E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Primary (phase Ib part)
• To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with weekly trastuzumab to adult patients with HER2 overexpressing relapsing breast cancer
Primary (phase II part)
• To determine the activity of BKM120 in combination with weekly trastuzumab as measured by objective response rate (ORR) in patients with PIK3CA wild type (arm A) and patients with PIK3CA mutated type (arm B) HER2 overexpressing relapsing breast cancer |
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E.2.2 | Secondary objectives of the trial |
Phase Ib and II:
• further assess the safety and tolerability, and the activity of BKM120 as measured by DCR, non-early progression rate, PFS and OS
• characterize the PK profile of BKM120 and monitor exposure to trastuzumab
• assess ttt induced pathway inhibition in tumor
• obtain evidence of anti-tumor activity at molecular and cellular levels in tumor and blood
• assess 18F-FDG-PET changes reflecting the inhibition of tumor metabolic activity and molecular status of other markers related to PI3K signaling in tumor tissue and blood and investigate their relationship with any clinical responses
• evaluate the relationship between inhibition of the pathway and/or antitumor activity and drug exposures
Phase Ib:assess ttt induced pathway inhibition in Skin (phosphoS6, phospho4EBP1) and blood (glc metabolism markers)
Phase II:evaluate the difference in ORR between a PIK3CA mutated and a wild type subpopulation |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
•World Health Organization (WHO) Performance Status of ≤ 2
•Patients with HER2+ breast cancer by local laboratory testing
(immunohistochemistry [IHC] 3+ staining or fluorescence in situ
hybridization [FISH] confirmation for IHC 2+ and 1+)
•Documented tumor resistance to trastuzumab:
◦Recurrence while on trastuzumab or within 12 months since the last infusion for patients who received trastuzumab as adjuvant treatment
◦Progression while on or within 4 weeks since the last infusion of
trastuzumab for patients who received trastuzumab for metastatic
disease.
•Documented evidence of progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) on trastuzumab-based therapy defined as:
◦Phase Ib: at any time before study entry
◦Phase II: within 16 weeks before date of first dosing
•Received at least 1 but no more than 4 prior anit-HER2 based regimens including at least 1 regimen containing trastuzumab (adjuvant or neoadjuvant trastuzumab will be considered as one prior regimen). HER2 directed therapies are defined as comprising trastuzumab, lapatinib, and trastuzumab-DM1 (T-DM1) only.
• Phase II only: trastuzumab, T-DM1 or lapatinib must be part of the most recent line of therapy
•Previous lines of cytotoxic chemotherapy:
◦Phase Ib: no more than 4 lines of cytotoxic chemotherapy
◦Phase II: no more than 3 lines of cytotoxic chemotherapy
Measurable disease:
•Phase Ib: patient has at least one measurable lesion or non-measurable disease as defined per RECIST
•Phase II: patient has at least one measureable lesion as defined per RECIST
//
Specific Inclusion Criteria for patients in BM cohorts:
•Patient has evidence of progressing brain metastases and/or new
metastatic brain lesion(s) without leptomeningeal disease.
•Patient has received prior WBRT and/or SRS at at >28 and >/= 14 days, respectively, prior to starting study drug and the patient must have recovered from the side effects of the therapy
•WHO performance status of </=1
•PT INR </= 1.5
•Any number of prior HER2-directed and cytotoxic regimens, and the most recent line may be any type of anti-neoplastic therapy |
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E.4 | Principal exclusion criteria |
•Patients with untreated brain metastases
•Patients with acute or chronic liver, renal disease or pancreatitis
•Patients with any peripheral neuropathy ≥ Common Terminology
Criteria for Adverse Events (CTCAE) grade 2
•Patients with a history of mood disorders or ≥ CTCAE grade 3 anxiety
•Patient with clinical manifest diabetes mellitus or steroid-induced
diabetes mellitus
Specific Exclusion Criteria for patients in BM cohorts
•Prior treatment with capecitabine
•Patient has known dihydropyrimidine dehydrogenase (DPD) deficiency
•Patient is currently receiving treatment with EIAED
•Other protocol-defined inclusion/exclusion criteria may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint - Phase Ib dose escalation
• Incidence rate of DLT (first cycle only) at each dose level
Primary endpoint - Phase II efficacy expansion
• Overall response rate (ORR) according to RECIST |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
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 | 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.8.4.1 | 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 | 16 |
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
| |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |