| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with metastatic NSCLC with activated PI3Kpathway. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of BKM120 based on Progression Free Survival (PFS) as
measured using RECIST criteria,in metastatic NSCLC patientswith activated PI3K pathway
|
|
| E.2.2 | Secondary objectives of the trial |
To determine Objective Response Rate (ORR)
To determine Time to Response (TTR)
To determine Duration of Response
To determine Disease Control Rate (DCR)
To determine Overall Survival (OS)
To characterize the Safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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. Note: a representative archival or fresh tumor biopsy must be available for shipping to a Novartis designated lab for molecular profiling
5. 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
6. 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)
7. Patient has measurable and/or non-measurable disease as per RECIST 1.1 criteria
(Appendix 8)
8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
9. 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 Section5.1.2.3 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
|
|
| E.4 | Principal exclusion criteria |
1. Patient has received previous treatment with PI3K inhibitors
2. Patient in Stage 2 only:
a. Squamous Patients: previous treatment with docetaxel
b. Nonsquamous Patients: previous treatment with docetaxel and pemetrexed
3. Patient with squamous NSCLC has received more than one line of chemotherapy
treatment for metastatic disease; patient with non-squamous NSCLC has received more than two lines of systemic antineoplastic treatment for metastatic disease (for definition of prior lines of therapy please refer to inclusion criterion 4)
4. Patient with uncontrolled or symptomatic CNS metastases
• Patients with controlled and asymptomatic CNS metastases may participate in this
trial. The patient must have completed any prior treatment for CNS metastases ≥ 28
days (must include radiotherapy and/or surgery) and, if on corticosteroid therapy,
should be receiving a stable low dose (e.g. dexamethasone 4 mg or equivalent dose of another corticosteroid for at least 14 days before start of study treatment)
5. Patient with a concurrent malignancy or malignancy within 5 years of study enrollment,(with the exception of adequately treated, basal or squamous cell carcinoma, nonmelanomatous skin cancer or curatively resected cervical cancer)
6. Patient 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
7. Patient has any of the following mood disorders as judged by the Investigator or a
Psychiatrist, or 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, 3’ to question
number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9)
• 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 (immediate risk of doing harm to others)
• ≥ CTCAE grade 3 anxiety
8. Patient is concurrently using any other approved or investigational antineoplastic agent
9. Patient has received therapeutic radiotherapy ≤ 28 days prior to starting study drug or has not recovered from side effects of such therapy
10. Patient has had major surgery within 28 days prior to starting study drug or who have not recovered from major side effects
11. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %)
12. Patient has active cardiac disease
13. Patient has history of cardiac dysfunction
14. Patient is currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
15. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
16. Patient receiving chronic treatment with steroids or another immunosuppressive agent. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g.,dexamethasone 4 mg/day or other steroids equivalent dose) for at least 14 days before start of study treatment, are eligible.
17. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment contraindicate patient participation in the clinical study (e.g. chronic pancreatitis, chronic active hepatitis, etc.)
18. Patient has a history of non-compliance to medical regimen and inability to grant consent
19. Patient is currently being treated with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment. 20. Patient is currently receiving Warfarin or another coumarin derivative
21. Patient has a known history of HIV (testing not mandatory) infection
22. Peripheral sensory neuropathy with functional impairment (CTC grade 2 neuropathy, regardless of causality)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS per RECIST 1.1
12 week PFS rate (patients who progressed, died or discontinued before 12 weeks of observation are counted as failure; other cases are reported as success) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| China |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Taiwan |
| Thailand |
| Turkey |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The patient will continue on study treatment until disease progression, discontinuation of treatment due to intolerable toxicity patient decision or death. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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