgo | Aguascalientes | Mexico | 20230 | |
| 103 | Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre | Chihuahua | Mexico | 31000 | |
| 104 | Hospital General de México; Unidad de Oncologia | Mexico DF | Mexico | 06726 | |
| 105 | Centro Hemato Oncologico Paitilla | Panama City | Panama | 083200752 | |
| 106 | Hospital Nacional Almanzor Aguinaga Asenjo; Unidad De Investigacion Del Servicio De Oncologia Medica | Chiclayo | Peru | CIX | |
| 107 | Hospital Nacional Adolfo Guevara Velasco | Cusco | Peru | 08006 | |
| 108 | Hospital Nacional Edgardo Rebagliati Martins | Jesus Maria | Peru | Lima 11 | |
| 109 | Instituto Nacional de Enfermedades Neoplasicas | Lima | Peru | 34 | |
| 110 | Perpetual Succour Hospital | Cebu | Philippines | 6000 | |
| 111 | Veterans Memorial Medical Ctr; Cancer Research Centre | Quezon City, Luzon | Philippines | 1101 | |
| 112 | Uniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii | Gdansk | Poland | 80-952 | |
| 113 | Szpital Uniwersytecki w Krakowie | Krakow | Poland | 31-501 | |
| 114 | Wielkopolskie Centrum Onkologii; im. Marii Skłodowskiej-Curie | Poznan | Poland | 61-866 | |
| 115 | Wojewódzki Szpital Specjalistyczny Nr 3 | Rybnik | Poland | 44-200 | |
| 116 | Centrum Onkologii - Instytut im. M. Sklodowskiej-Curie; Klinika Gastroenterologii Onkologicznej | Warszawa | Poland | 02-781 | |
| 117 | Institutul Clinic Fundeni Bucuresti | Bucharest | Romania | 022328 | |
| 118 | Spitalul Universitar CF Cluj-Napoca; Sectia Oncologie | Cluj-Napoca | Romania | 400015 | |
| 119 | Medisprof SRL | Cluj-Napoca | Romania | 400058 | |
| 120 | Spitalul Clinic Judetean Mures; Oncologie Medicala | Targu Mures | Romania | 540141 | |
| 121 | Arkhangelsk Regional Clinical Oncology Dispensary | Arkhangelsk | Russian Federation | 163045 | |
| 122 | Ivanovo Regional Oncology Dispensary | Ivanovo | Russian Federation | 153040 | |
| 123 | Omsk Region Clinical Oncology Dispensary; 1St Sergical Department | Omsk | Russian Federation | 644013 | |
| 124 | State Budget Institution of Healthcare of Stavropol region Pyatigorsk Oncology Dispensary | Pyatigorsk | Russian Federation | 357502 | |
| 125 | Tula Regional Oncology Dispensary | Tula | Russian Federation | 300053 | |
| 126 | National Cancer Centre | Singapore | Singapore | 169610 | |
| 127 | Hospital Univ. Central de Asturias; Servicio de Oncologia | Oviedo | Asturias | Spain | 33011 |
| 128 | Hospital Universitario Marques de Valdecilla; Servicio de Oncologia | Santander | Cantabria | Spain | 39008 |
| 129 | Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia | Santiago de Compostela | La Coruña | Spain | 15706 |
| 130 | Hospital Clinic i Provincial; Servicio de Farmacia | Barcelona | Spain | 08036 | |
| 131 | Hospital General Universitario Gregorio Marañon; Servicio de Oncologia | Madrid | Spain | 28007 | |
| 132 | Hospital Universitario La Paz; Servicio de Oncologia | Madrid | Spain | 28046 | |
| 133 | Hospital Universitario Virgen del Rocio; Servicio de Oncologia | Sevilla | Spain | 41013 | |
| 134 | Hospital Universitario Miguel Servet; Servicio Oncologia | Zaragoza | Spain | 50009 | |
| 135 | Kaohsiung Chang Gung Memorial Hospital; Dept of Hem and Onc | Kaohsung | Taiwan | 883 | |
| 136 | National Taiwan Uni Hospital; Dept of Oncology | Taipei | Taiwan | 100 | |
| 137 | Chang Gung Medical Foundation - Linkou; Division of Hematology- Oncology | Taoyuan | Taiwan | 333 | |
| 138 | Ataturk University Medical Faculty Yakutiye Research Hospital Medical Oncology Department | Erzurum | Turkey | 25240 | |
| 139 | Istanbul Bilim University School Of Medicine; Department Of Medical Oncology | Istanbul | Turkey | 34300 | |
| 140 | Marmara Uni Faculty of Medicine; Medical Oncology | Istanbul | Turkey | 34890 | |
| 141 | Ege Uni Medical Faculty; Oncology Dept | Izmir | Turkey | 35100 | |
| 142 | Hacettepe Uni Medical Faculty Hospital; Oncology Dept | Sıhhiye, ANKARA | Turkey | 06100 | |
| 143 | Velindre Cancer Centre; Oncology Dept | Cardiff | United Kingdom | CF14 2TL | |
| 144 | The Beatson West of Scotland Cancer Centre; Cancer Clinical Trials Unit | Glasgow | United Kingdom | G12 0YN | |
