Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV
Conditions
Keywords
MEK1/2 inhibitor,, Non Small Cell Lung Cancer,, metastatic,, first line treatment for Non Small Cell Lung Cancer
Brief summary
This is a Phase I, open label multicentre study of selumetinib administered orally in combination with first line chemotherapy regimens to patients with advanced/metastatic NSCLC. The study has been designed to allow an investigation of the optimal dose of selumetinib in combination with various standard first line double-platinum chemotherapy regimens. Initial assessment will be based on tolerability of selumetinib in combination with one or more selected regimens that are considered to be tolerated also being assessed for preliminary evidence of activity. This study is a dose finding and optional cohort expansion; In addition all patients will be assessed for anti-cancer efficacy of the combination of selumetinib and chemotherapy.
Detailed description
A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Selumetinib (AZD6244; ARRY-142886) in Combination with First Line Chemotherapy Regimens in Patients with Non-Small Cell Lung Cancer (NSCLC)
Interventions
DRUGselumetinib
2 x 25mg capsules bd continuously in cohort 1 (with gemcitabine and cisplatin). If tolerated - next cohort 3 x 25mg capsules bd continuously. if higher doses are explored, required number of capsules will be provided. Option to administer on D2-19 of each 21 day cycle if required to assess tolerability of combinations with chemotherapy
DRUGgemcitabine
1250 mg/m2 iv on Day 1 and 8 of each 21 day cycle. If combination not tolerated, option to give 1000 mg/m2 iv on Day 1 and Day 8 of each 21 day cycle
DRUGcisplatin
75 mg/m2 iv on Day 1 of each 21 day cycle. If combination not tolerated, option to give 50 mg/m2 iv on Day 1 or 25mg/m2 iv on Day 1 and Day 8 of each 21 day cycle
DRUGcarboplatin
If it is not possible to identify a tolerable combination of selumetinib, gemcitabine and cisplatin, cisplatin may be replaced with carboplatin (AUC5) iv on Day 1 of each 21 day cycle
DRUGpemetrexed
Gemcitabine may be replaced with pemetrexed 500 mg/m2 iv on Day 1 of each 21 day cycle.
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed, written and dated consent prior to any study specific procedures * Male or female, aged 18 years or older * Histological or cytological confirmation of locally advanced or metastatic NSCLC (IIIB-IV) * Female patients must not be breast-feeding and have a negative pregnancy test prior to start of dosing or must have evidence of non-child-bearing potential * Patients must be eligible to receive treatment with the platinum doublet combination with which selumetinib is being combined and in accordance with the local product information
Exclusion criteria
* Prior chemotherapy or other systemic anti-cancer treatment for advanced NSCLC. * Prior surgery or radiotherapy within 6 months or palliative radiotherapy within 4 weeks of start of study treatment. * Female patients who are breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control * Another primary malignancy within 5 years of starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ. * As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, renal transplant, or active infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks | Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline at 6 Weeks in Target Lesion Size | Week 6 | The percentage change in the sum of the diameters of target lesions |
| Best Percentage Change From Baseline in Target Lesion Size | Screening, week 6 and week 12 | The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions |
| Objective Response Rate (ORR) | Up until progression or last evaluable assessment in the absence of progression, up to 9 months | The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm; Objective Response Rate (ORR) = CR + PR |
| Best Objective Response | Screening, week 6 and week 12 | The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), \>=20% increase in the sum of the longest diameter of target lesions, the sum must also demonstrate an absolute increase of \>=5mm; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm |
| Cmax,ss | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose | Maximum plasma concentration at steady state |
| Tmax,ss | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose | Time to reach maximum plasma concentration at steady state |
| CL/F | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose | Apparent oral plasma clearance |
| AUC (0-tau) | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose | Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau) |
Countries
United Kingdom
Participant flow
Recruitment details
Patients were enrolled into dose-finding cohorts to evaluate escalating doses of selumetinib (AZD6244; ARRY-142886) to determine the maximum tolerated dose in combination with standard first-line chemotherapy regimens. Chemotherapy was administered on Day 1 (and Day 8 for gemcitabine) of each 3-week cycle.
