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

• Establish the maximum tolerated doses (MTDs) of BKM120 and erlotinib that can be administered in combination (Phase I) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• Evaluate the percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment with the BKM120/erlotinib combination in patients with advanced NSCLC, previously sensitive to erlotinib (Phase II). [ Time Frame: 18 months ] [ Designated as safety issue: No ]

• Evaluate the toxicity of the BKM120/erlotinib combination (Phases I and II)using CTCAE v4.0. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  Efficacy data will be analyzed and summarized on an intent-to-treat (ITT) basis. The ITT population will consist of all patients enrolled. Safety data will be analyzed and summarized on a modified intent-to-treat (mITT) basis. The mITT population will consist of all patients in the ITT population and receiving at least one dose of study treatment. If more than 5 patients are enrolled but never receive study treatment, then efficacy data will also be analyzed and summarized on the mITT population.
• Assess pharmacokinetics (PK) (Phase I) [ Time Frame: Cycle 1, Day 1 prior to doses, Day 2 prior to doses, Day 8 prior to doses and Cycle 2 Day 1 prior to doses ] [ Designated as safety issue: No ]
  Samples for PK testing will be collected predose on the days specified. On those days, the dose of BKM120 & erlotinib will be taken at the trial site. The purposes of PK sampling are: 1) to assess any alteration in BKM120 PK or erlotinib PK caused by concurrent administration of both agents, and 2) to detect any alterations in patients receiving concurrent treatment with mild CYP3A4 inhibitors or inducers.
• objective response rate (ORR)(Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• duration of response (DOR)(Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• progression-free survival (PFS) (Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• overall survival (OS) (Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Correlate specific tumor biomarkers with treatment efficacy (exploratory) (Phase II) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Exploratory correlative analyses are to include assessments of EGFR mutation (Exons 18-21 [including L858R], L861Q, Exon 19 deletion, T790M), K-ras mutation, MET amplification, molecular status of PIK3CA (gene mutation, Exons 9 and 20) and PTEN (gene mutation, Exons 1-9, and protein expression by IHC).

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 trial is designed in two phases: a Phase I portion to establish the dosing of the combination of BKM120 and erlotinib, and a Phase II portion where this combination will be studied in patients with Non Small Cell Lung Cancer (NSCLC), previously sensitive to erlotinib, defined by either the presence of an activating mutation or evidence of disease control for at least 6 months. It is hypothesized that sensitivity to erlotinib can be restored by continuing EGFR TKI treatment while inhibiting PI3K signaling.

This is an open-label, non-randomized trial to be conducted in two phases: a Phase I portion to establish the dosing of the combination of BKM120 and erlotinib, and a Phase II portion where this combination will be studied in patients with NSCLC, previously sensitive to erlotinib.

The duration of a patient's participation in the trial will vary. Treatment will continue as long as the patient is benefiting from the treatment, has no evidence of disease progression, and does not meet any criteria for discontinuation or withdrawal.

• Drug: BKM120
  PO Daily until irreversible or intolerable toxicity or abnormal laboratory values related to drug toxicity, or disease progression.
• Drug: Erlotinib
  PO daily until irreversible or intolerable toxicity or abnormal laboratory values related to drug toxicity, or disease progression
  Other Name: Tarceva

• Experimental: Phase I Dose Level 1
  BKM120 60mg PO daily; Erlotinib 100mg PO daily
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib
• Experimental: Phase I Dose Level 2a
  BKM120 80mg PO daily; Erlotinib 100mg PO daily
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib
• Experimental: Phase I Dose Level 2b
  BKM120 80mg PO daily; Erlotinib 150mg PO daily
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib
• Experimental: Phase I Dose Level 3
  BKM120 100mg PO daily; Erlotinib 150mg PO daily
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib
• Experimental: Phase I Dose Level -1
  BKM120 40mg PO daily; Erlotinib 100mg PO daily
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib
• Experimental: Phase II
  MTD will be determined from Phase I portion of the study
  Interventions:

  • Drug: BKM120
  • Drug: Erlotinib

Inclusion Criteria:

PHASE I ONLY

• ECOG of 0 to 1
• Histologically or cytologically confirmed diagnosis of solid tumor malignancy with a failure of at least 1, but not more than 3, prior chemotherapy regimens for advanced disease
• Patient must be ≥4 weeks or ≥5 half lives from administration of last dose, whichever is shorter, from administration of last dose of cancer therapy PHASE II ONLY
• One site of measurable disease by RECIST v1.1
• ECOGof 0 to 2
• Patients with progressive NSCLC (any histology).
• Archival tumor tissue available for correlative testing
• Failure of at least 1, and no more than 3, prior systemic treatments for advanced disease with the last treatment being with erlotinib, gefitinib, or other EGFR TKI.

• 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 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.
  • 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).

ALL PATIENTS

• Must be ≥18 years-of-age.
• Patients may have received radiation for palliation prior to starting trial drug if they have recovered from the side effects of such therapy. Time from last palliative radiation to beginning of trial treatment should be ≥1 week. Patients may have received prior wide-field radiation prior to starting trial drug if they have recovered from the side effects of such therapy. Time from last wide-field radiation to beginning of trial treatment should be ≥4 weeks.
• Fasting plasma glucose (FPG) ≤120 mg/dL (6.7 mmol/L)

• Adequate hematologic function defined as:

  • Absolute neutrophil count ≥1500/μL
  • Hgb ≥9 g/dL
  • Platelets ≥100,000/uL

• Adequate liver function defined as:

  • ALT & AST WNL or ≤3.0 x ULN, if liver metastases are present.
  • Serum bilirubin WNL (or ≤1.5 x the institutional ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert Syndrome)

• Adequate renal function defined as:

  • Serum creatinine ≤1.5 x institutional ULN or calculated 24-hour creatinine clearance ≥50 mL/min

• Total calcium (corrected for serum albumin) WNL(biphosphonate use for malignant hypercalcemia control is not allowed)
• Magnesium ≥ the LLN
• Potassium WNL.
• Serum amylase ≤ ULN.
• Serum lipase ≤ ULN.
• Ability to swallow oral medication.
• Fertile males, defined as all males physiologically capable of conceiving offspring, must use condoms during treatment, for 5 T1/2 after stopping treatment, and for an additional 12 weeks, and should not father a child in this period
• 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.
• Willingness and ability to comply with trial and follow-up procedures.
• Ability to understand the investigational nature of this trial and give written informed consent.

Exclusion Criteria:

• Prior treatment with a P13K inhibitor
• Known hypersensitivity to BKM120, and/or erlotinib/gefitinib.
• Patients who have not recovered to Grade 1 or better from any adverse events (except alopecia) related to previous antineoplastic therapy before screening procedures are initiated
• Patients with untreated brain metastases are excluded. Patients with treated brain metastases may participate in this trial, if the patient is ≥4 weeks from therapy completion , has recovered from all effects treatment, is clinically stable at the time of trial entry, and is not receiving high-dose steroid therapy
• Acute or chronic liver or renal disease or pancreatitis.

• Patients with 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 in the PHQ-9 or a cut-off of ≥15 in the 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 trial

• 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

• 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
• Poorly controlled diabetes mellitus (HbA1c >8%
• Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant.
• Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol.
• Diarrhea ≥ Grade 2.
• Impairment of GI function or GI disease that may significantly alter the absorption of trial drugs
• Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤1 week prior to starting trial drug. Erythropoietin or darbepoetin therapy, if initiated at least 1 week prior to enrollment, may be continued.
• Patients who are 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 trial drug.
• Patients who have taken herbal medications and certain fruits within 7 days prior to starting trial 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.
• Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting trial drug
• Patients who have received 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 trial (with the exception of EGFR targeting TKIs).
• Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies or EGFR targeting TKIs) ≤5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy.
• Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives.
• Any condition that would prevent patient comprehension of the investigative nature of the trial and its associated risks or prevent the ability to comply with trial and/or follow-up procedures