| 145 | Royal Marsden Hospital; Dept of Med-Onc | London | United Kingdom | SW3 6JJ | |
| 146 | Christie Hospital Nhs Trust; Medical Oncology | Manchester | United Kingdom | M2O 4BX | |
| 147 | Royal Marsden Hospital; Dept of Medical Oncology | Sutton | United Kingdom | SM2 5PT | |
| 148 | BRISTOL ONCOLOGY CENTRE; CLINICAL TRIALS UNIT; R & D department | Weston Super Mare | United Kingdom | BS23 4TQ |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01641939
Other Study ID Numbers:
- BO27952
- 2012-000660-22
First Posted:
Jul 17, 2012
Last Update Posted:
May 12, 2017
Last Verified:
May 1, 2017
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 415 participants were randomized, of these 117 participants in taxane arm, 228 participants in 2.4 milligram per kilogram (mg/kg) trastuzumab emtansine arm, and 70 participants in 3.6 mg/kg trastuzumab emtansine arm received at least one dose of the treatment. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 milligram per meter square (mg/m^2) intravenously (IV) on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Period Title: Overall Study | |||
| STARTED | 117 | 228 | 70 |
| Stage 1 | 37 | 75 | 70 |
| Stage 2 | 80 | 153 | 0 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 117 | 228 | 70 |
Baseline Characteristics
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg | Total |
|---|---|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Total of all reporting groups |
| Overall Participants | 117 | 228 | 70 | 415 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
62.1
(10.3)
|
60.5
(10.9)
|
61.2
(11.4)
|
61.1
(10.8)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
22
18.8%
|
51
22.4%
|
17
24.3%
|
90
21.7%
|
| Male |
95
81.2%
|
177
77.6%
|
53
75.7%
|
325
78.3%
|
Outcome Measures
| Title | Overall Survival (OS)- Phase 3 |
|---|---|
| Description | Overall survival was defined as the time between the date of randomization and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Participants for whom no death was reported prior to an analysis cutoff (30 June 2015) was censored at the latest date before the cutoff in which they were known to be alive. All data from the standard taxane therapy and trastuzumab emtansine 2.4 mg (selected treatment arm) from phase 2 and phase 3 (Stage 2) are combined into phase 3 data, and thus cumulative data are provided within the results presented for phase 3. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg). |
| Time Frame | Date of randomization until death (up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants; participants grouped according to the therapy they were randomized to receive. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 117 | 228 |
| Median (95% Confidence Interval) [months] |
8.6
|
7.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard Taxane Therapy, Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Comments | The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% Confidence Interval (CI) for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8589 |
| Comments | One sided p-value with correction for interim treatment selection due to adaptive seamless phase design. | |
| Method | Log Rank | |
| Comments | Log-Rank test, inverse normal combination test. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.15 | |
| Confidence Interval |
(2-Sided) 95% 0.87 to 1.60 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival (OS) - Phase 2 (Dose Selection Portion of the Study) |
|---|---|
| Description | Overall survival was defined as the time between the date of randomization and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Participants for whom no death was reported prior to an analysis cutoff (10 August 2013) was censored at the latest date before the cutoff in which they were known to be alive. |
| Time Frame | Date of randomization until death (up to 1 year) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population included all participants that had been enrolled in phase 2 (stage 1) up to a clinical cut-off date of 10 August 2013; participants grouped according to the therapy they were randomized to receive. Here, N (number of participants analyzed)=number of evaluable participants during phase 2 up to 10 August 2013. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 3.6 mg | Trastuzumab Emtansine 2.4 mg |
