E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Solid tumors (part 1) and metastatic 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 compare the objective response rate (ORR = CR + PR) for subjects with erbB-2 positive breast cancer treated at the MTD of neratinib + capecitabine vs neratinib monotherapy vs. lapatinib + capecitabine. |
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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 confirm the MTD identified in Part 1 of the study, obtain safety and PK information, and assess additional efficacy parameters including Progression Free Survival (PFS), Overall Survival (OS), Clinical benefit Rate (CR + PR +SD?24 weeks), and duration of response for each treatment arm. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and/or surgically sterile or postmenopausal female OR 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 confirmed pathologic 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 erbB-2 overexpression (IHC 3+) 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 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).
6. Subjects enrolled in Part 2 must have received prior treatment (neoadjuvant, adjuvant, or metastatic) with at least 4 cycles of both a taxane and an anthracycline given sequentially or concurrently (2 cycles of treatment are acceptable if disease progresses during treatment).
7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
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 limits of normal.
11. Screening laboratory values within the following parameters: ANC : ?1.5×109/L (1500/mm3) Platelet count: ?75×109/L (100,000/mm3) Hemoglobin: ?9.0 g/dL (90 g/L) Serum creatinine: ? 1.5×upper limit of normal (ULN) Total bilirubin: ?1.5×ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ? 2.5×ULN (?5×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 for the duration of the study and for 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 lapatinib, capecitabine, or any erbB-2 targeted agents except trastuzumab.
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, radical (curative intent) radiotherapy, any investigational agents, or other cancer therapy within 2 weeks of treatment day 1.
4. Subjects with bone or skin as the only site of disease.
5. Active 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 definitively treated, have been clinically stable for at least three months, and off anticonvulsants before first dose of test article (steroids are permitted, provided subject is on stable doses).
6. QTc interval >0.47 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 women.
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 define the maximum tolerated dose of the combination of neratinib with capecitabine in subjects with solid tumors, and to compare the objective response rate (ORR = CR + PR) for subjects with erbB-2 positive breast cancer treated at the MTD of neratinib in combination with capecitabine versus neratinib monotherapy versus lapatinib in combination 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) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 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 | Yes |
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.8.3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | 3 |
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 | 3 |
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 |