| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive metastatic breast cancer and HER2-positive locally advanced or metastatic gastric cancer. |
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| E.1.1.1 | Medical condition in easily understood language |
HER2-positive metastatic breast cancer (progressed/relapsed on trastuzumab and chemotherapy) and HER2-positive inoperable gastric cancer or gastric cancer, which spread to other organs or tissues.
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066896 |
| E.1.2 | Term | HER-2 positive gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I: To determine the Maximum Tolerated Dose (MTD) of the combination of trastuzumab emtansine and capecitabine in HER2-positive metastatic breast cancer (mBC) and locally advanced/metastatic gastric cancer (mGC) patients.
Phase II (mBC): To explore the efficacy of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone in HER2-positive mBC patients, as measured by Overall Response Rate (ORR) by RECIST v.1.1 per investigator local assessment. Phase II will be conducted in mBC patients only. |
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| E.2.2 | Secondary objectives of the trial |
Phase I: Pharmacokinetics (PK) of trastuzumab emtansine, capecitabine, and their metabolites. Safety of the combination of trastuzumab emtansine and capecitabine. Overall Response Rate (ORR).
Phase II (mBC):
• Safety profile of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone
• To explore the efficacy of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone in mBC patients, as measured by: 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) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For mBC Patients:
1. Male or female
2. Age ≥ 18 years old
3.Signed informed consent before any study-specific procedure
4.Able and willing to comply with protocol
5.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
6.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 7 months after the last dose of study treatment (see Section 5.2.4)
7.ECOG performance status of 0, 1, or 2
8.Blood: a)Platelet count > 100,000 cells/mm3
b)International normalized ratio (INR) < 1.5
c)Absolute neutrophil count (ANC) > 1,500 cells/mm3
d)Hemoglobin > 9.0 g/dL. Patients are allowed to have received transfusion to achieve this level.
9.Liver function:
a)Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤1.5 × ULN in patients with documented Gilbert’s syndrome.
b)Serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (ALT) ≤ 2.5 × ULN
c)Alkaline phosphatase ≤ 2.5 × ULN. In patients with bone metastases: alkaline phosphatase ≤ 5 × ULN
d) Evidence of stable liver function during the month prior to enrollment with liver function test (LFT) fluctuations not exceeding 2.5 × ULN (for AST, ALT) and 1.5 × ULN (for total bilirubin).
10.Renal function:
a)Serum creatinine of < 177 µmol/L or calculated creatinine CL > 50 mL/min. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hours
11.Cardiac function:
a)LVEF ≥ 50% by echocardiogram (ECHO) or multiple-gated acquisition (scan) (MUGA)
12.Life expectancy ≥12 weeks
13.Histologically or cytologically confirmed breast cancer
14.HER2-positive disease, defined as IHC 3+ or ISH positive
15.Tumor block or 8 slides available for retrospective central confirmation of HER2-positivity (central confirmation not necessary for enrollment)
16.Metastatic breast cancer (mBC) with at least one measurable lesion according to RECIST v.1.1
17.Disease progression on at least one prior regimen containing trastuzumab and chemotherapy either separately or in combination.
Patients may be eligible to receive study therapy in the first-line setting if trastuzumab and chemotherapy were given in the [neo] adjuvant setting.
18.Patients must have recovered from previous treatments
For mGC Patients: Inclusion criteria 1-12 same as mBC.
13.Histologically or cytologically confirmed mGC or locally advanced gastric cancer.
14.HER2 positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or IHC 2+ and 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.
15. Inoperable locally advanced/mGC |
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| E.4 | Principal exclusion criteria |
For mBC Patients:
1. Prior treatments before first study treatment
a)Investigational therapy within ≤ 28 days or 5 half-lives, whichever is longest
b)Hormonal therapy within 14 days
c)Trastuzumab within 21 days
2.Prior treatment with trastuzumab emtansine or 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 or unexpected reactions to fluoropyrimidine or 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, Lapp lactase deficiency, or glucose-galactose malabsorption
c)Known complete absence of dihydropyrimidine dehydrogenase activity
6.History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any component of the product.
7.History of exposure to the following cumulative doses of anthracyclines:
a)Doxorubicin or liposomal doxorubicin > 500 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 500 mg/m2 doxorubicin.
8.Brain metastases that are symptomatic, or require any radiation, surgery, or steroid therapy to control symptoms within 28 days before first study drug administration
9.Current peripheral neuropathy of Grade ≥ 3 according to 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 currently requiring 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 HIV, HBV, and/or HCV
a)For patients who are known carriers of 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 mBC is not allowed if:
a)The last fraction of radiotherapy has been administered within 14 days prior to first study drug administration (28 days for patients with radiotherapy to control symptoms of brain metastases, see exclusion criterion 8).
b)More than 25% of marrow-bearing bone has been irradiated.
c)Any acute toxicity has not resolved to Grade ≤ 1 before first study drug administration.
For mGC Patients: Exclusion criteria 1-20 same as mBC.
21.Previous chemotherapy for advanced/metastatic disease
a)Prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrollment into the study
22.Lapatinib ≤ 14 days before first study drug administration
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I (mBC): Maximum Tolerated Dose Finding of Trastzumab Emtansine and Capecitabine in Metastatic Breast Cancer
Phase II (mBC): ORR by Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1 per investigators local assessment
Phase I (LA/ mGC): To determine the MTD of the combination of trastuzumab emtansine and capecitabine in patients with LA/ mGC
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I, mBC and LA/ 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: final analysis of BOR will be done when 70% of the patients have experienced a PFS event or at the end of the trial, whichever comes first. It is estimated that 70% of patients will have experienced a PFS event approximately 26 months after the randomization of the first patient. The EOS analysis (appproximately 24 months after the last patient is randomized) will include an updated analysis of BOR, which will be done in a purely exploratory manner.
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| E.5.2 | Secondary end point(s) |
Phase I (mBC):
•Pharmacokinetics (PK) of trastuzumab emtansine, capecitabine and their metabolites
•Safety of the combination of trastuzumab emtansine and capecitabine
•Overall response rate (ORR)
Phase II (mBC):
•To assess the safety profile of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone
•To explore the efficacy of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone in mBC patients, as measured by:
•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 (LA/ mGC):
•PK of trastuzumab emtansine, capecitabine and their metabolites
•Safety of the combination of trastuzumab emtansine and capecitabine
•ORR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I (mBC and LA/ mGC) and Phase II, (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.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| France |
| Germany |
| Greece |
| Italy |
| Lebanon |
| Peru |
| Portugal |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Patient Last Visit (LPLV) at the end of the follow-up period as defined in Section 3.1.1 of the study protocol. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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