Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

This is a multicentered, open-label, non-randomized Phase II study of BKM120 and erlotinib in patients with advanced NSCLC previously sensitive to erlotinib. After six patients are enrolled and complete one treatment cycle a safety analysis of adverse events (AEs) will be conducted to assure there are no unexpected or prohibitive toxicities of the combination. The planned study enrollment will continue to up to 37 patients. Duration of a patient's participation in the study will vary. Treatment will continue as long as the patient is benefitting from the treatment, has no evidence of disease progression, and does not meet any criteria for discontinuation or withdrawal.

Inclusion Criteria:

Patients must have recovered to Grade 1 or better from any adverse events (except alopecia) related to prior antineoplastic therapy before screening procedures are initiated.

1. Patients with progressive NSCLC (any histology)

2. Prior sensitivity to erlotinib or gefitinib or other EGFR TKI. Sensitivity is defined as follows:

   • Patients treated with erlotinib (or gefitinib or other EGFR TKI) for any duration in the presence of a known EGFR activating mutation that confers sensitivity to TKI treatment. These include, but are not limited to mutations in L858R (Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment).
   • Prior treatment with erlotinib (or gefitinib, or other EGFR TKI), regardless of mutation status, where there was ≥6 months of disease control (no disease progression).

3. At least one site of measurable disease as defined by RECIST criteria Version 1.1

4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2

5. Archival tumor tissue available for correlative testing (analysis of resistance mechanism to erlotinib).

6. Failure of at least 1, and no more than 3, prior systemic treatments for advanced disease (either due to progressive disease or toxicity).

7. Male or female ≥18 years of age.

8. Patients may have received radiation for palliation prior to starting study drug if they have recovered from the side effects of such therapy. Time from last palliative radiation to beginning of study treatment should be ≥1 week. Patients may have received prior wide-field radiation prior to starting study drug if they have recovered from the side effects of such therapy. Time from last wide-field radiation to beginning of study treatment should be ≥2 weeks.

9. Fasting plasma glucose (FPG) ≤120 mg/dL (6.7 mmol/L)

10. Adequate hematologic, hepatic and renal function.

11. Total calcium (corrected for serum albumin) WNL (bisphosphonate use for malignant hypercalcemia control is allowed)

12. Magnesium ≥ the lower limit of normal (LLN)

13. Potassium WNL for the institution

14. Serum amylase and lipase ≤ ULN

15. Ability to swallow oral medication

16. Fertile males, defined as all males physiologically capable of conceiving offspring, must use condoms during treatment, and for an additional 24 weeks (6 months in total after study drug discontinuation), and should not father a child in this period.

17. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test performed within 48 hours prior to start of treatment.

18. Willingness and ability to comply with study and follow-up procedures.

19. Ability to understand the investigational nature of this study and give written informed consent.

Exclusion Criteria:

1. Prior treatment with a phosphatidylinositide 3-kinase (PI3K) inhibitor

2. Known hypersensitivity to BKM120, and/or erlotinib/gefitinib

3. Failure to recover to Grade 1 or better from any AEs (except alopecia) related to previous antineoplastic therapy before screening procedures are initiated.

4. Untreated brain metastases. Patients with treated brain metastases may participate in this study, if the patient is ≥2 weeks from therapy completion (including radiation and/or surgery), has recovered from all effects of treatment, is clinically stable at the time of study entry, and is not receiving high-dose steroid therapy (patients on a low stable dose of steroids may be enrolled).

5. Acute or chronic liver or renal disease or pancreatitis

6. The following mood disorders, as judged by the Investigator or a Psychiatrist, or as a result of patient's mood assessment questionnaire:

   • Medically documented history of active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
   • ≥ Grade 3 anxiety
   • Meets the cut-off score of ≥10 12 in the Patient Health Questionnaire (PHQ-9) or a cut-off of ≥15 in the Generalized Anxiety Disorder Assessment (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) will be excluded from the study.

7. Active cardiac disease including any of the following:

   • Angina pectoris that requires the use of anti-anginal medication
   • Ventricular arrhythmias except for benign premature ventricular contractions
   • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
   • Conduction abnormality requiring a pacemaker
   • Valvular disease with documented compromise in cardiac function
   • Symptomatic pericarditis
   • Uncontrolled hypertension

8. History of cardiac dysfunction including any of the following:

   • Myocardial infarction within the last 6 months
   • History of documented congestive heart failure (New York Heart Association functional classification III-IV) within the last 6 months
   • Documented cardiomyopathy
   • Stroke or transient ischemic attack within the past 6 months

9. Poorly controlled diabetes mellitus (HbA1c >8%)

10. Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant. Therapy with low molecular weight heparin (LMWH), rivaroxaban, or fondaparinux is allowed.

11. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol

12. Diarrhea ≥ Grade 2.

13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs (e.g., Crohn's disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

14. Prior treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤1 week prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 1 week prior to enrollment, may be continued.

15. Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug.

16. Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug. Herbal medications include, but are not limited to, St. John's Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors: Seville oranges, grapefruit, pummelos, or exotic citrus fruits.

17. Currently treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. (Concurrent treatment with moderate or weak inhibitors of CYP3A is allowed).

18. Chemotherapy or targeted anticancer therapy ≤4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a Grade 1 before starting the study (with the exception of EGFR targeting TKIs).

19. Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies or EGFR targeting TKIs) ≤21 days or 5 half-lives (whichever is shorter) prior to starting study drug or who have not recovered from side effects of such therapy. A minimum of 10 days between termination of study drug and administration of BKM120/erlotinib is required.

20. Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives.

21. Any condition that would prevent patient comprehension of the investigative nature of the study and its associated risks or prevent the ability to comply with study and/or follow-up procedures.