DS-1205c With Osimertinib for Metastatic or Unresectable Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer
Study Details
Study Description
Brief Summary
This study has two parts: dose escalation and dose expansion.
The primary objectives are:
-
For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population
-
For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population
In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles.
The number of treatment cycles is not fixed in this study. Participants will continue study treatment until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DS-1205c with osimertinib Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1200 mg) in combination with daily 80 mg oral dose of osimertinib |
Drug: DS-1205c
DS-1205c 200 mg capsule
Drug: Osimertinib
Osimertinib 80 mg tablet
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib [Cycle 0, Day 1 (7-day cycle) to Cycle 1, Day 21 of Dose Escalation (each cycle was 21 days)]
A dose-limiting toxicity (DLT) was defined as any TEAE not attributable to disease or disease-related processes that occurred during the DLT-evaluation period (Cycle 0, Day 1 to Cycle 1, Day 21 of Dose Escalation) and was Grade 3 or above, according to NCI-CTCAE Version 5.0.
- Number of Participants With Treatment-emergent Adverse Events Occurring in More Than 1 Participant Following Administration With DS-1205c in Combination With Osimertinib [Screening; Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year]
Treatment-emergent adverse events were defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiating the study drug until 30 days after last dose of the study drug.
Secondary Outcome Measures
- Number of Participants With Best Overall Response Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib [Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year]
Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.
- Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib [Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year]
Disease control rate (DCR) is defined as the sum of complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
- Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib [Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year]
Progression-free survival is defined as the time from the date of first dose to the earliest date of the first objective documentation of disease progression or death due to any cause. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions.
- Overall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib [Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year]
Overall survival was defined as the time from the date of first dose to the date of death due to any cause.
- Maximum Concentration (Cmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib [Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)]
The maximum concentration (Cmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.
- Area Under the Plasma Concentration Curve Following Administration of DS-1205c Alone and in Combination With Osimertinib [Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)]
The area under the plasma concentration curve from time 0 until last quantifiable time point (AUClast) and the area under the plasma concentration curve over a dosing interval (AUCtau) of DS-1205c alone and in combination with osimertinib were assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.
- Time to Maximum Concentration (Tmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib [Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)]
The time to maximum concentration (Tmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.
- Trough Plasma Concentration (Ctrough) Following Administration of DS-1205c Alone and in Combination With Osimertinib [Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)]
The trough plasma concentration (Ctrough) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.
- Terminal Half-life (t1/2) Following Administration of DS-1205c Alone and in Combination With Osimertinib [Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib)]
The terminal half-life (t1/2) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Has histologically or cytologically documented adenocarcinoma NSCLC.
-
Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation.
-
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):
-
Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or
-
Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
-
Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib.
-
Has been receiving erlotinib, gefitinib, or afatinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period.
-
Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib.
-
Has at least one measurable lesion per RECIST version 1.1.
-
Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with erlotinib, gefitinib, afatinib , or osimertinib OR has at least one lesion not previously irradiated, amenable to core biopsy, and is willing to undergo screening tumor biopsy.
-
Demonstrates absence of EGFR T790M. No EGFR mutation testing is required if treated with osimertinib.
-
Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks.
Exclusion Criteria:
-
Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in screening biopsy performed since progression.
-
Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.
-
Has received treatment with any of the following:
-
Any cytotoxic chemotherapy, immune checkpoint inhibitor therapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment.
-
Immune checkpoint inhibitor therapy within 30 days of first dose of study treatment.
-
Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
-
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment.
-
Has history of other active malignancy within 3 years prior to enrollment, except:
-
Adequately treated non-melanoma skin cancer OR
-
Superficial bladder tumors (tumor stage "a" [Ta], tumor stage "is" [Tis], tumor stage "1" [T1]) OR
-
Curatively treated in situ disease OR
-
Low risk non-metastatic prostate cancer (with Gleason score < 7, and following local treatment or undergoing active surveillance)
-
Has spinal cord compression or clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
-
Presence of retinal disease in the eye that is not due to neovascular age-related macular degeneration (nAMD; eg, significant diabetic retinopathy, glaucomatous retinal atrophy, retinal detachment).
-
Has history of myocardial infarction within the past 6 months.
-
Has symptomatic congestive heart failure (New York Heart Association [NYHA] Classes II-IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment.
-
Has left ventricular ejection fraction (LVEF) <45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
-
Has any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval >250 milliseconds (ms).
-
Has a mean QT interval corrected using Fridericia's correction (QTcF) prolongation
470 ms for females and >450 ms for males in three successive Screening measurements.
-
Unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval.
-
Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives.
-
Has any history of interstitial lung disease (pulmonary fibrosis or severe radiation pneumonitis) or is suspected to have such disease by imaging during screening.