|---|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 30 | 58 | 64 |
| Median (95% Confidence Interval) [weeks] |
28.0
|
23.0
|
36.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard Taxane Therapy, Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Comments | The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.81 | |
| Confidence Interval |
(2-Sided) 95% 0.32 to 2.03 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Standard Taxane Therapy, Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Comments | The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 2.01 | |
| Confidence Interval |
(2-Sided) 95% 0.82 to 4.92 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Trastuzumab Emtansine 2.4 mg, Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Comments | The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Trastuzumab Emtansine 3.6 mg | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.47 | |
| Confidence Interval |
(2-Sided) 95% 0.23 to 0.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Disease Progression or Death According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 |
|---|---|
| Description | Progressive disease could base on symptom deterioration or was defined as at least a 20 percent (%) increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Tumor assessment was performed using modified RECIST v1.1. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants; participants grouped according to the therapy they were randomized to receive. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 117 | 228 |
| Number [percentage participants] |
88.9
76%
|
93.0
40.8%
|
| Title | Progression Free Survival (PFS) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 |
|---|---|
| Description | Progression-free survival was defined as the time between the date of randomization and the first date of documented progression or date of death due to any cause, whichever occurred first. Tumor assessment was performed using modified RECIST v1.1. Progressive disease could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Kaplan-Meier estimates were used for analysis. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg). |
| Time Frame | Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants; participants grouped according to the therapy they were randomized to receive. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 117 | 228 |
| Median (95% Confidence Interval) [months] |
2.89
|
2.66
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard Taxane Therapy, Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Comments | The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.308 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.13 | |
| Confidence Interval |
(2-Sided) 95% 0.89 to 1.43 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Objective Response According to mRECIST v1.1 - Phase 3 |
|---|---|
| Description | Objective response referred to participants with complete response (CR) or partial response (PR). CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: greater than or equal to (>=) 30% decrease in sum of the longest diameter (LD) of all target lesions taking as reference the screening sum LD. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants with measurable disease were included in analysis of this outcome measure. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 102 | 204 |
| Number (95% Confidence Interval) [percentage of participants] |
19.6
16.8%
|
20.6
9%
|
| Title | Duration of Objective Response (DOR) - Phase 3 |
|---|---|
| Description | DOR: time from the date when a clinical response [CR or PR] was first documented to the date of first documented progressive disease (PD) or death. CR:disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: >= 30% decrease in sum of the LD of all target lesions taking as reference the screening sum LD. PD: could base on symptom deterioration or at least a 20% increase in the sum of diameters of target or non-target lesions and new lesions, taking as reference the smallest sum on study (nadir), including baseline. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Date of randomization until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants evaluable for this outcome measure. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 102 | 204 |
