An open label two-stage study of orally administered BKM120 in patients with metastatic non-small cell lung cancer with activated PI3K pathway

Summary

investigate the efficacy and safety of BKM120 in adult patients with metastatic non-small cell
lung cancer (NSCLC) and activated PI3K pathway. PI3K pathway activation (independent of
the EGFR mutational status) in this trial is being defined as one of the following:
1. PIK3CA mutation
2. PTEN mutation
3. PTEN negative ( and amp;lt;10% protein expression by IHC).
The two arms will enroll simultaneously and patients will be classified upon enrollment into one of two groups based on histopathology and the number of prior antineoplastic lines of treatment.

* Group 1: Diagnosis of squamous NSCLC that progressed after one prior platinum-based chemotherapy line for metastatic disease

* Group 2: Diagnosis of non-squamous NSCLC that progressed after one or two prior antineoplastic therapy lines for metastatic disease
In order to be preliminarily eligible, patients must be molecularly pre-screened in both blood and tumor tissue to confirm PI3K pathway activation as defined above. All blood testing will be performed centrally by a Novartis designated laboratory. Tissue testing to confirm PI3K pathway activation may be performed by a Novartis designated laboratory or locally by the site if an approved validated central or site lab, within the allowable limits of Table 3-1. If the PI3K pathway definition to confirm pre-screening eligibility is PTEN negative, this assessment must be performed by a central Novartis designated laboratory. Results from a local laboratory will not be accepted for enrollment purposes if the only evidence of PI3K pathway activation is PTEN negative. The results from the assessment of the tumor alone may determine whether the patient is eligible for screening. Results from blood alone are not
satisfactory for confirming PI3K pathway activation. The primary objective is to evaluate the efficacy of BKM120 based on PFS as measured using RECIST criteria, in metastatic NSCLC patients with activated PI3K pathway.
An exploratory analysis will be conducted to explore the relationship between the PI3K activating factors (PIK3CA mutant versus PTEN alterations) and the clinical outcome. Therefore a predefined minimal number of PIK3CA mutated patients (at least 35% of the total population) is required to be enrolled in the study. To implement this order, the alterations will be considered in the following order: PIK3CA mutations and amp;gt; PTEN mutations and amp;gt; PTEN
negative, in order to constitute mutually exclusive subsets of patients (i.e. patients with PIK3CA mutations regardless of PTEN status vs. patients without PIK3CA mutations, but with PTEN mutations vs. patients with neither PIK3CA nor PTEN mutations, but with PTEN negative)

Participant Eligibility

Patients eligible for inclusion in this study must meet all of the following criteria:
1. Patient has signed the general Informed Consent Form (ICF) prior to any screening
procedures being performed
2. Patient is ≥ 18 years of age on the day of consent signature
3. Patient has a histologically confirmed diagnosis of NSCLC with activated PI3K pathway
as defined by PIK3CA mutation and/or PTEN mutation an/or PTEN Negative (<10%
protein expression by IHC)
4. Patient has experienced objective progressive disease after the prior systemic
antineoplastic treatment(s) for advanced NSCLC is/are required as follows:
a. Group 1: Diagnosis of squamous NSCLC that progressed after one prior systemic
platinum based chemotherapy-line for metastatic disease
b. Group 2: Diagnosis of non-squamous NSCLC that progressed after one to two prior
systemic antineoplastic therapy lines for metastatic disease
Note: a prior systemic therapy line is defined as any prior systemic antineoplastic treatment
followed by disease progression; e.g. A first-line treatment for metastatic disease followed
(without any disease progression) by a maintenance therapy (e.g. pemetrexed or erlotinib)
counts as one prior line of therapy
Note: Patients who have a known EGFR activating mutation (assessed prior to signing the
ICF) must have previously been treated with at least one prior EGFR TKI (e.g. erlotinib or
gefitinib)
5. A representative archival or fresh tumor biopsy must be available for shipping to a
Novartis designated laboratory for profiling (See Section 6.1.8.3.1)
6. Patient has measurable and/or non-measurable disease as per RECIST 1.1 criteria
(Appendix 8 in protocol)
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
8. Patient has adequate bone marrow and organ function as defined by the following
laboratory values:
• Absolutely Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• INR ≤ 2
• Potassium, calcium, magnesium within normal limits for the institution
• Serum Creatinine ≤ 1.5 x ULN and creatinine clearance > 45 mL/min (refer to Section
5.1.2.3 for calculation formula)
• Total Serum Bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are
present, or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in
patients with well documented Gilbert’s Syndrome)
• AST and ALT ≤ ULN or < 3.0 x ULN if liver metastases are present
• Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L