-
Has history of pancreatitis within the past 6 months.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Taipei Medical University, Shuang Ho Hospital | New Taipei City | Taiwan | 23561 | |
| 2 | China Medical University Hospital | Taichung | Taiwan | 40447 | |
| 3 | Taichung Veterans General Hospital | Taichung | Taiwan | 40705 | |
| 4 | National Cheng-Kung University Hospital | Tainan | Taiwan | 70457 | |
| 5 | National Taiwan University Hospital | Taipei | Taiwan | 10048 | |
| 6 | Taipei Medical University Hospital | Taipei | Taiwan | 11031 | |
| 7 | Taipei Veterans General Hospital | Taipei | Taiwan | 11217 |
Sponsors and Collaborators
- Daiichi Sankyo, Inc.
Investigators
- Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.
Study Documents (Full-Text)
More Information
Publications
- DS1205-A-U101
Study Results
Participant Flow
| Recruitment Details | A total of 13 participants who met all inclusion criteria and no exclusion criteria were enrolled from 10 April 2019 to 04 September 2020 in the study at 7 clinical sites in Taiwan. |
|---|---|
| Pre-assignment Detail | In the dose escalation phase, the recommended dose for expansion of DS-1205c in combination with a fixed dose of osimertinib was assessed. The doses of DS-1205c selected for this study were based on nonclinical data and were expressed in doses of DS-1205a (free base). |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Period Title: Overall Study | ||||
| STARTED | 6 | 3 | 3 | 1 |
| COMPLETED | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 6 | 3 | 3 | 1 |
Baseline Characteristics
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Total of all reporting groups |
| Overall Participants | 6 | 3 | 3 | 1 | 13 |
| Age (Count of Participants) | |||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
4
66.7%
|
1
33.3%
|
2
66.7%
|
0
0%
|
7
53.8%
|
| >=65 years |
2
33.3%
|
2
66.7%
|
1
33.3%
|
1
100%
|
6
46.2%
|
| Age (years) [Median (Full Range) ] | |||||
| Median (Full Range) [years] |
57.5
|
73.0
|
64.0
|
70
|
64.0
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
6
100%
|
2
66.7%
|
1
33.3%
|
1
100%
|
10
76.9%
|
| Male |
0
0%
|
1
33.3%
|
2
66.7%
|
0
0%
|
3
23.1%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
6
100%
|
3
100%
|
3
100%
|
1
100%
|
13
100%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||||
| Taiwan |
6
100%
|
3
100%
|
3
100%
|
1
100%
|
13
100%
|
Outcome Measures
| Title | Number of Participants With Dose-limiting Toxicities (DLTs) Following Administration With DS-1205c in Combination With Osimertinib |
|---|---|
| Description | A dose-limiting toxicity (DLT) was defined as any TEAE not attributable to disease or disease-related processes that occurred during the DLT-evaluation period (Cycle 0, Day 1 to Cycle 1, Day 21 of Dose Escalation) and was Grade 3 or above, according to NCI-CTCAE Version 5.0. |
| Time Frame | Cycle 0, Day 1 (7-day cycle) to Cycle 1, Day 21 of Dose Escalation (each cycle was 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Dose-limiting toxicities were assessed in the Safety Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Count of Participants [Participants] |
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Number of Participants With Treatment-emergent Adverse Events Occurring in More Than 1 Participant Following Administration With DS-1205c in Combination With Osimertinib |
|---|---|
| Description | Treatment-emergent adverse events were defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiating the study drug until 30 days after last dose of the study drug. |
| Time Frame | Screening; Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treatment-emergent adverse events (TEAEs) were assessed in the Safety Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Any TEAEs |
6
100%
|
3
100%
|
3
100%
|
1
100%
|
| Upper respiratory tract infection |
2
33.3%
|
0
0%
|
1
33.3%
|
0
0%
|
| Urinary tract infection |
2
33.3%
|
1
33.3%
|
0
0%
|
0
0%
|
| Pneumonia |
1
16.7%
|
0
0%
|
0
0%
|
1
100%
|
| Anaemia |
0
0%
|
1
33.3%
|
1
33.3%
|
1
100%
|
| Insomnia |
1
16.7%
|
2
66.7%
|
1
33.3%
|
0
0%
|
| Dizziness |
1
16.7%
|
1
33.3%
|
0
0%
|
0
0%
|
| Headache |
1
16.7%
|
0
0%
|
1
33.3%
|
0
0%
|
| Cough |
1
16.7%
|
1
33.3%
|
0
0%
|
0
0%
|
| Dyspnoea |
1
16.7%
|
1
33.3%
|
0
0%
|
0
0%
|
| Haemoptysis |
1
16.7%
|
1
33.3%
|
0
0%
|
0
0%
|
| Vomiting |
3
50%
|
1
33.3%
|
0
0%
|
0
0%
|
| Diarrhoea |
0
0%
|
1
33.3%
|
2
66.7%
|
0
0%
|
| Constipation |
2
33.3%
|
0
0%
|
0
0%
|
0
0%
|
| Rash |
1
16.7%
|
1
33.3%
|
0
0%
|
0
0%
|
| Fatigue |
1
16.7%
|
2
66.7%
|
0
0%
|
0
0%
|
| Pyrexia |
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
| Alanine aminotransferase increased |
1
16.7%
|
0
0%
|
1
33.3%
|
1
100%
|
| Aspartate aminotransferase increased |
1
16.7%
|
0
0%
|
1
33.3%
|
1
100%
|
| Blood Creatinine Phosphokinase Increased |
0
0%
|
1
33.3%
|
1
33.3%
|
1
100%
|
| Blood Creatinine Increased |
0
0%
|
1
33.3%
|
1
33.3%
|
0
0%
|
| Ejection Fraction Decreased |
0
0%
|
1
33.3%
|
1
33.3%
|
0
0%
|
