Tumors Characterized by Genetic Abnormalities of ALK
Conditions
Keywords
ALK inhibitor,, NSCLC,, LDK378,, ceritinib,, genetic abnormalities
Brief summary
This study assessed the safety and efficacy of LDK378 in adult patients with genetic abnormalities in anaplastic lymphoma kinase (ALK).
Interventions
DRUGLDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ECOG Performance Status of ≤ 2 and life expectancy of ≥ 12 weeks. * Diagnosed with a locally advanced or metastatic malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists. Only patients with tumors characterized by genetic abnormalities in ALK were enrolled. * For NSCLC, an ALK translocation must be detected by FISH in ≥ 15% of tumor cells. * In patients with diseases other than NSCLC, ALK translocation is not required and overexpression of ALK protein may be considered indicative of a genetic abnormality in ALK. * Patients with measurable or non-measurable disease as determined by modified RECIST version 1.0 in dose-escalation phase, and patients with at least one measurable lesion as determined by RECIST 1.0 in expansion phase.
Exclusion criteria
* Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or required increasing doses of steroids to control their CNS disease were excluded. * Patients with a prior or current history of a second malignancy, impaired GI function, history of pancreatitis or increased amylase or lipase, known diagnosis of HIV, and clinically significant cardiac disease were excluded. * Patients treated with chemotherapy or biologic therapy or other investigational agent \< 2 weeks prior to starting study drug for compounds with a half-life ≤ 3 days, and \< 4 weeks prior to starting study drug for compounds with a prolonged half-life were excluded. * Further, patients treated with medications that were known to be strong inhibitors or inducers of CYP3A4/5 that could not be discontinued at least a week prior to start of treatment with LDK378 and for the duration of the study were also excluded. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | 33 months | The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. A patient with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. MTD was determined at 750mg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment | 275 weeks | Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR). |
| Duration of Response (DOR) Based on Investigator Assessment | 275 weeks | Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0. |
| Duration of Response (DOR) Based on BIRC | 275 weeks | Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0. |
| Progression-free Survival Based on Investigator Assessment | 275 weeks | Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause. |
| Progression-free Survival Based on BIRC Assessment | 275 weeks | Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause. |
| Primary Pharmacokinetics (PK) Parameter: AUC0-last | PK run-in of Dose Escalation phase | The AUC from time zero to the last quantifiable concentration point (Tlast). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. |
| Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases | Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. AUC0 - 24 is the AUC calculated to 24 hour. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter AUC0-24. |
| Overall Response Rate (ORR) Based on Investigator Assessment | 275 weeks | Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR). |
| Primary Pharmacokinetics (PK) Parameter: Cmax | PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation ion phase, Cycle 2 Day 1 of dose escalation & expansion phases | Cmax is the maximum observed concentration. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Cmax. |
| Secondary Pharmacokinetics (PK) Parameter: T1/2 | PK Run-in dose escalation phase | T1/2 is the elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. |
| Secondary Pharmacokinetics (PK) Parameter: CL/F | PK Run-in dose escalation phase | CL/F is the apparent total body clearance of drug from the plasma |
| Secondary Pharmacokinetics (PK) Parameter: Vz/F | PK Run-in dose escalation phase | Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda\_z) |
| Secondary Pharmacokinetics (PK) Parameter: CLss/F | Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases | CLss/F is the apparent total body clearance of drug from the plasma. There was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter CLss/F. |
| Secondary Pharmacokinetics (PK) Parameter: Racc | Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases | Racc is the accumulation ratio calculated using AUCtau values obtained from a dosing interval at steady-state divided by AUCtau at day 1 or PK run-in phase. AUCtau is the AUC calculated to the end of the dosing interval, tau. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Racc. |
| Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases | Tmax is the time to reach Cmax. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Tmax. |
Countries
Australia, Belgium, Canada, Germany, Italy, Netherlands, Singapore, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Study was considered completed when all patients discontinued ceritinib treatment, & all required follow-up was completed or patient died, was lost to follow-up or withdrew their consent to further participate in study or last patient on treatment was enrolled to a separate protocol to continue receiving ceritinib treatment, whichever came first.
Pre-assignment details
A total of 304 patients were treated with LDK378 in the study, including 59 patients from the dose-escalation phase (including 10 patients at 750 mg) and 245 patients from the expansion phase treated at LDK378 750 mg.
Participants by arm
| Arm | Count |
|---|---|
| LDK378 50 mg Participants receiving 50 mg of LDK378 | 2 |
| LDK378 100 mg Participants receiving 100 mg of LDK378 | 2 |
| LDK378 200 mg Participants receiving 200 mg of LDK378 | 3 |
| LDK378 300 mg Participants receiving 300 mg of LDK378 | 3 |
| LDK378 400 mg Participants receiving 400 mg of LDK378 | 14 |
| LDK378 500 mg Participants receiving 500 mg of LDK378 | 10 |
| LDK378 600 mg Participants receiving 600 mg of LDK378 | 10 |
| LDK378 700 mg Participants receiving 700 mg of LDK378 | 5 |
| LDK378 750 mg Participants receiving 750 mg of LDK378. | 255 |
| Total | 304 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Administrative problems | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 39 |
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 28 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 12 |
| Overall Study | Disease Progression | 2 | 2 | 3 | 3 | 13 | 8 | 6 | 3 | 139 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 36 |
Baseline characteristics
| Characteristic | LDK378 750 mg | Total | LDK378 100 mg | LDK378 200 mg | LDK378 300 mg | LDK378 400 mg | LDK378 500 mg | LDK378 600 mg | LDK378 50 mg | LDK378 700 mg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 51.9 Years STANDARD_DEVIATION 12.08 | 52.0 Years STANDARD_DEVIATION 12.41 | 30.5 Years STANDARD_DEVIATION 12.02 | 53.7 Years STANDARD_DEVIATION 10.69 | 58.7 Years STANDARD_DEVIATION 5.03 | 48.7 Years STANDARD_DEVIATION 15.62 | 55.0 Years STANDARD_DEVIATION 15.99 | 54.6 Years STANDARD_DEVIATION 13.22 | 46.5 Years STANDARD_DEVIATION 23.33 | 56.4 Years STANDARD_DEVIATION 4.67 |
| Age, Customized <65 years | 215 Participants | 255 Participants | 2 Participants | 2 Participants | 3 Participants | 12 Participants | 7 Participants | 7 Participants | 2 Participants | 5 Participants |
| Age, Customized >=65 years | 40 Participants | 49 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Body Mass Index | 24.5 kg/m^2 STANDARD_DEVIATION 4.4 | 24.4 kg/m^2 STANDARD_DEVIATION 4.48 | 21.8 kg/m^2 STANDARD_DEVIATION 5.3 | 26.5 kg/m^2 STANDARD_DEVIATION 5.69 | 20.2 kg/m^2 STANDARD_DEVIATION 5.08 | 24.0 kg/m^2 STANDARD_DEVIATION 5.38 | 25.9 kg/m^2 STANDARD_DEVIATION 5.41 | 23.1 kg/m^2 STANDARD_DEVIATION 2.78 | 21.1 kg/m^2 STANDARD_DEVIATION 5.16 | 24.3 kg/m^2 STANDARD_DEVIATION 6.06 |
| Height | 167.5 centimenters (cm) STANDARD_DEVIATION 9.87 | 167.5 centimenters (cm) STANDARD_DEVIATION 9.78 | 178.0 centimenters (cm) STANDARD_DEVIATION 14.14 | 161.3 centimenters (cm) STANDARD_DEVIATION 3.04 | 164.6 centimenters (cm) STANDARD_DEVIATION 5.82 | 169.9 centimenters (cm) STANDARD_DEVIATION 9.35 | 166.4 centimenters (cm) STANDARD_DEVIATION 12.24 | 165.1 centimenters (cm) STANDARD_DEVIATION 8.67 | 169.0 centimenters (cm) STANDARD_DEVIATION 7.07 | 163.6 centimenters (cm) STANDARD_DEVIATION 5.05 |
| Predominant Race Asian | 87 Participants | 95 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 1 Participants |
| Predominant Race Black | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Predominant Race Caucasian | 160 Participants | 199 Participants | 2 Participants | 2 Participants | 2 Participants | 12 Participants | 8 Participants | 8 Participants | 2 Participants | 3 Participants |
| Predominant Race Native American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Predominant Race Other | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Predominant Race Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Chinese | 17 Participants | 19 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 26 Participants | 32 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Indian (Indian subcontinent) | 6 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Mixed Ethnicity | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 205 Participants | 244 Participants | 2 Participants | 2 Participants | 3 Participants | 12 Participants | 8 Participants | 6 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Female | 136 Participants | 170 Participants | 1 Participants | 3 Participants | 2 Participants | 10 Participants | 6 Participants | 7 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 119 Participants | 134 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants |
| Smoking History Current Smoker | 8 Participants | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Smoking History Ex-Smoker | 88 Participants | 104 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants |
| Smoking History Never Smoked | 159 Participants | 192 Participants | 1 Participants | 1 Participants | 2 Participants | 9 Participants | 7 Participants | 8 Participants | 2 Participants | 3 Participants |
| Weight | 69.2 Kilograms (kg) STANDARD_DEVIATION 15.64 | 68.8 Kilograms (kg) STANDARD_DEVIATION 15.61 | 67.8 Kilograms (kg) STANDARD_DEVIATION 5.94 | 69.2 Kilograms (kg) STANDARD_DEVIATION 17.2 | 54.1 Kilograms (kg) STANDARD_DEVIATION 9.7 | 69.2 Kilograms (kg) STANDARD_DEVIATION 15.91 | 72.2 Kilograms (kg) STANDARD_DEVIATION 18.74 | 63.8 Kilograms (kg) STANDARD_DEVIATION 13.23 | 60.8 Kilograms (kg) STANDARD_DEVIATION 19.8 | 61.6 Kilograms (kg) STANDARD_DEVIATION 16.05 |
