Her2 postive metastatic breast cancer and Her2 positive locally advanced or metastatic gastric cancer. MedDRA version: 14.1 Level: LLT Classification code 10066896 Term: HER-2 positive gastric cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 14.1 Level: LLT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: trastuzumab emtansine (T-DM1)
Product Code: RO530-4020/F02-01
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: trastuzumab emtansine
CAS Number:
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For mBC Patients: 1.Age ? 18 years old 2.Signed informed consent prior to any study specific procedure 3.Able and willing to comply with protocol 4.Negative serum pregnancy test for women of childbearing potential (including pre menopausal women who have had a tubal ligation) and for all women not meeting the definition of postmenopausal ( ? 12 months of amenorrhea), and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential 5.For women of childbearing potential and men with partners of childbearing potential, agreement by the patient and/or partner to use a highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment (see Section 5.2.4) 6.ECOG performance status of 0, 1, or 2 7.Blood: a)Platelet count > 100,000 cells/mm3 b)International normalized ratio (INR) 1500 cells/mm3 d)Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve this level. 8.Liver function: a)Total bilirubin ? 1.5 × ULN except in patients with previously documented Gilbert?s syndrome in which case total bilirubin ? 3 mg/dL is acceptable b)Serum glutamic oxaloacetic transaminase (SGOT)/AST and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (ALT) ? 2.5 × the ULN c)Alkaline phosphatase ? 2.5 × the ULN. Patients with hepatic and/or bone metastases: alkaline phosphatase ? 5 × the ULN 9.Renal function: a)Serum creatinine of 50 mL/min. I urine dipstick for proteinuria is ? 2+ at baseline, the patient must undergo 24 hour urine collection and demonstrate ? 1 g of protein/24 hours 10.Cardiac function: a)LVEF ? 50% by echocardiogram (ECHO) or multiple gated acquisition (scan) (MUGA) 11.Histologically or cytologically confirmed breast cancer 12.HER2-positive disease IHC 3+ or ISH positive 13.Tumor block available or 15 slides for retrospective central confirmation of HER2-positivity (central confirmation not necessary for enrolment) 14.Metastatic breast cancer (mBC) with at least one measurable lesion according to RECIST 15.Disease progression on at least one regimen containing trastuzumab and chemotherapy 16.Patients must have recovered from previous treatments For mGC Patients: Inclusion criterias 1-10 same as mBC. 11.Histologically or cytologically confirmed GC 12.HER2 positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ alone or IHC 2+ in combination with ISH+, prospectively confirmed by a Sponsor-designated central laboratory prior to enrollment. ISH positivity is defined as a ratio of ? 2.0 for the number of HER2 gene copies to the number of signals for CEP17. a)Archival tumor samples obtained from primary or metastatic sites are acceptable. b)Invasive tumor for central confirmation of HER2 status is required. c)A formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5 mm of invasive tumor for central confirmation is preferred. If FFPE tissue blocks (or partial block) are unavailable due to country or site regulations, a minimum of 8 freshly cut unstained slides MUST be available for central review of HER2 status. 13. Inoperable locally advan
Exclusion criteria
Exclusion criteria: For mBC Patients: 1. Prior treatments before first study treatment a)Investigational therapy within ? 28 days or 5 half lives, whatever is longest b)Hormonal therapy within 14 days c)Trastuzumab within 21 days 2.Prior enrollment in a trastuzumab emtansine?containing study, regardless of whether the patient received prior trastuzumab emtansine 3.Prior treatment with capecitabine 4.History of severe and unexpected reactions to fluoropyrimidine or with known hypersensitivity to fluorouracil 5.Related capecitabine contraindications: a)Treatment with sorivudine or its chemically related analogues, such as brivudine b)Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption 6.History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins 7.History of exposure to the following cumulative doses of anthracyclines: a)Doxorubicin or liposomal doxorubicin > 360 mg/m2 b)Epirubicin > 900 mg/m2 c)Mitoxantrone > 120 mg/m2 d)If another anthracycline, or more than one anthracycline, has been used, the cumulative dose must not exceed the equivalent of 360 mg/m2 doxorubicin. 8.Brain metastases that are symptomatic, or require any radiation, surgery, or steroid therapy to control their symptoms within 28 days of first study drug administration 9.Current peripheral neuropathy of Grade ? 3 per the NCI CTCAE, v4.0 10.History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those mentioned above 11.Current unstable ventricular arrhythmia requiring treatment 12.History of symptomatic CHF (New York Heart Association [NYHA] Classes II?IV) 13.History of myocardial infarction or unstable angina within 6 months prior to first study drug administration 14.History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment 15.Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy 16.Clinically significant malabsorption syndrome or inability to take oral medication 17.Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) 18.Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment 19.Current pregnancy or lactation 20.Current known active infection with human influenca virus (HIV), hepatitis B, and/or hepatitis C virus a)For patients who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled out based on negative serologic testing and/or determination of HBV DNA viral load per local guidelines 21.Lapatinib ? 14 days before first study drug administration 22.Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or mBC is not allowed if: a)The last fraction of radiotherapy has been administered within 14 days prior to first study drug administration. b)More than 25% of marrow-bearing bone has been irradiated. c)The patient has not recovered from any resulting acute toxicity to Grade ? 1 prior to first study drug administration. For mGC Patients: Exclusion criterias 1- 20 same as mBC. 21.Previous chemotherapy for advanced/metastatic disease a)Prior adjuvant/neoadjuvant ther
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: To determine the Maximum Tolerated Dose (MTD) of the combination of trastuzumab emtansine and capecitabine in metastatic breast cancer (mBC) and metastatic gastric cancer (mGC) patients. Phase 2: ORR by investigator assessment. Phase II will be conducted in mBC patients only. The primary objectives are reaching the MTD and establishing a safety profile.;Secondary Objective: Phase 1: Pharmacokinetics (PK) of trastuzumab emtansine and metabolites and capecitabine, Safety of the combination of trastuzumab emtansine and capecitabine, Overall Response Rate (ORR) Phase 2: Phase II will be conducted in mBC patients only. Safety profile of the combination at the dose established during Phase I, Time to response (TTR), Duration of response (DoR), Time to progression (TTP), Time to treatment failure (TTF), Progression free survival (PFS), Clinical benefit rate (CBR), Overall survival (OS);Primary end point(s): Phase I: Maximum Tolerated Dose Finding of Trastzumab Emtansine and Capecitabine in Metastatic Breast Cancer Primary Objective ?To determine the Maximum Tolerated Dose (MTD) of the combination of trastuzumab emtansine and capecitabine in metastatic breast cancer (mBC) patients Phase II: Exploration of Efficacy: mBC Primary Objective: ?ORR by investigator assessment Phase I: MTD Finding of Trastzumab Emtansine and Capecitabine in Metastatic Gastric Cancer Primary Objective ?To determine the MTD of the combination of trastuzumab emtansine and capecitabine in metastatic gastric cancer (mGC) patients;Timepoint(s) of evaluation of this end point: Phase I, mBC and mGC: time for endpoint assessment dependent on number of dose levels required to reach MTD however determination of MTD expected within 1 year of FPI) Phase II, mBC: all analysis in phase II will be done at the time all patients have been followed up until intolerable toxicity, withdrawn consent, death or up to a maximum of 2 years after the last patient was enrolled in the Phase II pa | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I: Maximum Tolerated Dose Finding of Trastzumab Emtansine and Capecitabine in Metastatic Breast Cancer ?Pharmacokinetics (PK) of trastuzumab emtansine and metabolites and capecitabine ?Safety of the combination of trastuzumab emtansine and capecitabine ?Overall Response Rate (ORR) Phase II: Exploration of Efficacy: mBC ?Safety profile of the combination at the dose established during Phase I ?Time to response (TTR) ?Duration of response (DoR) ?Time to progression (TTP) ?Time to treatment failure (TTF) ?Progression free survival (PFS) ?Clinical benefit rate (CBR) ?Overall survival (OS) Phase I: MTD Finding of Trastzumab Emtansine and Capecitabine in Metastatic Gastric Cancer ?PK of trastuzumab emtansine and metabolites and capecitabine ?Safety of the combination of trastuzumab emtansine and capecitabineOverall Response Rate (ORR);Timepoint(s) of evaluation of this end point: Phase I, mBC: Final analysis will be done after all patients will be followed up until intolerable toxicity, withdrawn consent, death or up to a maximum of 2 years after the last patient was enrolled in the Phase II part of the study whichever occurs first. Phase II, mBC: all analysis in phase II will be done at the time all patients have been followed up until intolerable toxicity, withdrawn consent, death or up to a maximum of 2 years after the last patient was enrolled in the Phase II part of the study whichever occurs first. Phase II: Final analysis will be done after all patients will be followed up until intolerable toxicity, withdrawn consent, death or up to a maximum of 2 years after the last patient was enrolled in the Phase II part of the study whichever occurs first. | — |
Countries
Canada, France, Germany, Greece, Italy, Portugal, Slovakia, Spain
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd.
Outcome results
None listed