Pre-assignment details
Data cut off (DCO) was 7 Jan 16. DCO was defined as the earliest of 12 (±1) weeks after last patient started, or 28 days after final patient discontinued, selumetinib or chemotherapy doublet regimen.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 sel50, Gem, Cis selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | 3 |
| Cohort 2 sel50, Gem, Carb selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | 9 |
| Cohort 3 sel75, Gem, Cis selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | 7 |
| Cohort 4 sel150, Pem, Carb selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | 3 |
| Cohort 5 sel75, Pem, Carb selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | 6 |
| Cohort 6 sel75, Pem, Cis selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | 15 |
| Cohort 7 sel100, Pem, Carb selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | 12 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 2 | 0 | 1 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 0 | 4 |
Baseline characteristics
| Characteristic | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.7 Years STANDARD_DEVIATION 3.79 | 69.2 Years STANDARD_DEVIATION 3.53 | 55.1 Years STANDARD_DEVIATION 8.65 | 64.7 Years STANDARD_DEVIATION 7.23 | 59.5 Years STANDARD_DEVIATION 5.28 | 61.8 Years STANDARD_DEVIATION 5.86 | 60.2 Years STANDARD_DEVIATION 8.39 | 61.5 Years STANDARD_DEVIATION 7.45 |
| Race/Ethnicity, Customized Black Or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 9 Participants | 7 Participants | 3 Participants | 5 Participants | 13 Participants | 11 Participants | 50 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 3 Participants | 1 Participants | 4 Participants | 5 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 10 Participants | 5 Participants | 29 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 9 / 9 | 7 / 7 | 3 / 3 | 6 / 6 | 15 / 15 | 12 / 12 |
| serious Total, serious adverse events | 1 / 3 | 6 / 9 | 3 / 7 | 2 / 3 | 3 / 6 | 9 / 15 | 9 / 12 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib
Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting
Time frame: The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks
Population: Safety analysis set - all patients who received at least 1 dose of selumetinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 3 participants |
| Cohort 1 sel50, Gem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 0 participants |
| Cohort 2 sel50, Gem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 7 participants |
| Cohort 2 sel50, Gem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 2 participants |
| Cohort 3 sel75, Gem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 4 participants |
| Cohort 3 sel75, Gem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 1 participants |
| Cohort 4 sel150, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 3 participants |
| Cohort 4 sel150, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 0 participants |
| Cohort 5 sel75, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 6 participants |
| Cohort 5 sel75, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 0 participants |
| Cohort 6 sel75, Pem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 12 participants |
| Cohort 6 sel75, Pem, Cis | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 1 participants |
| Cohort 7 sel100, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients | 6 participants |
| Cohort 7 sel100, Pem, Carb | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib | Evaluable patients with a DLT Event | 1 participants |
Secondary
AUC (0-tau)
Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau)
Time frame: Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Population: Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | AUC (0-tau) | NA h*ng/mL | — |
| Cohort 2 sel50, Gem, Carb | AUC (0-tau) | 3571 h*ng/mL | Geometric Coefficient of Variation 42.13 |
| Cohort 3 sel75, Gem, Cis | AUC (0-tau) | 3339 h*ng/mL | Geometric Coefficient of Variation 15.08 |
| Cohort 4 sel150, Pem, Carb | AUC (0-tau) | 4813 h*ng/mL | Geometric Coefficient of Variation 30.93 |
| Cohort 5 sel75, Pem, Carb | AUC (0-tau) | 4366 h*ng/mL | Geometric Coefficient of Variation 48.14 |
| Cohort 6 sel75, Pem, Cis | AUC (0-tau) | 4116 h*ng/mL | Geometric Coefficient of Variation 33.92 |
| Cohort 7 sel100, Pem, Carb | AUC (0-tau) | 5202 h*ng/mL | Geometric Coefficient of Variation 52.94 |
Secondary
Best Objective Response
The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), \>=20% increase in the sum of the longest diameter of target lesions, the sum must also demonstrate an absolute increase of \>=5mm; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm
Time frame: Screening, week 6 and week 12
