Due to DLTs/AEs safety profile considered challenging.

The Phase Ib part of the study aimed to determine the maximum tolerated dose/recommended Phase II dose (MTD/RP2D) of once daily buparlisib in combination with every-three-week carboplatin and paclitaxel in patients with previously untreated metastatic squamous NSCLC.

The purpose of the Phase II portion of the study was to assess the treatment effect of adding buparlisib versus buparlisib-matching placebo to every-three-week carboplatin and paclitaxel on progression free survival (PFS) in patients with previously untreated metastatic squamous NSCLC.

Based on the observation of DLTs and AEs, the safety profile of this investigational treatment was considered challenging requiring dose reductions/interruptions and even the evaluation of an alternative schedule of buparlisib administration. The study was early terminated, and the primary objective was not met. Therefore the phase ll portion of the study was never initiated.

Inclusion Criteria:

• Patient has histologically and/or cytologically confirmed diagnosis of squamous NSCLC. Diagnosis of mixed squamous with a squamous component will be acceptable for enrollment.

• Patient has archival or new tumor tissue for the analysis of PI3K biomarkers

• Tumor is Stage IV at the time of signed informed consent (UICC/AJCC version 7)

• Patient has measurable or non-measurable disease according to RECIST v1.1 criteria

  • For the Phase II portion, the patient must have measurable disease according to RECIST 1.1 criteria

• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 that the investigator believes is stable at the time of screening

• Patient has adequate bone marrow and organ function

Exclusion Criteria:

• Patient has received any prior systemic therapies for metastatic NSCLC. Study treatment in this clinical trial must be the patient's first systemic treatment for metastatic NSCLC. Patients are eligible if they received neo-adjuvant or adjuvant systemic therapy followed by a disease-free interval exceeding 12 months.

• Patient has symptomatic CNS metastases

  • Patients with asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior local treatment for CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery, or ≥14 days for stereotactic radiosurgery).

• Patient is currently receiving warfarin or other coumadin derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.

• Patient is currently receiving treatment with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to randomization is allowed.

• Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others) or patients with active severe personality disorders (defined according to DSM- IV) are not eligible. Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug

• Patient has ≥ CTCAE grade 3 anxiety

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)

• Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment.