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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by SCRI Development Innovations, LLC
Information provided by (Responsible Party):
SCRI Development Innovations, LLC Identifier:
First received: December 1, 2011
Last updated: May 1, 2014
Last verified: May 2014

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 multicentered, open-label, non-randomized Phase II study of BKM 120 and erlotinib in patients with advanced NSCLC previously sensitive to erlotinib.

Condition Intervention Phase
Non Small Cell Lung Cancer
Drug: BKM120 and Erlotinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Resource links provided by NLM:

Further study details as provided by SCRI Development Innovations, LLC:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    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.

Secondary Outcome Measures:
  • Evaluate toxicity of the BKM120/erlotinib combination 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 anti-tumor activity [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Assess antitumor activity of this combination in terms of objective response rate (ORR), duration of response (DOR) and progression free survival (PFS).

  • Correlate specific tumor biomarkers with treatment efficacy (exploratory) [ 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).

Estimated Enrollment: 37
Study Start Date: May 2014
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BKM120 and Erlotinib

Cycle 1: BKM120 80 mg PO daily; Erlotinib 100mg PO daily

Cycles 2 and beyond: BKM120 100 mg PO daily; Erlotinib 100mg PO daily

Drug: BKM120 and Erlotinib
BKM120 and Erlotinib will be given once daily. Erlotinib 100 mg PO will be administered. During Cycle 1-Week 1 all patients will receive 80 mg PO daily BKM120. After the first week of Cycle 1, the dose of BKM120 will escalate to 100 mg PO daily and treatment will continue as long as there are no unexpected or prohibitive toxicities, or disease progression.
Other Name: Buparlisib (BKM 120) and Tarceva (erlotinib)

Detailed Description:

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 benefiting from the treatment, has no evidence of disease progression, and does not meet any criteria for discontinuation or withdrawal.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  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). A fresh biopsy is preferred, but optional.
  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 function defined as:

    • Absolute neutrophil count (ANC) ≥1500/μL
    • Hemoglobin (Hgb) ≥9 g/dL
    • Platelets ≥100,000/uL
  11. Adequate liver function defined as:

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal limits (WNL) or ≤3.0 x upper limit of normal (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)
  12. Adequate renal function defined as: Serum creatinine ≤1.5 x institutional ULN or calculated 24-hour creatinine clearance ≥50 mL/min
  13. Total calcium (corrected for serum albumin) WNL (bisphosphonate use for malignant hypercalcemia control is allowed)
  14. Magnesium ≥ the lower limit of normal (LLN)
  15. Potassium WNL for the institution
  16. Serum amylase and lipase ≤ ULN
  17. Ability to swallow oral medication
  18. 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.
  19. 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.
  20. Willingness and ability to comply with study and follow-up procedures.
  21. 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 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 (Appendix B)
    • 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
  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 moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Please refer to Appendix E. (Please note that concurrent treatment with 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01487265

Contact: David Spigel, MD 615-329-7274
Contact: Trial Info 877-691-7274

United States, Florida
Florida Cancer Specialists North Recruiting
Ft. Myers, Florida, United States, 33916
Florida Cancer Specialists South Recruiting
Ft. Myers, Florida, United States, 33916
United States, Ohio
Oncology Hematology Cre, Inc. Recruiting
Cincinnati, Ohio, United States, 45242
United States, Tennessee
Tennessee Oncology, PLLC Recruiting
Nashville, Tennessee, United States, 37023
Principal Investigator: David Spigel, MD         
United States, Texas
Center for Cancer and Blood Disorders Recruiting
Fort Worth, Texas, United States, 76104
Sponsors and Collaborators
SCRI Development Innovations, LLC
Study Chair: David R Spigel, MD SCRI Development Innovations, LLC
  More Information

No publications provided

Responsible Party: SCRI Development Innovations, LLC Identifier: NCT01487265     History of Changes
Other Study ID Numbers: SCRI LUN 214
Study First Received: December 1, 2011
Last Updated: May 1, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by SCRI Development Innovations, LLC:

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors processed this record on October 22, 2014