Phase II Study of Buparlisib + Docetaxel in Advanced or Metastatic Squamous Non-small Cell Lung Cancer (NSCLC) Patients

Based on an overall review of safety and preliminary efficacy data done on 01-Dec-2014 showing marginal anti-tumor activity and newly emerged treatment options, a decision was taken to stop further development of this combination in patients with advanced or metastatic squamous NSCLC and Phase II of the study was not conducted.

• Buparlisib (Drug), also known as BKM120
• Buparlisib matching placebo (Drug)
• Docetaxel (Drug)

Primary outcomes

• Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 [Day 21]: To determine the maximum tolerated dose/recommended phase ll dose (MTD/RP2D) of buparlisib in combination with docetaxel by assessing the incidence of DLTs in Cycle 1; Cycle 1 = 21 days
• Phase II: Progression Free Survival (PFS) [After 70 PFS events have been observed at 9 months after patient enrollment]: PFS as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. To estimate the treatment effect of docetaxel and buparlisib or placebo on PFS in patients with advanced or metastatic squamous NSCLC.

Secondary outcomes

• Number of patients with at least one adverse event. [Up to 30 days after the last dose]
• Number of patients with laboratory abnormalities. [Up to 30 days after the last dose]
• Overall Survival (OS) [Treatment start (phase Ib)/randomization (phase II), every 6 weeks to the date of first document progression for up to 3 years]: Overall survival (OS) time is measured from the start of study drug to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. Data will be collected post treatment every 6 weeks until approximately 75% of patients have reached the survival endpoint (Phase I + Phase II)
• Overall response rate (ORR) [Every 6 weeks from randomization until first documented progression for up to 3 years]: Overall response is the number of participants who had a complete response (CR) or a partial response (PR) based on local investigator's assessment of RECIST 1.1 criteria.
• Time to response (ToR) [Every 6 weeks from randomization until first documented progression for up to 3 years]: Time to overall response is defined as the time from the date of first drug intake in Phase Ib and from the date of randomization in Phase II to the date of first documented response.
• Duration of response (DR) [Every 6 weeks from randomization until first documented progression for up to 3 years]: Duration of overall response is defined as the elapsed time between the date of first documented response and the following date of event defined as the first documented progression or death due to underlying cancer.
• Change in electrocardiogram (ECG) and cardiac imaging [Up to 30 days after the last dose]
• Changes in vital signs [Up to 30 days after the last dose]
• Shift in ECOG performance status [Baseline, worst post-baseline result at day 1 of every cycle and at end of study treatment (3 years)]: cycle = 21 days; end of treatment is defined as 15 days after treatment discontinuation; There is no treatment duration as patients continue to receive drug till toxicity or they withdraw consent
• Change in Mood scales [Up to 30 days after the last dose]
• Time to definitive 10% deterioration in the global health status/quality of life (QOL) scale score of the EORTC QLQ-C30 [Baseline, Every 6 weeks until disease progression for up to 3 years]: Date of event is defined as at least 10% relative to baseline worsening of the corresponding scale score or death due to any cause
• Change in the global health status/quality of life (QOL) scale score of the EORTC QLQ-C30 [Baseline, Every 6 weeks until disease progression for up to 3 years]: Change in the domain scores
• Docetaxel and buparlisib plasma concentrations [Cycle 1 day 8 and 15, Cycle 2-Cycle n day 1]
• PFS Phase Ib [at 3 months after patient enrollment, every 6 weeks until disease progression for up to 3 years]: PFS as per RECIST 1.1

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patient is an adult ≥ 18 years old at the time of informed consent
* Patient has histologically and/or cytologically confirmed diagnosis of squamous NSCLC. Diagnosis of mixed squamous and non-squamous or adenosquamous NSCLC will be acceptable for enrollment.
* Patient has received one prior approved regimen of platinum-based chemotherapy (excluding a docetaxel-containing regimen) for advanced or metastatic (Stage IIIb or Stage IV) squamous NSCLC, followed by disease progression. A drug provided as maintenance therapy following cytotoxic chemotherapy will be considered to be part of that regimen.

Note: Patients who received paclitaxel therapy are eligible for this trial. •Patient has adequate tumor tissue (either archival or new tumor biopsy) for the analysis of PI3K-related biomarkers.

Enrollment in the Phase II part of the study is contingent on the central laboratory confirming receipt of an adequate amount of tissue including sufficient DNA for analysis.

•Patient has measurable or non-measurable disease according to RECIST version 1.1 criteria.

Phase II only: Patient must have at least one measurable lesion as per RECIST criteria.

* Patient has an ECOG performance status ≤ 1
* Patient has adequate bone marrow and organ function

Exclusion Criteria:

* Patient has received previous treatment with a PI3K or AKT inhibitor
* Patient has symptomatic Central Nervous System (CNS) metastases Patients with asymptomatic CNS metastases may participate in this trial. The patient must have completed prior local treatment, if any, for CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery, or ≥ 14 days for stereotactic radiosurgery).
* Patient has a score ≥ 12 on the PHQ-9 questionnaire.
* Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9).
* Patient has a GAD-7 mood scale score ≥ 15.
* 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 or patients with active severe personality disorders.
* Patient has ≥ CTCAE grade 3 anxiety

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals