BKM120

Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

Percent of patients with Objective response and the Binomial Exact 95% confidence interval. Objective response is defined as having a best response of Complete Response (defined as disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10mm) or Partial Response (defined as at least a 30% decrease in the sum of diameters of target lesions from the baseline sum diameters) by RECIST v1.1 criteria.

Clinical benefit rate (CBR) was defined as the percentage of participants achieving complete response (CR), partial response (PR), or stable disease (SD) for 4 months or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is the complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.

Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.

Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.

Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.

Clinical benefit rate for patients with solid tumors will be assessed using RECIST 1.1 and will include responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) at \>=16 weeks. For hematologic tumors other appropriate hematological response criteria was applied. Response criteria: CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm., PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline

PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression or death due to any cause. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

PFS rate was defined as the percentage of participants who were progression free at 12 weeks. Participants were considered as a "success" for PFS rate evaluated at 12 weeks if they presented an overall response at their 2nd post-baseline tumor assessment.The enrollment into the study in either histology group would stop for futility if a PFS rate \<50% at 12 weeks was observed. No statistical analysis was planned for this primary outcome. The results of the primary objective was based on the data from the interim analysis that took place at the cut off dates: 10-Apr-2013 for non-squamous and 08-Jan-2014 for squamous group.

BOR was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

The maximum tolerated dose (MTD) was defined as the highest dose at which no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experience a dose limiting toxicity (DLT). The study was carried out using a 3+3 dose escalation design. DLTs were defined per NCI CTCAE v 4.0. The following were considered DLT if they occur at any point whilst the patient is on study: 1) Any ≥ grade 3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea) that requires hospital admission or which does not resolve to ≤ grade 2 within 7 consecutive days of optimal treatment. 2) Any ≥ grade 3 nausea, vomiting or diarrhoea will be considered DLT only if any of them persist for \>48 hours despite maximum supportive care. 3) ≥ Grade 3 pneumonitis 4) Any ≥ Grade 4 haematological toxicity. 5) Mood deterioration from baseline. DLT will be any grade ≥3 mood change if BL score of 2. DLT will be any grade ≥2 mood change if baseline score of ≤ 1.

Adverse events (AEs) and Serious Adverse Events (SAEs) were also analysed for frequency. For further details, please consult the AEs/SAEs section.

An adaptive Bayesian logistic regression model (BLRM) for dose escalation with overdose control will guide the dose escalation. The recommended dose is the one with the highest posterior probablity of DLT in the target interval(16%,33%) among the doses fulfilling the overdose criterion that there is less than 25 % chance of excessive toxicity. A clinical synthesis of the available toxicity information including adverse event that are not DLTs, Pharmacokinetics, Pharmacodynamics, efficacy as well as the recommnendations from the BLRM will be used to determine the dose.

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter TMax (time to maximum concentration)

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CMax (maximum concentration)

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-t (Area under the curve at specified timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-last (Area under the curve at last timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-inf (Area under the curve to time infinity)

infMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CL/F (clearance)

FMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter Vz/F (Volume distribution)

Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter terminal T 1/2 (terminal half-life)