| Median (95% Confidence Interval) [months] |
3.65
|
4.27
|
| Title | Percentage of Participants With Clinically Significant Improvement in European Organisation for Research and Treatment of Cancer Quality of Life Core Module 30 (EORTC QLQ-C30) Score - Phase 3 |
|---|---|
| Description | The EORTC QLQ-C30 is a validated, cancer-specific 30-item patient-reported measure, and contains 14 domains to assess the impact of cancer treatment on 5 aspects of participants functioning (physical, role, cognitive, emotional, and social), 9 aspects of disease/treatment-related symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) and a global QoL/overall health status scale. Questions used 4 point scale (1 'Not at all' to 4 'Very much'; with the exception of the QoL/health status scale which uses a 7-point scale (1 'very poor' to 7 'Excellent'). Each scale is transformed on a scale of 0-100; a higher score equals (=) a better level of functioning or greater degree of symptoms. Change of greater than or equal to (>=) 10-points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at follow-up (up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants with baseline and at least one post-baseline valid score. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 91 | 189 |
| Global Health Status/QoL |
44.0
37.6%
|
34.4
15.1%
|
| Appetite loss |
39.6
33.8%
|
30.2
13.2%
|
| Cognitive Functioning |
31.9
27.3%
|
28.0
12.3%
|
| Constipation |
40.7
34.8%
|
25.9
11.4%
|
| Diarrhoea |
23.1
19.7%
|
21.7
9.5%
|
| Dyspnea |
19.8
16.9%
|
21.7
9.5%
|
| Emotional Functioning |
24.2
20.7%
|
29.1
12.8%
|
| Fatigue |
46.2
39.5%
|
40.7
17.9%
|
| Nausea/Vomiting |
33.0
28.2%
|
28.0
12.3%
|
| Pain |
49.5
42.3%
|
33.9
14.9%
|
| Physical Functioning |
17.6
15%
|
25.9
11.4%
|
| Role Functioning |
29.7
25.4%
|
30.7
13.5%
|
| Social Functioning |
34.1
29.1%
|
37.6
16.5%
|
| Insomnia |
33.0
28.2%
|
33.3
14.6%
|
| Title | Percentage of Participants With Clinically Significant Improvement in Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) Score - Phase 3 |
|---|---|
| Description | The Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) supplements the EORTC QLQ-C30 to assess symptoms and treatment-related side effects commonly reported in participants. There are 22 questions which comprise 5 scales (dysphagia, pain, reflux symptom, dietary restrictions, and anxiety) and 4 single items (dry mouth, hair loss, taste, body image). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. Change of >=10 points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants with baseline and at least one post-baseline valid score. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 90 | 185 |
| Overall |
88.9
76%
|
88.1
38.6%
|
| Body image |
20.0
17.1%
|
29.7
13%
|
| Dry Mouth |
30.0
25.6%
|
21.1
9.3%
|
| Dietary Restrictions |
41.1
35.1%
|
32.4
14.2%
|
| Dysphagia |
35.6
30.4%
|
23.8
10.4%
|
| Hair Loss |
11.1
9.5%
|
22.7
10%
|
| Pain/discomfort |
52.2
44.6%
|
45.4
19.9%
|
| Specific Emotional Problems |
63.3
54.1%
|
57.8
25.4%
|
| Upper Gastrointestinal Symptoms |
46.7
39.9%
|
42.7
18.7%
|
| Title | Percentage of Participants With Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 |
|---|---|
| Description | AGC symptomatic progression: a worsening of >=10-points in any 1 of the abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and/or weight loss scales of the EORTC QLQ-C30 and QLQ-STO22. QLQ-STO22 supplements EORTC QLQ-C30 to assess symptoms and commonly reported treatment-related side effects. There are 22 questions comprise 5 scales (dysphagia, pain, reflux symptom, diet restrictions, anxiety), 4 single items (dry mouth, hair loss, taste, body image), which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'). All scores and single-items transformed to a scale of 0-100; higher score=better level of functioning or greater degree of symptoms. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants evaluable for this measure. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 117 | 228 |
| Number [percentage of participants] |
90.6
77.4%
|
93.0
40.8%
|
| Title | Time to Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 |
|---|---|
| Description | Time to AGC symptom were defined as the time from randomization to the first documentation of an increase in at least one of the pre-specified abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and weight loss subscales of the QLQ STO22 and EORTC QLQ-C30. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. |
| Time Frame | Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants, participants grouped according to the therapy they were randomized to receive. Here, N=number of participants evaluable for this measure. |
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg |
|---|---|---|
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 117 | 228 |
| Median (95% Confidence Interval) [months] |
1.61
|
1.51
|
| Title | Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 1 |
|---|---|
| Description | Maximum observed plasma concentration of Trastuzumab Emtansine (T-DM1) and total trastuzumab were reported. Stage 1 consists of all participants recruited before the regimen selection, which was carried out after 12 weeks of randomization. |
| Time Frame | Day 1 (D1) of Cycle 1 (C1) and C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. Here, n=number of participants evaluable at specified timepoint. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 41 | 37 |
| T-DM1 Cycle 1 First Dose (n=41, 37) |
43.0
(11.8)
|
58.6
(12.9)
|
| T-DM1 Cycle 4 First Dose (n=25, 10) |
52.6
(19.4)
|
61.6
(14.5)
|
| Total trastuzumab Cycle 1 First Dose (n=41, 37) |
46.8
(12.3)
|
61.2
(14.6)
|
| Total trastuzumab Cycle 4 First Dose (n=25, 10) |
71.2
(23.2)
|
66.3
(14.7)
|
| Title | Maximum Observed Plasma Concentration (Cmax) of N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) - Stage 1 |
|---|---|
| Description | Maximum observed plasma concentration of DM1 were reported. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization. |
| Time Frame | C1D1 and C1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. Here, n=number of participants evaluable at specified timepoint. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 40 | 35 |
| DM1 Cycle 1 First Dose (n=40, 35) |
2.47
(1.05)
|
4.61
(6.26)
|
| DM1 Cycle 4 First Dose (n=22, 9) |
3.41
(1.61)
|
3.86
(0.83)
|
| Title | Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 2 |
|---|---|
| Description | Stage 2 consists of all participants recruited after the regimen selection decision up to primary data cut-off date 30-June-2015. |
| Time Frame | C1D1; C4D1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. Here, n=number of participants evaluable at specified timepoint. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg |
|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 57 |
| T-DM1 Cycle 1 First Dose (n=56) |
34.1
(15.2)
|
| T-DM1 Cycle 4 First Dose (n=26) |
38.0
(13.4)
|
| Total trastuzumab Cycle 1 First Dose (n=57) |
44.5
(15.4)
|
| Total trastuzumab Cycle 4 First Dose (n=26) |
69.7
(21.3)
|
| Title | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] - Stage 1 |
|---|---|
| Description | AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization. |
| Time Frame | D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 41 | 37 |
| T-DM1 |
179
(51.0)
|
262
(90.3)
|
| Total trastuzumab |
289
(129)
|
403
(237)
|
| Title | Plasma Decay Half-Life (t1/2) - Stage 1 |
|---|---|
| Description | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization. |
| Time Frame | D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 41 | 37 |
| T-DM1 |
3.48
(0.747)
|
3.33
(1.21)
|
| Total trastuzumab |
5.22
(1.53)
|
5.40
(2.15)
|
| Title | Volume of Distribution at Steady State (Vss) - Stage 1 |
|---|---|
| Description | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization. |
| Time Frame | D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 41 | 37 |
| T-DM1 |
66.2
(19.2)
|
67.7
(14.0)
|
