Primary Outcome Measures: | |
1. |
Number of patients with Dose-limiting toxicities (DLT) [ Time Frame: First Cycle ]
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2. |
Percentage of Patients With Overall and Intracranial Objective Response [ Time Frame: Every 6 weeks from the time of patient enrollment up to 4 years ]
Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1. |
Secondary Outcome Measures: | |
1. |
Adverse Events [ Time Frame: At end of cycle 1 ]
Including type, frequency, severity, seriousness and relationship |
2. |
Change from Baseline in Mini Mental State Examination (MMSE) across treatment cycles [ Time Frame: Prior to dosing (Day -7 or Cycle 1 Day 1), Every 3 weeks from the time of enrollment up to 4 years ]
MMSE measured general cognitive functioning: orientation, memory, attention, calculation, language, visuospatial functions. Total score derived from sub-scores; total ranges from 0 to 30, higher score indicates better cognitive state. Change: across treatment cycles |
3. |
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: 7 days prior to first dose of treatment ]
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) |
4. |
Volume of Distribution at Steady State (Vz/F) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. |
5. |
Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
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6. |
Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
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7. |
Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
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8. |
Apparent Volume of Distribution (Vz/F) [ Time Frame: 7 days prior to the first dose of treatment ]
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
9. |
Plasma Decay Half-Life (t1/2) [ Time Frame: 7 days prior to the first dose of treatment ]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
10. |
Urine clearance of drug (Clr) for subjects in food effect and Midazolam substudy [ Time Frame: Pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
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11. |
Urine Ae% for subjects in food effect and Midazolam substudy [ Time Frame: Pre Cycle 1 Day 15 dose of treatment ]
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12. |
Maximum Observed Plasma Concentration (Cmax) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
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13. |
Time to Reach Maximum Observed Plasma Concentration (Tmax) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
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14. |
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for subjects in Midazolam substudy [ Time Frame: 7 days prior to first dose and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) after administration of MDZ |
15. |
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8). |
16. |
Plasma Decay Half-Life (t1/2) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half after administration of MDZ |
17. |
Apparent Oral Clearance (CL/F) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood after administration of MDZ |
18. |
Apparent Oral Clearance (CL/F) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
19. |
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: 7 days prior to the first dose of treatment ]
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) |
20. |
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] [ Time Frame: 7 days prior to the first dose of treamtent ]
AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8). |
21. |
Selective molecular profiling of circulating nucleic acids (CNA) [ Time Frame: Within 28 days of first dose of treatment, at the end of Cycle 2 (Phase 2 only) and at 28 days after the last dose of treatment ]
Selective molecular profiling of circulating nucleic acids (CNA) at the end of treatment visit defined as 28 days after the last treatment administration. |
22. |
Selective molecular profiling of tumor tissue [ Time Frame: Within 28 days prior to first dose of treatment ]
Blood specimen optimized for plasma preparation for nucleic acid analysis will be collected at screening and at end of treatment. |
23. |
QTc interval [ Time Frame: Within 28 days prior to first dose of treatment, 7 days prior to the first dose of treatment and Day 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-5 and 28 days after the last dose of treatment ]
ECGs performed to assess QTc (msec) at baseline and on study treatment and at the end of treatment visit defined as 28 days after the last treatment administration. |
24. |
Patient reported Outcomes [ Time Frame: Prior to first dosing (Day -7 or Cycle 1 Day 1), Day 1 of every cycle, pre dose, up to 4 years and at 28 days after the last dose of treatment ]
To assess impact of disease /treatment related symptoms of lung cancer and quality of life at D1 of every cycle and at the end of treatment visit defined as 28 days after the last treatment administration. |
25. |
Duration of Response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. |
26. |
Progression-Free Survival (PFS) [ Time Frame: Every 6 weeks from the time of enrollment to the first documented progression or date of death from any cause, assessed up to 4 years ]
The period from study entry until disease progression, death or date of last contact. |
27. |
Overall Survival (OS) [ Time Frame: From the time of enrollment until the date of death from any causes at 18 months and 1 year. ]
Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact. |
28. |
Disease Control Rate (DCR) [ Time Frame: Every 12 weeks from the time of enrollment up to 4 years ]
DCR is defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1, at 6 weeks. |
29. |
Objective tumor response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1. |
30. |
Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Within 28 days prior to the first dose of treatment, pre dose on Day 1 of Cycle 2, pre dose on Day 1 of Cycle 3, pre dose on Day 1 of Cycle 5 and pre dose on Day 1 of every 2 Cycles thereafter; and at 28 days after the last dose of treatment ]
Left Ventricular Ejection Fraction percentage change by echocardiogram or by multigated acquisition gated scan (MUGA) |
31. |
Apparent Volume of Distribution (Vz/F) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
32. |
Time to Tumor Response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). For patients whose OR proceeds from PR to CR, the onset of PR is taken as the onset of response. TTR will only be calculated for the subgroup of patients with a confirmed objective tumor response. |
33. |
Time to Tumor Progression (phase 2 only) [ Time Frame: From the time of enrollment up to 4 years ]
TTP is defined as the time from first dose to first documentation of objective disease progression. |
34. |
Time to Intracranial progression (phase 2 only) [ Time Frame: From the time of enrollment up to 4 years. ]
Time to Intracranial Progression is defined as the time from first dose to first documentation of objective intracranial disease progression. |
35. |
Time to Extracranial Progression (phase 2 only) [ Time Frame: From the time of enrollment up to 4 years. ]
Time to Extracranial defined as the time from first dose to first documentation of objective extracranial disease progression. |
36. |
Laboratory abnormalities [ Time Frame: First dose of study medication through 28 days after the last dose of study medication. ]
Including type, frequency and severity |
37. |
Vital signs [ Time Frame: First dose of study medication through 28 days after the last dose of study medication. ]
heart rate and blood pressure. |