| WHO/ECOG Performance status 0:Fully active,in line with pre-disease activities | 65 Participants | 76 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants |
| WHO/ECOG Performance status 1: Able to carry out light work | 161 Participants | 193 Participants | 1 Participants | 2 Participants | 3 Participants | 8 Participants | 7 Participants | 7 Participants | 1 Participants | 3 Participants |
| WHO/ECOG Performance status 2:Capable of self-care up & about >50% of the time | 28 Participants | 34 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants |
| WHO/ECOG Performance status 3: Limited self-care, confined to bed/chair >50% | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 3 / 3 | 3 / 3 | 14 / 14 | 10 / 10 | 10 / 10 | 5 / 5 | 254 / 255 | 303 / 304 |
| serious Total, serious adverse events | 0 / 2 | 1 / 2 | 1 / 3 | 1 / 3 | 7 / 14 | 4 / 10 | 7 / 10 | 3 / 5 | 145 / 255 | 169 / 304 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. A patient with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. MTD was determined at 750mg.
Time frame: 33 months
Population: Dose-determining Set (DDS) consists of all patients (NSCLC and non-NSCLC) from the safety set who either meet the minimum exposure criterion and have sufficient safety evaluations or have experienced a dose limiting toxicity (DLT) during Cycle 1 (including the PK run-in period). This constitutes all evaluable patients for the determination of MTD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 50 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 100 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 200 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 1 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 1 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 1 Participants |
| LDK378 400 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 500 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 1 Participants |
| LDK378 600 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 1 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 0 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 700 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 0 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Hypophosphataemia | 0 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Dehydration | 0 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Diarrhea | 2 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Transaminases Increased | 0 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Alanine Aminotransferase Increased | 0 Participants |
| LDK378 750 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | Vomiting | 1 Participants |
Secondary
Duration of Response (DOR) Based on BIRC
Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group and had a confirmed overall complete response or partial response after initiation of LDK378.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 50 mg | Duration of Response (DOR) Based on BIRC | 8.31 months |
| LDK378 100 mg | Duration of Response (DOR) Based on BIRC | 21.75 months |
| LDK378 200 mg | Duration of Response (DOR) Based on BIRC | 12.45 months |
Secondary
Duration of Response (DOR) Based on Investigator Assessment
Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group and had a confirmed overall complete response or partial response after initiation of LDK378.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 50 mg | Duration of Response (DOR) Based on Investigator Assessment | 8.25 months |
| LDK378 100 mg | Duration of Response (DOR) Based on Investigator Assessment | 14.19 months |
| LDK378 200 mg | Duration of Response (DOR) Based on Investigator Assessment | 10.12 months |
Secondary
Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment
Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 50 mg | Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment | 49.1 Percentage of participants |
| LDK378 100 mg | Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment | 65.1 Percentage of participants |
| LDK378 200 mg | Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment | 54.5 Percentage of participants |
Secondary
Overall Response Rate (ORR) Based on Investigator Assessment
Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDK378 50 mg | Overall Response Rate (ORR) Based on Investigator Assessment | 56.4 Percentage of Participants |
| LDK378 100 mg | Overall Response Rate (ORR) Based on Investigator Assessment | 73.5 Percentage of Participants |
| LDK378 200 mg | Overall Response Rate (ORR) Based on Investigator Assessment | 62.2 Percentage of Participants |
Secondary
Primary Pharmacokinetics (PK) Parameter: AUC0-24h
Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. AUC0 - 24 is the AUC calculated to 24 hour. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter AUC0-24.
