A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations
- Conditions
- ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC
- Interventions
- Registration Number
- NCT01970865
- Lead Sponsor
- Pfizer
- Brief Summary
Phase 1 and 2 trial to study the safety, pharmacokinetics, pharmacodynamics, patient reported outcomes and efficacy of PF-06463922 in ALK + advanced non-small cell lung cancer patients and ROS1+ advanced non small cell lung cancer patients .
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 364
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Crizotinib Crizotinib ALK+ NSCLC patients who are treatment naïve may be eligible to receive crizotinib following PF-06463922 as a substudy to the main study. PF-06463922 PF-06463922 -
- Primary Outcome Measures
Name Time Method Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1 Cycle 1 (21 days) DLT: any of following adverse events (AEs) attributable to PF-06463922: (1) hematologic: grade 4 neutropenia for \>7 days; febrile neutropenia; grade\>=3 neutropenic infection; grade\>=3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) non-hematologic: grade\>=3 pancreatitis; grade\>=3 toxicities (excluding grade \>=3 laboratory abnormalities not requiring dose modifications) persisting after optimal treatment with standard medical therapy; symptomatic grade \>=3 QT interval corrected for heart rate (QTc) prolongation, or asymptomatic grade \>=3 prolongation that had been confirmed by repeat testing, re-evaluation by qualified person, persisted after correction of reversible causes; \>=20% decrease from baseline in left ventricular ejection fraction (LVEF); (3) other: failure to deliver at least 16 out of 21 prescribed daily total dose due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicity attributable to study drug.
Percentage of Participants With Overall and Intracranial Objective Response (Phase 2) 3 years Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 milliliter (mm) on Target Lesions electronic case report form (eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 percent (%) or more decrease in sum of lesion dimensions (SLD) of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
- Secondary Outcome Measures
Name Time Method Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups). Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Renal Clearance (CLr) of PF-06463922 (Phase 1) 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 Renal clearance was calculated as Aetau/AUCtau, where Aetau was the cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen).
Time for Cmax (Tmax) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Tmax of midazolam was observed directly from data as time of first occurrence. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time to Tumor Response (TTR) and Intracranial TTR (Phase 1) From start of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 8 years approximately) Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1) 12 and 24 weeks Tumor response was evaluated according to RECIST version 1.1, and disease control: confirmed CR, confirmed PR, or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. CR was defined as disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as 30% or more decrease in SLD of target lesions, taking as reference baseline SLD. Progressive disease: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition to relative increase of 20%, SLD must also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose. Results presented here were based on independent central review.
Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours post-dose on Day -7 for all other groups. Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups) Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Percentage of Participants With Overall and Intracranial Objective Response (Phase 1) From start of study treatment until CR or PR (maximum of 8 years approximately) Objective response (OR) refers to confirmed CR or PR according to RECIST version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1) From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately) Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of disease progression (PD) or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
Progression-Free Survival (PFS) (Phase 1) From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately) PFS was defined as the time from the first dose of study treatment to the first documentation of objective PD or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups) Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups) Rac was calculated as Day 15 AUCtau/Day -7 AUCtau or Day 1 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively).
Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups). Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.
Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. Vz/F was 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, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1) 3 years The probability of the first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either "CNS progression" or "non CNS progression" or "Death") was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. The results are based on independent central review.
Overall Survival (OS) (Phase 1) 3 years OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups. AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups) Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Vz/F was 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, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Terminal Half-Life of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1) Screening (up to 28 days) Plasma circulating nucleic acid (CNA) samples were analyzed for ALK kinase domain mutations by digital polymerase chain reaction (PCR) BEAMing technology. Number of participants with one or more ALK mutations is presented.
Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1) Screening (up to 28 days) Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2) From first dose of study treatment until first event of CNS progression (maximum of 7.5 years for Phase 2) Probability of first event being CNS progression, non-CNS progression, or death was evaluated with competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to analysis set. Time to first event being Competing Event (either "CNS progression" or "non CNS progression" or "Death") = time from first dose until date of that specific event. Participants not known to have any of Competing Events were censored on date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as competing cause of failure for analysis of other type of events. For each type of event, cumulative incidence function corresponding to nearest time point preceding 1 year is presented. PD:20% or more increase in SLD of target lesion relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must demonstrate absolute increase of atleast 5mm(\>=5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 Vz/F was 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, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1) 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 Dosing interval was 24 hours for QD dosing regimen. Aetau% was calculated as 100\*Ae24/dose, where Ae24 was the cumulative amount of drug recovered unchanged in urine up to 24 hours post-dose.
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Apparent Oral Clearance (CL/F) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1) Baseline, Day 1 of Cycle 1-52, and end of treatment (up to 3 years) In Phase 1, the MMSE was collected to assess mental status. The MMSE is a 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30 and minimum score is 0. Highest score indicates no cognitive impairment, lowest score indicates severe cognitive impairment. The MMSE was removed under Amendment 6 of the study protocol, and not required for Phase 2, as the tool was not considered meaningful for assessment of cognitive function.
Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy) From first dose of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of PD or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Cmax of midazolam was observed directly from data. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflected the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflected the PK assessment after multiple doses of PF-06463922 were administered.
Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI Sub-study) From first dose of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
Time to Progression on the Last Prior Therapy (Phase 2) From first dose of study treatment to the date of progression (maximum of 7.5 years for Phase 2) TTP on the last prior therapy was defined as time from the first dose date of the last prior treatment regimen to the date of progression. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose.
Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy) From first dose of study treatment to the first documentation of objective PD (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective PD. Intracranial TTP was defined as the time from the first dose of study treatment to the date of the first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Tau refers to the dosing interval, and it equals to 24 hours for QD dosing which was adopted in Phase 2. AUCtau was determined using linear/log trapezoidal method.
Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Coagulation, Lipids and Urinalysis From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included Cholesterol and triglycerides.
Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1) Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1) From start of study treatment until end of treatment (maximum of 8 years approximately) European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1) From start of study treatment until end of treatment (maximum of 8 years approximately) EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy) Weeks 12 and 24 Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed CR, confirmed PR, or stable disease (SD). CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. SD= when neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD is observed, taking as reference the smallest sum diameters while on study. Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
Time for Cmax (Tmax) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Terminal Half-Life of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Rac was calculated as Day 15 AUCtau/Day -7 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2).
Progression-Free Survival (PFS) (Phase 2 and DDI Substudy) From first dose of study treatment to first documentation of objective PD or death due to any cause, whichever came first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) PFS was defined as the time from the first dose of study treatment to the first documentation of objective PD or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
Overall Survival (Phase 2 and DDI Substudy) From first dose of study treatment until date of death (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2) Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2) Screening (up to 28 days) Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of participants with one or more ALK mutations is presented.
Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2) From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2) The Columbia Suicide Severity Rating Scale (C-SSRS) was used to analyze participants' suicidal ideation and behavior, and it is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), all of which are significantly predictive of completed suicide. Maximum score of 4 or 5 indicates maximum suicidal ideation and minimum score of "0" indicates no suicidal ideation.
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Hematology From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils. Hematology parameters with any abnormalities were reported in this outcome measure.
Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2) Screening (up to 28 days) Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
Number of Participants With Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) AE: any untoward medical occurrence in clinical investigation participant administered a product or medical device, regardless of causal relationship to study treatment. Treatment-emergent AEs (TEAEs): AEs which occurred for first time during effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs): any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of ability to conduction normal life function). AEs included SAEs and non-serious AEs. Severity was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Grade1: mild, Grade2: moderate, Grade3: severe, Grade4: Life threatening consequences; urgent intervention indicated, Grade 5: death related to AE.
Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Triplicate 12-lead electrocardiograms (ECGs) were performed approximately 2 minutes apart to determine mean QTc interval (QT interval corrected for heart rate). QT interval was corrected for heart rate using Fridericia's formula to provide QTcF. Absolute values and changes from baseline were summarized according to pre-defined criteria. Baseline was defined as the last evaluation on or prior to the first dose of study treatment.
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Chemistry From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Chemistry evaluation included alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), blood bilirubin, creatine phosphokinase (CPK), creatinine, gamma-glutamyl transferase (GGT), calcium, sodium, potassium, magnesium, albumin, glucose (non-fasted), albumin, phosphorus or phosphate, serum amylase and lipase.
Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) The Identification Test is a measure of visual attention and uses a well validated choice reaction time paradigm with playing card stimuli. In this task, the playing cards are all red or black jokers. The on-screen instructions ask: "Is the card red?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as it flips over the participant must decide whether the card is red or not. If it is red the participant should press "Yes", and if it is not red the participant should press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) The One Back Test is a measure of working memory and uses a well validated n back paradigm with playing cards. In this task, the on-screen instructions ask: "Is the previous card the same?". A playing card is presented in the center of the screen. The participant must decide whether the card is the same as the previous card. If it is the same the participant should press "Yes", and if not press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded, mean of the log10 transformed reaction times for correct responses is used to demonstrate speed of performance, and the arcsine transformation of the square root of the proportion of correct responses is used to demonstrate accuracy. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured.
Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1, Phase 2 and DDI Sub-study) From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) Left Ventricular Ejection Fraction (LVEF) was determined by echocardiogram. Baseline was defined as the measurement prior to the first dose of study treatment.
Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) The Beck Depression Inventory (BDI)-II is a 21-item self-report scale, with each item rated by participants on a 4-point scale (ranging from 0-3, where 0 indicated lowest depression and 3 indicated severe depression). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike, pessimism, and poor concentration) as well as somatic signs (appetite, sleep, fatigue and libido). Scores were obtained by adding up the total points from the series of answers. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.
Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) The International Shopping List task is a measure of verbal learning and uses a well validated list learning paradigm administered using a computer. High frequencies, high imagery, concrete nouns (items from a shopping list) were read to the participant at the rate of one word every 2 seconds. Once all 12 words had been read, the participant was asked to recall as many of the words as quickly as possible. The words recalled by the participant were marked on the computer screen. When the participant could recall no more words, the same list was read again. The words recalled by the participant were recorded. This was then repeated a third time. Total number of correct responses on 3 consecutive trials at a single assessment was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) The Detection Test is a measure of psychomotor function and uses a well validated simple reaction time paradigm with playing card stimuli. In this test, the on-screen instructions ask: "Has the card turned over?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as the card flips over the participant must press "Yes". The participant is encouraged to work as quickly as they can and be as accurate as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Number of Participants With Absolute Values and Change From Baseline in PR Interval Meeting Pre-defined Criteria (Phase 2 and DDI Substudy) From first dose of study treatment to end of treatment maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study) PR Interval was determined by ECG measurement. PR interval had following categories: change from baseline\>=25 percent, 40 to \<60 milliseconds (msec), 60 to \<80 msec and \>=80 msec. Baseline was defined as the average of the triplicate measurements prior to the first dose of study drug.
Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2) Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) This test was performed in the same way as the International Shopping List Test, with the exception that, the delayed recall condition required the participant to recall the words from the list 15 30 minutes later without having the list read again. During the recognition condition, the qualified personnel read a shopping list item that may or may not have been on the original list and the participant had to respond either affirmatively (if the item was on the original list) or negatively (if it was not). Total number of correct responses made in remembering the word list after a delay was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Trial Locations
- Locations (71)
Karmanos Center Institute
🇺🇸Detroit, Michigan, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
Highlands Oncology Group/Research
🇺🇸Fayetteville, Arkansas, United States
Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
UC Irvine Medical Center
🇺🇸Orange, California, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Karmanos Cancer Institute
🇺🇸Farmington Hills, Michigan, United States
Barnes-Jewish Hospital
🇺🇸Saint Louis, Missouri, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
Royal Prince Alfred Hospital
🇦🇺Sydney, New South Wales, Australia
University Hospital Antwerp
🇧🇪Edegem, Belgium
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
The Ottawa Hospital Cancer Centre
🇨🇦Ottawa, Ontario, Canada
CHU Grenoble/ Hôpital Albert Michallon
🇫🇷Grenoble Cedex 9, France
CHU de Rennes - Hôpital Pontchaillou - CIC Inserm
🇫🇷Rennes Cedex 9, France
CHU de Rennes - Hôpital Pontchaillou
🇫🇷Rennes Cedex 9, France
Institut Universitaire du Cancer de Toulouse (IUCT-O)
🇫🇷Toulouse Cedex 9, France
Institut Gustave Roussy (comite poumon-pneumologie)
🇫🇷Villejuif Cedex, France
Institut Gustave Roussy- Pharmacie-Unite Essais Cliniques
🇫🇷Villejuif, France
Unita di Farmacologia Clinica e Nuovi Farmaci
🇮🇹Milano, Italy
Dipartimento di Oncologia Medica, UO Medicina 1Q A, Unita' Nuovi Farmaci e Terapie Innovative
🇮🇹Milano, Italy
Struttura Operativa Complessa Oncologia
🇮🇹Aviano (PN), Italy
Oncologia Medica
🇮🇹Perugia, Italy
Aichi Cancer Center Hospital
🇯🇵Nagoya, Aichi, Japan
National Cancer Center Hospital East
🇯🇵Kashiwa, Chiba, Japan
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka, Japan
Seoul National University Hospital / Department of Internal Medicine
🇰🇷Seoul, Korea, Republic of
Hospital Universitario Quiron Dexeus
🇪🇸Barcelona, Spain
Clinica Universidad De Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Universitari de la Vall D'Hebron Edificio General. Planta Baja. UITM. Servicio de Oncologia
🇪🇸Barcelona, Spain
Hospital of Lausanne (CHUV)
🇨🇭Lausanne, Switzerland
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)
🇺🇸Aurora, Colorado, United States
University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)
🇺🇸Aurora, Colorado, United States
University of Colorado Hospital - Anschutz Outpatient Pavillion (AOP)
🇺🇸Aurora, Colorado, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Sarah Cannon Research Institute (Pharmacy)
🇺🇸Nashville, Tennessee, United States
Rockefeller Patient Pavilion - Memorial Sloan Kettering
🇺🇸New York, New York, United States
Chris O'Brien Lifehouse
🇦🇺Sydney, New South Wales, Australia
Siteman Cancer Center-West County
🇺🇸Creve Coeur, Missouri, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Rochester Regional Health System
🇺🇸Rochester, New York, United States
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Universitaetsklinik Koeln
🇩🇪Cologne, Germany
Hospital Universitario Quiron Madrid
🇪🇸Pozuelo de Alarcón, Madrid, Spain
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Nagoya University Hospital
🇯🇵Nagoya, Aichi, Japan
Kantonsspital Winterthur
🇨🇭Winterthur, Switzerland
MDZ: Yale-New Haven Hospital
🇺🇸New Haven, Connecticut, United States
The Ohio State University
🇺🇸Columbus, Ohio, United States
National University Hospital Medical Centre
🇸🇬Singapore, Singapore
National Cancer Center
🇸🇬Singapore, Singapore
Tennessee Oncology PLLC
🇺🇸Nashville, Tennessee, United States
National Hospital Organization Shikoku Cancer Center
🇯🇵Matsuyama, Ehime, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Hokkaido, Japan
The Cancer Institute Hospital of JFCR
🇯🇵Koto-ku, Tokyo, Japan
National University Hospital
🇸🇬Singapore, Singapore
Highlands Oncology Group
🇺🇸Rogers, Arkansas, United States
Smilow Cancer Hospital at Yale-New Haven
🇺🇸New Haven, Connecticut, United States
British Columbia Cancer Agency-Vancouver Centre
🇨🇦Vancouver, British Columbia, Canada
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Hyogo Cancer Center
🇯🇵Akashi, Hyogo, Japan
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Kindai University Hospital
🇯🇵Osakasayama, Osaka, Japan
Shizuoka Cancer Center
🇯🇵Sunto-gun, Shizuoka, Japan
Department of Clinical Oncology, Prince of Wales Hospital
🇭🇰Shatin, Hong Kong