| Total trastuzumab |
65.9
(21.9)
|
72.1
(16.1)
|
| Title | Systemic Clearance (CL) - Stage 1 |
|---|---|
| Description | CL is a quantitative measure of the rate at which a drug substance is removed from the body. Stage 1 consists of all participants recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomization. |
| Time Frame | D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who had at least one PK parameter estimated were included for analysis. |
| Arm/Group Title | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg |
|---|---|---|
| Arm/Group Description | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. |
| Measure Participants | 41 | 37 |
| T-DM1 |
14.6
(4.64)
|
15.4
(5.61)
|
| Total trastuzumab |
10.2
(4.87)
|
11.3
(5.46)
|
Adverse Events
| Time Frame | Baseline up to data cut-off date 30-April-2016 (up to 3 years 8 months) | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety Analysis Population included all participants who received at least one dose of study medication. The safety parameters were analyzed and presented according to the therapy participants received. Cumulative data (up to primary analysis cut-off date of 30-April-2016) are provided for both phase 2 and phase 3. | |||||
| Arm/Group Title | Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg | |||
| Arm/Group Description | Docetaxel was administered at 75 mg/m^2 IV on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or participants and/or physician decision to discontinue. | |||
All Cause Mortality |
||||||
| Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 31/111 (27.9%) | 65/224 (29%) | 23/69 (33.3%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 3/111 (2.7%) | 8/224 (3.6%) | 2/69 (2.9%) | |||
| Coagulopathy | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Disseminated intravascular coagulation | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Febrile neutropenia | 4/111 (3.6%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Neutropenia | 3/111 (2.7%) | 0/224 (0%) | 0/69 (0%) | |||
| Thrombocytopenia | 0/111 (0%) | 3/224 (1.3%) | 0/69 (0%) | |||
| Cardiac disorders | ||||||
| Atrial fibrillation | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Cardiac failure | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Supraventricular tachycardia | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 1/111 (0.9%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Diarrhoea | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Dysphagia | 1/111 (0.9%) | 2/224 (0.9%) | 1/69 (1.4%) | |||
| Gastric haemorrhage | 2/111 (1.8%) | 6/224 (2.7%) | 4/69 (5.8%) | |||
| Gastric ulcer haemorrhage | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Gastrointestinal haemorrhage | 1/111 (0.9%) | 5/224 (2.2%) | 0/69 (0%) | |||
| Gastrointestinal ulcer | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Haematemesis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Ileus | 0/111 (0%) | 2/224 (0.9%) | 1/69 (1.4%) | |||
| Intestinal obstruction | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Jejunal perforation | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Lower gastrointestinal haemorrhage | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Nausea | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Oesophageal haemorrhage | 0/111 (0%) | 3/224 (1.3%) | 0/69 (0%) | |||
| Oesophageal stenosis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Pancreatitis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Regurgitation | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Small intestinal haemorrhage | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Upper gastrointestinal haemorrhage | 0/111 (0%) | 8/224 (3.6%) | 1/69 (1.4%) | |||
| Vomiting | 1/111 (0.9%) | 1/224 (0.4%) | 1/69 (1.4%) | |||
| General disorders | ||||||
| Death | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Fatigue | 2/111 (1.8%) | 0/224 (0%) | 0/69 (0%) | |||
| General physical health deterioration | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Pyrexia | 1/111 (0.9%) | 2/224 (0.9%) | 3/69 (4.3%) | |||
| Hepatobiliary disorders | ||||||
| Bile duct stenosis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Cholangitis acute | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Immune system disorders | ||||||
| Anaphylactic reaction | 2/111 (1.8%) | 0/224 (0%) | 0/69 (0%) | |||
| Hypersensitivity | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Infections and infestations | ||||||
| Atypical pneumonia | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Cellulitis | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Device related infection | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Escherichia infection | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Gastrointestinal infection | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Infection | 0/111 (0%) | 2/224 (0.9%) | 0/69 (0%) | |||
| Lower respiratory tract infection | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Lung abscess | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Lung infection | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Meningitis | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Pneumonia | 5/111 (4.5%) | 7/224 (3.1%) | 2/69 (2.9%) | |||
| Respiratory tract infection | 1/111 (0.9%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Sepsis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Septic shock | 0/111 (0%) | 2/224 (0.9%) | 0/69 (0%) | |||
| Staphylococcal sepsis | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Urinary tract infection | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Intervertebral discitis | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Facial bones fracture | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Fall | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Overdose | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Investigations | ||||||
| Blood bilirubin increased | 0/111 (0%) | 4/224 (1.8%) | 0/69 (0%) | |||
| Blood creatinine increased | 0/111 (0%) | 2/224 (0.9%) | 0/69 (0%) | |||
| Hepatic enzyme increased | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Liver function test abnormal | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Dehydration | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Diabetes mellitus | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Hyperglycaemia | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Hypophagia | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Myalgia | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Bladder transitional cell carcinoma | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Myelodysplastic syndrome | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Tumour haemorrhage | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Nervous system disorders | ||||||
| Encephalopathy | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Hepatic encephalopathy | 0/111 (0%) | 2/224 (0.9%) | 0/69 (0%) | |||
| Metabolic encephalopathy | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Subarachnoid haemorrhage | 0/111 (0%) | 0/224 (0%) | 1/69 (1.4%) | |||
| Syncope | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Psychiatric disorders | ||||||
| Confusional state | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/111 (0%) | 1/224 (0.4%) | 1/69 (1.4%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Interstitial lung disease | 1/111 (0.9%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Pleural effusion | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Pneumonia aspiration | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Pneumonitis | 1/111 (0.9%) | 2/224 (0.9%) | 0/69 (0%) | |||
| Pulmonary alveolar haemorrhage | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Pulmonary embolism | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Pulmonary oedema | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Respiratory failure | 1/111 (0.9%) | 0/224 (0%) | 0/69 (0%) | |||
| Aspiration | 0/111 (0%) | 1/224 (0.4%) | 0/69 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Standard Taxane Therapy | Trastuzumab Emtansine 2.4 mg | Trastuzumab Emtansine 3.6 mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 105/111 (94.6%) | 211/224 (94.2%) | 62/69 (89.9%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 35/111 (31.5%) | 75/224 (33.5%) | 15/69 (21.7%) | |||