Time frame: PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 435 ng*h/mL | Geometric Coefficient of Variation 42.1 |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C2D1 dose escalation & expansion phases | 376 ng*h/mL | — |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 226 ng*h/mL | — |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 1520 ng*h/mL | Geometric Coefficient of Variation 41.1 |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 467 ng*h/mL | Geometric Coefficient of Variation 10.7 |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C2D1 dose escalation & expansion phases | 894 ng*h/mL | — |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 4150 ng*h/mL | Geometric Coefficient of Variation 32.2 |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 703 ng*h/mL | Geometric Coefficient of Variation 55.6 |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 3440 ng*h/mL | Geometric Coefficient of Variation 44.7 |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 7660 ng*h/mL | Geometric Coefficient of Variation 402.8 |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 1920 ng*h/mL | Geometric Coefficient of Variation 78 |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 7680 ng*h/mL | Geometric Coefficient of Variation 77.4 |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 12300 ng*h/mL | Geometric Coefficient of Variation 37.4 |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 2350 ng*h/mL | Geometric Coefficient of Variation 87.9 |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 3590 ng*h/mL | Geometric Coefficient of Variation 53.4 |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 14700 ng*h/mL | Geometric Coefficient of Variation 71.7 |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 35200 ng*h/mL | Geometric Coefficient of Variation 0.8 |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 3450 ng*h/mL | Geometric Coefficient of Variation 137.9 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C2D1 dose escalation & expansion phases | 22600 ng*h/mL | Geometric Coefficient of Variation 37.1 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D8: dose escalation phase | 13900 ng*h/mL | Geometric Coefficient of Variation 74.8 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | C1D1 dose escalation phase for 750mg | 3340 ng*h/mL | Geometric Coefficient of Variation 111.9 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-24h | PK Run-in dose escalation phase | 3390 ng*h/mL | Geometric Coefficient of Variation 121.4 |
Secondary
Primary Pharmacokinetics (PK) Parameter: AUC0-last
The AUC from time zero to the last quantifiable concentration point (Tlast). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
Time frame: PK run-in of Dose Escalation phase
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 366 ng*h/mL | — |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 938 ng*h/mL | Geometric Coefficient of Variation 24.3 |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 1460 ng*h/mL | Geometric Coefficient of Variation 62.9 |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 7470 ng*h/mL | Geometric Coefficient of Variation 46.5 |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 4070 ng*h/mL | Geometric Coefficient of Variation 81.8 |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 5140 ng*h/mL | Geometric Coefficient of Variation 141.7 |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 8180 ng*h/mL | Geometric Coefficient of Variation 57.4 |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 9210 ng*h/mL | Geometric Coefficient of Variation 111.7 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: AUC0-last | 7870 ng*h/mL | Geometric Coefficient of Variation 127.3 |
Secondary
Primary Pharmacokinetics (PK) Parameter: Cmax
Cmax is the maximum observed concentration. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Cmax.
Time frame: PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation ion phase, Cycle 2 Day 1 of dose escalation & expansion phases
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 25.1 ng/mL | Geometric Coefficient of Variation 37.5 |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C2D1 dose escalation & dose expansion phases | 21.9 ng/mL | Geometric Coefficient of Variation 9.4 |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 13.1 ng/mL | — |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 76.7 ng/mL | Geometric Coefficient of Variation 20.9 |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 29.3 ng/mL | Geometric Coefficient of Variation 10.1 |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C2D1 dose escalation & dose expansion phases | 53.5 ng/mL | — |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 212 ng/mL | Geometric Coefficient of Variation 18 |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 40.2 ng/mL | Geometric Coefficient of Variation 88.5 |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C2D1 dose escalation & dose expansion phases | 229 ng/mL | Geometric Coefficient of Variation 120.7 |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 198 ng/mL | Geometric Coefficient of Variation 41.5 |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 381 ng/mL | Geometric Coefficient of Variation 167.5 |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 419 ng/mL | Geometric Coefficient of Variation 69.7 |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 120 ng/mL | Geometric Coefficient of Variation 80.9 |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 153 ng/mL | Geometric Coefficient of Variation 86.5 |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 641 ng/mL | Geometric Coefficient of Variation 40 |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 688 ng/mL | Geometric Coefficient of Variation 68.3 |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 212 ng/mL | Geometric Coefficient of Variation 59.7 |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 206 ng/mL | Geometric Coefficient of Variation 145.6 |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 1140 ng/mL | Geometric Coefficient of Variation 37.7 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D1 dose escalation phase for 750mg | 203 ng/mL | Geometric Coefficient of Variation 100.9 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C1D8 dose escalation phase | 674 ng/mL | Geometric Coefficient of Variation 76.2 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | C2D1 dose escalation & dose expansion phases | 1010 ng/mL | Geometric Coefficient of Variation 44.8 |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Cmax | PK Run-in dose escalation phase | 186 ng/mL | Geometric Coefficient of Variation 126.9 |
Secondary
Primary Pharmacokinetics (PK) Parameter: Tmax
Tmax is the time to reach Cmax. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Tmax.
Time frame: PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 2.46 hour |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C2D1 dose escalation & dose expansion phases | 5.00 hour |
| LDK378 50 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 5.95 hour |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 3.49 hour |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 15.0 hour |
| LDK378 100 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C2D1 dose escalation & dose expansion phases | 2.08 hour |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 3.00 hour |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 5.08 hour |
| LDK378 200 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C2D1 dose escalation & dose expansion phases | 8.00 hour |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 4.00 hour |
| LDK378 300 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 4.00 hour |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 6.08 hour |
| LDK378 400 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 4.99 hour |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 3.98 hour |
| LDK378 500 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 3.95 hour |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 4.00 hour |
| LDK378 600 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 6.00 hour |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 6.00 hour |
| LDK378 700 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 5.97 hour |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D1 dose escalation phase for 750mg | 6.00 hour |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C1D8 dose escalation phase | 5.03 hour |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | C2D1 dose escalation & dose expansion phases | 6.00 hour |
| LDK378 750 mg | Primary Pharmacokinetics (PK) Parameter: Tmax | PK run-in dose escalation phase | 6.02 hour |
Secondary
Progression-free Survival Based on BIRC Assessment
Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 50 mg | Progression-free Survival Based on BIRC Assessment | 6.97 months |
| LDK378 100 mg | Progression-free Survival Based on BIRC Assessment | 19.32 months |
| LDK378 200 mg | Progression-free Survival Based on BIRC Assessment | 9.53 months |
Secondary
Progression-free Survival Based on Investigator Assessment
Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
Time frame: 275 weeks
Population: Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LDK378 50 mg | Progression-free Survival Based on Investigator Assessment | 6.93 months |
| LDK378 100 mg | Progression-free Survival Based on Investigator Assessment | 15.21 months |
| LDK378 200 mg | Progression-free Survival Based on Investigator Assessment | 8.74 months |
Secondary
Secondary Pharmacokinetics (PK) Parameter: CL/F
CL/F is the apparent total body clearance of drug from the plasma
Time frame: PK Run-in dose escalation phase
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 126 Litres/hour | — |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 116 Litres/hour | — |
| LDK378 200 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 77.5 Litres/hour | — |
| LDK378 300 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 44.5 Litres/hour | Geometric Coefficient of Variation 36.8 |
| LDK378 400 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 95.9 Litres/hour | Geometric Coefficient of Variation 58.6 |
| LDK378 500 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 147.0 Litres/hour | Geometric Coefficient of Variation 170.3 |
| LDK378 600 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 46.3 Litres/hour | Geometric Coefficient of Variation 9.6 |
| LDK378 700 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 66.6 Litres/hour | Geometric Coefficient of Variation 35.8 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: CL/F | 88.5 Litres/hour | Geometric Coefficient of Variation 162.5 |
Secondary
Secondary Pharmacokinetics (PK) Parameter: CLss/F
CLss/F is the apparent total body clearance of drug from the plasma. There was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter CLss/F.
