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 | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
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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 of the study are to assess the safety and tolerability and to define the maximum tolerated dose (MTD) of HKI-272 in combination with vinorelbine in subjects with advanced solid tumors.
Part 2: The primary objective of part 2 of the study is to estimate the ORR for subjects with ErbB-2-positive breast cancer treated at the MTD of HKI-272 in combination with vinorelbine. |
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E.2.2 | Secondary objectives of the trial |
Part 1: The secondary objectives of part 1 are to obtain preliminary data describing antitumor activity for the combination of HKI-272 with vinorelbine.
Part 2: The secondary objectives of part 2 are to confirm the MTD identified in part 1 of the study, to obtain safety and PK information, and to assess additional efficacy parameters including clinical benefit (complete response [CR]+partial response [PR]+stable disease [SD] >=24 weeks), PFS rate, and duration of response to HKI-272 in combination with vinorelbine. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Aged ≥18 years.
2. Confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which HKI-272 plus vinorelbine is a reasonable treatment option (part 1 only).
3. Confirmed pathologic diagnosis of ErbB-2-positive breast cancer (current stage IV) in female subjects for which vinorelbine plus HKI-272 is a reasonable treatment option (part 2 only).
4. At least 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease (part 2 only).
5. At least 1 prior treatment with a trastuzumab-containing regimen for at least 6 weeks, for metastatic disease (part 2 only).
6. erbB-2 gene amplified tumor detected by fluorescence in situ hybridization (FISH) (part 2 only).
7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).
8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks before signing the informed consent form (ICF)).
9. Recovery from all clinically significant AEs related to prior therapies (excluding alopecia).
10. Left ventricular ejection fraction (LVEF) within the study site’s limits of normal.
11. Screening laboratory values within the following parameters: Absolute neutrophil count (ANC): >=1.5×109/L (1500/mm3) Platelet count: >=100×109/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 childbearing potential, a negative urine or serum pregnancy test result before study entry.
13. All subjects who are not surgically sterile or postmenopausal 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. |
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E.4 | Principal exclusion criteria |
1. More than 2 prior cytotoxic chemotherapy treatment regimens for metastatic disease (part 2 only).
2. Prior treatment with vinorelbine for metastatic setting, or prior treatment with any ErbB-2 targeted agents except trastuzumab (part 2 only). Up to 20 subjects with ErbB-2-overexpressing metastatic breast cancer who have been previously exposed to lapatinib but are not refractory to lapatinib may be enrolled in part 2.
3. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, or of epirubicin dose of >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (part 2 only).
4. Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within at least 2 weeks before treatment day 1.
5. Bone or skin as the only site of disease.
6. Subject with history of inflammatory breast cancer
7. Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
8. QT (QTc) interval >0.47 second or known history of QTc prolongation or torsades de pointes (TdP).
9. 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.
10. Pregnant or breastfeeding women.
11. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade >=2 diarrhea of any etiology at baseline).
12. Inability or unwillingness to swallow tablets (HKI-272).
13. Preexisting grade 2 or greater motor or sensory neuropathy.
14. Subject known to be human immunodeficiency virus (HIV) seropositive and/or acute chronic hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive).
15. History of known hypersensitivity to vinorelbine and any of its components.
16. Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
17. Clinically significant ongoing or recent infection within 2 weeks before treatment day 1.
18. Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study.
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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 HKI-272 with vinorelbine in subjects with solid tumors, and to assess the efficacy of the optimal safe dose for the drug combination in subjects with metastatic breast cancer |
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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 | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First use in human for HKI 272 + Vinorelbine |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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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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 | 9 |
E.8.9.1 | In the Member State concerned days | |
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 | 9 |