Population: Tumour response analysis set - dosed patients with a baseline tumour assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Stable disease | 0 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Complete response | 0 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Incomplete post-baseline assessments | 0 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Partial response | 1 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Death | 0 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | Unconfirmed complete or partial response | 0 participants |
| Cohort 1 sel50, Gem, Cis | Best Objective Response | RECIST progression | 2 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Incomplete post-baseline assessments | 3 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Partial response | 2 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Death | 0 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | RECIST progression | 0 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Stable disease | 1 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Complete response | 0 participants |
| Cohort 2 sel50, Gem, Carb | Best Objective Response | Unconfirmed complete or partial response | 3 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Complete response | 0 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Unconfirmed complete or partial response | 0 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Partial response | 2 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Incomplete post-baseline assessments | 2 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Death | 0 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | Stable disease | 2 participants |
| Cohort 3 sel75, Gem, Cis | Best Objective Response | RECIST progression | 1 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Stable disease | 2 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Partial response | 1 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Complete response | 0 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Unconfirmed complete or partial response | 0 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | RECIST progression | 0 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Death | 0 participants |
| Cohort 4 sel150, Pem, Carb | Best Objective Response | Incomplete post-baseline assessments | 0 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Incomplete post-baseline assessments | 0 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Complete response | 0 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Stable disease | 3 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Unconfirmed complete or partial response | 2 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Partial response | 1 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | Death | 0 participants |
| Cohort 5 sel75, Pem, Carb | Best Objective Response | RECIST progression | 0 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Incomplete post-baseline assessments | 2 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Complete response | 0 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Partial response | 2 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | RECIST progression | 1 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Death | 1 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Stable disease | 7 participants |
| Cohort 6 sel75, Pem, Cis | Best Objective Response | Unconfirmed complete or partial response | 2 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Stable disease | 6 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | RECIST progression | 1 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Partial response | 2 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Death | 0 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Complete response | 0 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Incomplete post-baseline assessments | 1 participants |
| Cohort 7 sel100, Pem, Carb | Best Objective Response | Unconfirmed complete or partial response | 2 participants |
Secondary
Best Percentage Change From Baseline in Target Lesion Size
The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions
Time frame: Screening, week 6 and week 12
Population: Tumour response analysis set - dosed patients with a baseline tumour assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Best Percentage Change From Baseline in Target Lesion Size | -11.9 % change | Standard Deviation 26.52 |
| Cohort 2 sel50, Gem, Carb | Best Percentage Change From Baseline in Target Lesion Size | -34.6 % change | Standard Deviation 8.11 |
| Cohort 3 sel75, Gem, Cis | Best Percentage Change From Baseline in Target Lesion Size | -41.3 % change | Standard Deviation 21.25 |
| Cohort 4 sel150, Pem, Carb | Best Percentage Change From Baseline in Target Lesion Size | -28.3 % change | Standard Deviation 15.25 |
| Cohort 5 sel75, Pem, Carb | Best Percentage Change From Baseline in Target Lesion Size | -34.7 % change | Standard Deviation 33.3 |
| Cohort 6 sel75, Pem, Cis | Best Percentage Change From Baseline in Target Lesion Size | -24.4 % change | Standard Deviation 14.71 |
| Cohort 7 sel100, Pem, Carb | Best Percentage Change From Baseline in Target Lesion Size | -25.4 % change | Standard Deviation 20.51 |
Secondary
CL/F
Apparent oral plasma clearance
Time frame: Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Population: Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | CL/F | NA L/h | — |
| Cohort 2 sel50, Gem, Carb | CL/F | 14.72 L/h | Standard Deviation 5.156 |
| Cohort 3 sel75, Gem, Cis | CL/F | 22.64 L/h | Standard Deviation 3.521 |
| Cohort 4 sel150, Pem, Carb | CL/F | 10.72 L/h | Standard Deviation 3.328 |
| Cohort 5 sel75, Pem, Carb | CL/F | 18.82 L/h | Standard Deviation 9.777 |
| Cohort 6 sel75, Pem, Cis | CL/F | 19.08 L/h | Standard Deviation 5.881 |
| Cohort 7 sel100, Pem, Carb | CL/F | 21.02 L/h | Standard Deviation 9.857 |
Secondary
Cmax,ss
Maximum plasma concentration at steady state
Time frame: Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Population: Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Cmax,ss | 476.7 ng/mL | Geometric Coefficient of Variation 51.12 |
| Cohort 2 sel50, Gem, Carb | Cmax,ss | 1222 ng/mL | Geometric Coefficient of Variation 59.86 |
| Cohort 3 sel75, Gem, Cis | Cmax,ss | 1487 ng/mL | Geometric Coefficient of Variation 23.09 |
| Cohort 4 sel150, Pem, Carb | Cmax,ss | 1615 ng/mL | Geometric Coefficient of Variation 27.71 |
| Cohort 5 sel75, Pem, Carb | Cmax,ss | 1375 ng/mL | Geometric Coefficient of Variation 40.21 |
| Cohort 6 sel75, Pem, Cis | Cmax,ss | 1364 ng/mL | Geometric Coefficient of Variation 57.78 |
| Cohort 7 sel100, Pem, Carb | Cmax,ss | 2309 ng/mL | Geometric Coefficient of Variation 35.99 |
Secondary
Objective Response Rate (ORR)
The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm; Objective Response Rate (ORR) = CR + PR
Time frame: Up until progression or last evaluable assessment in the absence of progression, up to 9 months
Population: Tumour response analysis set - dosed patients with a baseline tumour assessment.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Objective Response Rate (ORR) | 1 participants | 26.52 |
| Cohort 2 sel50, Gem, Carb | Objective Response Rate (ORR) | 2 participants | 8.11 |
| Cohort 3 sel75, Gem, Cis | Objective Response Rate (ORR) | 2 participants | 21.25 |
| Cohort 4 sel150, Pem, Carb | Objective Response Rate (ORR) | 1 participants | 15.25 |
| Cohort 5 sel75, Pem, Carb | Objective Response Rate (ORR) | 1 participants | 33.3 |
| Cohort 6 sel75, Pem, Cis | Objective Response Rate (ORR) | 2 participants | 14.71 |
| Cohort 7 sel100, Pem, Carb | Objective Response Rate (ORR) | 2 participants | 20.51 |
Secondary
Percentage Change From Baseline at 6 Weeks in Target Lesion Size
The percentage change in the sum of the diameters of target lesions
Time frame: Week 6
Population: Tumour response analysis set - dosed patients with a baseline tumour assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -7.5 % change | Standard Deviation 19.79 |
| Cohort 2 sel50, Gem, Carb | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -29.3 % change | Standard Deviation 11.15 |
| Cohort 3 sel75, Gem, Cis | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -10.4 % change | Standard Deviation 24.45 |
| Cohort 4 sel150, Pem, Carb | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -14.7 % change | Standard Deviation 1.91 |
| Cohort 5 sel75, Pem, Carb | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -24.4 % change | Standard Deviation 32.6 |
| Cohort 6 sel75, Pem, Cis | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -18.9 % change | Standard Deviation 10.55 |
| Cohort 7 sel100, Pem, Carb | Percentage Change From Baseline at 6 Weeks in Target Lesion Size | -18.4 % change | Standard Deviation 19.58 |
Secondary
Tmax,ss
Time to reach maximum plasma concentration at steady state
Time frame: Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Population: Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Cohort 1 sel50, Gem, Cis | Tmax,ss | 1.00 h | Full Range 51.12 |
| Cohort 2 sel50, Gem, Carb | Tmax,ss | 1.25 h | Full Range 23.09 |
| Cohort 3 sel75, Gem, Cis | Tmax,ss | 1.00 h | Full Range 57.78 |
| Cohort 4 sel150, Pem, Carb | Tmax,ss | 1.00 h | Full Range 59.86 |
| Cohort 5 sel75, Pem, Carb | Tmax,ss | 1.75 h | Full Range 27.71 |
| Cohort 6 sel75, Pem, Cis | Tmax,ss | 1.48 h | Full Range 40.21 |
| Cohort 7 sel100, Pem, Carb | Tmax,ss | 1.50 h | Full Range 35.99 |