Time frame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C2D1:dose escalation & dose expansion phases | 133 Litres/hour | — |
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 115 Litres/hour | Geometric Coefficient of Variation 42.1 |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 65.8 Litres/hour | Geometric Coefficient of Variation 41.1 |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C2D1:dose escalation & dose expansion phases | 112 Litres/hour | — |
| LDK378 200 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 48.2 Litres/hour | Geometric Coefficient of Variation 32.2 |
| LDK378 300 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 39.2 Litres/hour | Geometric Coefficient of Variation 402.8 |
| LDK378 400 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 52.1 Litres/hour | Geometric Coefficient of Variation 77.4 |
| LDK378 500 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 40.7 Litres/hour | Geometric Coefficient of Variation 37.4 |
| LDK378 600 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 40.8 Litres/hour | Geometric Coefficient of Variation 71.7 |
| LDK378 700 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 19.9 Litres/hour | Geometric Coefficient of Variation 0.8 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C1D8: dose escalation phase | 53.9 Litres/hour | Geometric Coefficient of Variation 74.8 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: CLss/F | C2D1:dose escalation & dose expansion phases | 33.2 Litres/hour | Geometric Coefficient of Variation 37.1 |
Secondary
Secondary Pharmacokinetics (PK) Parameter: Racc
Racc is the accumulation ratio calculated using AUCtau values obtained from a dosing interval at steady-state divided by AUCtau at day 1 or PK run-in phase. AUCtau is the AUC calculated to the end of the dosing interval, tau. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Racc.
Time frame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C2D1: dose escalation & dose expansion phases | 1.67 unitless | — |
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 2.56 unitless | — |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C2D1: dose escalation & dose expansion phases | 1.77 unitless | — |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 3.25 unitless | Geometric Coefficient of Variation 53.5 |
| LDK378 200 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 6.62 unitless | Geometric Coefficient of Variation 17.6 |
| LDK378 300 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 1.83 unitless | Geometric Coefficient of Variation 215.9 |
| LDK378 400 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 3.80 unitless | Geometric Coefficient of Variation 124.7 |
| LDK378 500 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 6.08 unitless | Geometric Coefficient of Variation 71.5 |
| LDK378 600 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 3.55 unitless | Geometric Coefficient of Variation 51.7 |
| LDK378 700 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 6.84 unitless | Geometric Coefficient of Variation 89.4 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C1D8: dose escalation phase | 4.68 unitless | Geometric Coefficient of Variation 72.1 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: Racc | C2D1: dose escalation & dose expansion phases | 6.20 unitless | Geometric Coefficient of Variation 58.5 |
Secondary
Secondary Pharmacokinetics (PK) Parameter: T1/2
T1/2 is the elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
Time frame: PK Run-in dose escalation phase
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 19.5 hour | — |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 19.4 hour | — |
| LDK378 200 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 33.2 hour | — |
| LDK378 300 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 30.1 hour | Geometric Coefficient of Variation 10 |
| LDK378 400 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 30.7 hour | Geometric Coefficient of Variation 39.1 |
| LDK378 500 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 31.1 hour | Geometric Coefficient of Variation 11.1 |
| LDK378 600 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 37.6 hour | Geometric Coefficient of Variation 24.6 |
| LDK378 700 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 38.9 hour | Geometric Coefficient of Variation 98.4 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: T1/2 | 40.6 hour | Geometric Coefficient of Variation 34.7 |
Secondary
Secondary Pharmacokinetics (PK) Parameter: Vz/F
Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda\_z)
Time frame: PK Run-in dose escalation phase
Population: Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 \& had at least 1 evaluable PK sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LDK378 50 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 3540 Litre | — |
| LDK378 100 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 3250 Litre | — |
| LDK378 200 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 3720 Litre | — |
| LDK378 300 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 1880 Litre | Geometric Coefficient of Variation 50.7 |
| LDK378 400 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 3470 Litre | Geometric Coefficient of Variation 74.4 |
| LDK378 500 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 6230 Litre | Geometric Coefficient of Variation 218.9 |
| LDK378 600 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 1990 Litre | Geometric Coefficient of Variation 4.3 |
| LDK378 700 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 2340 Litre | Geometric Coefficient of Variation 56.5 |
| LDK378 750 mg | Secondary Pharmacokinetics (PK) Parameter: Vz/F | 4230 Litre | Geometric Coefficient of Variation 164.4 |