| Febrile neutropenia | 7/111 (6.3%) | 1/224 (0.4%) | 0/69 (0%) | |||
| Leukopenia | 10/111 (9%) | 2/224 (0.9%) | 1/69 (1.4%) | |||
| Neutropenia | 55/111 (49.5%) | 24/224 (10.7%) | 7/69 (10.1%) | |||
| Thrombocytopenia | 3/111 (2.7%) | 60/224 (26.8%) | 18/69 (26.1%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal distension | 4/111 (3.6%) | 10/224 (4.5%) | 6/69 (8.7%) | |||
| Abdominal pain | 12/111 (10.8%) | 42/224 (18.8%) | 10/69 (14.5%) | |||
| Abdominal pain upper | 8/111 (7.2%) | 19/224 (8.5%) | 6/69 (8.7%) | |||
| Constipation | 22/111 (19.8%) | 47/224 (21%) | 10/69 (14.5%) | |||
| Diarrhoea | 27/111 (24.3%) | 33/224 (14.7%) | 10/69 (14.5%) | |||
| Dry mouth | 2/111 (1.8%) | 20/224 (8.9%) | 4/69 (5.8%) | |||
| Dyspepsia | 11/111 (9.9%) | 17/224 (7.6%) | 6/69 (8.7%) | |||
| Dysphagia | 4/111 (3.6%) | 9/224 (4%) | 4/69 (5.8%) | |||
| Nausea | 30/111 (27%) | 57/224 (25.4%) | 15/69 (21.7%) | |||
| Stomatitis | 21/111 (18.9%) | 14/224 (6.3%) | 3/69 (4.3%) | |||
| Vomiting | 15/111 (13.5%) | 41/224 (18.3%) | 17/69 (24.6%) | |||
| General disorders | ||||||
| Asthenia | 9/111 (8.1%) | 39/224 (17.4%) | 9/69 (13%) | |||
| Chills | 2/111 (1.8%) | 12/224 (5.4%) | 4/69 (5.8%) | |||
| Fatigue | 51/111 (45.9%) | 68/224 (30.4%) | 24/69 (34.8%) | |||
| Malaise | 5/111 (4.5%) | 12/224 (5.4%) | 1/69 (1.4%) | |||
| Mucosal inflammation | 7/111 (6.3%) | 8/224 (3.6%) | 1/69 (1.4%) | |||
| Oedema peripheral | 16/111 (14.4%) | 14/224 (6.3%) | 5/69 (7.2%) | |||
| Pain | 11/111 (9.9%) | 6/224 (2.7%) | 3/69 (4.3%) | |||
| Pyrexia | 17/111 (15.3%) | 44/224 (19.6%) | 11/69 (15.9%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 4/111 (3.6%) | 21/224 (9.4%) | 5/69 (7.2%) | |||
| Aspartate aminotransferase increased | 5/111 (4.5%) | 36/224 (16.1%) | 10/69 (14.5%) | |||
| Blood alkaline phosphatase increased | 3/111 (2.7%) | 8/224 (3.6%) | 5/69 (7.2%) | |||
| Blood bilirubin increased | 3/111 (2.7%) | 13/224 (5.8%) | 1/69 (1.4%) | |||
| Weight decereased | 8/111 (7.2%) | 13/224 (5.8%) | 3/69 (4.3%) | |||
| Metabolism and nutrition disorders | ||||||
| Deceased appetite | 32/111 (28.8%) | 57/224 (25.4%) | 22/69 (31.9%) | |||
| Hypoalbuminaemia | 5/111 (4.5%) | 13/224 (5.8%) | 3/69 (4.3%) | |||
| Hypokalaemia | 1/111 (0.9%) | 22/224 (9.8%) | 3/69 (4.3%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 13/111 (11.7%) | 13/224 (5.8%) | 6/69 (8.7%) | |||
| Back pain | 6/111 (5.4%) | 13/224 (5.8%) | 6/69 (8.7%) | |||
| Myalgia | 18/111 (16.2%) | 13/224 (5.8%) | 6/69 (8.7%) | |||
| Nervous system disorders | ||||||
| Dizziness | 5/111 (4.5%) | 14/224 (6.3%) | 5/69 (7.2%) | |||
| Dysgeusia | 11/111 (9.9%) | 18/224 (8%) | 5/69 (7.2%) | |||
| Headache | 6/111 (5.4%) | 24/224 (10.7%) | 2/69 (2.9%) | |||
| Neuropathy peripheral | 11/111 (9.9%) | 22/224 (9.8%) | 2/69 (2.9%) | |||
| Peripheral sensory neuropathy | 22/111 (19.8%) | 21/224 (9.4%) | 4/69 (5.8%) | |||
| Psychiatric disorders | ||||||
| Depression | 0/111 (0%) | 5/224 (2.2%) | 4/69 (5.8%) | |||
| Insominia | 10/111 (9%) | 18/224 (8%) | 5/69 (7.2%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 12/111 (10.8%) | 13/224 (5.8%) | 7/69 (10.1%) | |||
| Dyspnoea | 9/111 (8.1%) | 21/224 (9.4%) | 10/69 (14.5%) | |||
| Hiccups | 8/111 (7.2%) | 5/224 (2.2%) | 6/69 (8.7%) | |||
| Epistaxis | 6/111 (5.4%) | 26/224 (11.6%) | 7/69 (10.1%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 57/111 (51.4%) | 7/224 (3.1%) | 1/69 (1.4%) | |||
| Nail disorder | 7/111 (6.3%) | 4/224 (1.8%) | 0/69 (0%) | |||
| Palmar-plantar erythrodysaesthesia syndrome | 8/111 (7.2%) | 8/224 (3.6%) | 2/69 (2.9%) | |||
| Pruritus | 11/111 (9.9%) | 7/224 (3.1%) | 4/69 (5.8%) | |||
| Rash | 12/111 (10.8%) | 15/224 (6.7%) | 3/69 (4.3%) | |||
Limitations/Caveats
The study was terminated by the Sponsor as the primary analysis results did not meet the primary endpoint.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-LaRoche |
| Phone | 800-821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01641939
Other Study ID Numbers:
- BO27952
- 2012-000660-22
First Posted:
Jul 17, 2012
Last Update Posted:
May 12, 2017
Last Verified:
May 1, 2017