E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Solid tumors (part 1) and metastatic/locally advanced breast cancer (part 2) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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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 |
Part 1: The primary objectives of Part 1 are to assess the safety and tolerability, and to define the MTD of neratinib in combination with capecitabine in subjects with advanced solid tumors.
Part 2: The primary objective of Part 2 of this study is to confirm that MTD identified in Part 1 by collecting further data on the safety and tolerability of the combination of neratinib and capecitabine at the MTD in subjects with erbB-2 positive breast cancer.
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E.2.2 | Secondary objectives of the trial |
Part 1: The secondary objective of Part 1 is to obtain preliminary anti-tumor activity for neratinib + capecitabine.
Part 2: The secondary objectives of Part 2 are to obtain PK information, and to assess additional efficacy parameters including Objective Response Rate (ORR=CR+PR), Progression Free Survival (PFS), Clinical benefit Rate (CR + PR +SD≥24 weeks), and duration of response for the combination of neratinib plus capecitabine.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male (part 1 only) and female subjects aged 18 years or older.
2. Subjects enrolled in Part 1 must have confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which neratinib plus capecitabine is a reasonable treatment option.
3. Subjects enrolled in Part 2 must have a histologically and/or cytologically confirmed diagnosis of breast cancer, metastatic or locally advanced.
4. Subjects enrolled in Part 2 must have erbB-2 gene amplified tumor. Documentation of erbB-2 status by FISH or CISH, or erbB-2 overexpression (IHC 3+, or IHC2+ with FISH or CISH confirmation) based on local testing is accepted. Otherwise, tumor tissue must be available and adequate for centralized FISH testing prior to study day 1. In case of more than one result, the status retrieved on the most recent biopsy should be used.
5. Subjects enrolled in Part 2 must have disease progression on or following at least 1 prior trastuzumab containing treatment regimen (at least 6 weeks) for metastatic or locally advanced disease. (Prior adjuvant trastuzumab is allowed but not required). A 2 week period is required between the last dose of trastuzumab treatment and first dose of the test article.
6. Subjects enrolled in Part 2 must have received prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, and/or metastatic disease treatment setting.
7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. (please note: ascites, pleural or pericardal effusion, osteoblastic bone metastases, and carcinomatous lymphangitis of the lung will not be considered measurable lesions). Subjects with skin lesions that are measurable by CT scans or MRI as the only site of measurable disease are allowed.
8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2, not declining within two weeks before informed consent signing.
9. Recovery from all clinically significant adverse effects related to prior therapies (excluding alopecia).
10. Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multi-gated acquisition (MUGA) or echocardiogram (ECHO).
11. Screening laboratory values within the following parameters: - ANC: ≥ 1.5 × 109/L (1,500/mm3) - Platelet count: ≥ 75 × 109/L (75,000/mm3) - Hemoglobin: ≥ 9.0 g/dL (90g/L) - Serum creatinine: ≤ 1.5 x upper limit of normal (ULN) - Total bilirubin: ≤1.5 × ULN (< 3 ULN if Gilbert's disease) - AST and ALT: ≤ 2.5 × ULN ≤ 5 x ULN if liver metastases are present)
12. For women of child bearing potential, a negative urine or serum pregnancy test result before study entry. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
13. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control starting 2 weeks prior to administration of the first dose of test article, until 28 days after the last dose of test article. A subject is biologically capable of having children if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives. Oral contraceptives may not be used as the sole form of birth control for this study; oral contraceptives must always be used in conjunction with a second medically approved method of contraception.
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E.4 | Principal exclusion criteria |
1. Subjects enrolled in Part 2 must have received no prior treatment with capecitabine, lapatibine ( excluding 20 subjects enrolled with prior treatment lapatinib) or any erbB-2 targeted agents except trastuzumab. Treatment with erbB-2 targeted therapy must exceed 2 weeks (14 days) in order to be exclusionary.
2. Subjects enrolled in Part 2 must not have received prior treatment with anthracyclines with a cumulative dose of doxorubicin of > 400 mg/m2, epirubicin dose of >800 mg/m2, or the equivalent dose for other anthracyclines.
3. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within 2 weeks of treatment day 1.
4. Subjects with bone as the only site of disease.
5. Active uncontrolled or symptomatic central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects with a history of CNS metastases or cord compression are allowable if they have been considered definitively treated, and are off convulsivants and steroids for at least 4 weeks before the first dose of test article.
6. Family history of congenital long or short QT syndrome, Bruganda syndrome or subjects with a QT/QTc interval >0.45 second or known history of QTc prolongation, or Torsade de Pointes (TdP).
7. Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of ≥ 2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention.
8. Pregnant, or breast-feeding, or women of child bearing potential who are not using effective contraception during participation in the study and do not agree to do so for at least 28 days after the final dose of test article.
9. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or Grade </=2 diarrhea of any etiology at baseline).
10. Inability or unwillingness to swallow tablets or capsules.
11. Any other cancer within 5 years prior to screening with the exception of adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
12. Any major medical illness or abnormal laboratory finding that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in and completion of the study. Examples include, but are not limited to, serious active infection (i.e. requiring intravenous antibiotic or antiviral agent), uncontrolled major seizure disorder, significant pulmonary disorder (e.g. interstitial pneumonitis, pulmonary hypertension), or psychiatric disorder that would interfere with subject safety or informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point of this study is to assess the safety and tolerability and define the maximum tolerated dose of the combination of neratinib with capecitabine |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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 | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The end of the study is the last visit of the last subject. |
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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 | 2 |
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 | 2 |
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 |