| Lipase Increased |
0
0%
|
0
0%
|
1
33.3%
|
1
100%
|
| Overdose |
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
| Title | Number of Participants With Best Overall Response Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib |
|---|---|
| Description | Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population. |
| Time Frame | Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Best overall response was assessed in the Full Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Complete response (CR) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Partial response (PR) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Stable disease (SD) |
2
33.3%
|
3
100%
|
3
100%
|
1
100%
|
| Progressive disease (PD) |
3
50%
|
0
0%
|
0
0%
|
0
0%
|
| Not evaluable (NE) |
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
| Overall response rate (ORR) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Disease Control Rate Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib |
|---|---|
| Description | Disease control rate (DCR) is defined as the sum of complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. |
| Time Frame | Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Disease control rate was assessed in the Full Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Count of Participants [Participants] |
2
33.3%
|
3
100%
|
3
100%
|
1
100%
|
| Title | Progression-free Survival Assessed by Investigator Following Administration of DS-1205c in Combination With Osimertinib |
|---|---|
| Description | Progression-free survival is defined as the time from the date of first dose to the earliest date of the first objective documentation of disease progression or death due to any cause. As per the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions. |
| Time Frame | Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Progression-free survival was assessed in the Full Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Median (95% Confidence Interval) [weeks] |
7.1
|
NA
|
22.0
|
12.4
|
| Title | Overall Survival in Participants Following Administration of DS-1205c in Combination With Osimertinib |
|---|---|
| Description | Overall survival was defined as the time from the date of first dose to the date of death due to any cause. |
| Time Frame | Screening; Cycle 0 (7-day cycle); Cycle 1 and beyond (21-day cycles), Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (± 7 days) thereafter; and end-of-treatment, 30 days after last dose, up to 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| Overall survival was assessed in the Full Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Median (95% Confidence Interval) [weeks] |
46.9
|
NA
|
NA
|
NA
|
| Title | Maximum Concentration (Cmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib |
|---|---|
| Description | The maximum concentration (Cmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate. |
| Time Frame | Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Cycle 0: Day 1 |
292
(94.8)
|
413
(94.0)
|
499
(222)
|
703
(NA)
|
| Cycle 0: Day 7 |
561
(191)
|
827
(299)
|
1041
(460)
|
1070
(NA)
|
| Cycle 2: Day 1 |
544
(176)
|
845
(328)
|
921
(260)
|
1150
(NA)
|
| Title | Area Under the Plasma Concentration Curve Following Administration of DS-1205c Alone and in Combination With Osimertinib |
|---|---|
| Description | The area under the plasma concentration curve from time 0 until last quantifiable time point (AUClast) and the area under the plasma concentration curve over a dosing interval (AUCtau) of DS-1205c alone and in combination with osimertinib were assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate. |
| Time Frame | Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| AUClast, Cycle 0: Day 1 |
1916
(530)
|
2493
(277)
|
2891
(1398)
|
5050
(NA)
|
| AUClast, Cycle 0: Day 7 |
4193
(1514)
|
5716
(1931)
|
7385
(4562)
|
8602
(NA)
|
| AUClast, Cycle 2: Day 1 |
4445
(1389)
|
6852
(2716)
|
7220
(2629)
|
9495
(NA)
|
| AUCtau, Cycle 0: Day 1 |
1975
(563)
|
2557
(257)
|
3002
(1472)
|
5255
(NA)
|
| AUCtau, Cycle 0: Day 7 |
4818
(1772)
|
6496
(2208)
|
6972
(NA)
|
10300
(NA)
|
| AUCtau, Cycle 2: Day 1 |
4596
(1488)
|
7117
(2883)
|
7640
(2918)
|
10000
(NA)
|
| Title | Time to Maximum Concentration (Tmax) Following Administration of DS-1205c Alone and in Combination With Osimertinib |
|---|---|
| Description | The time to maximum concentration (Tmax) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate. |
| Time Frame | Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Cycle 0: Day 1 |
4.1
|
4.0
|
3.9
|
6.2
|
| Cycle 0: Day 7 |
4.0
|
4.0
|
4.0
|
4.0
|
| Cycle 2: Day 1 |
4.1
|
4.0
|
2.1
|
3.9
|
| Title | Trough Plasma Concentration (Ctrough) Following Administration of DS-1205c Alone and in Combination With Osimertinib |
|---|---|
| Description | The trough plasma concentration (Ctrough) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate. |
| Time Frame | Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 6 | 3 | 3 | 1 |
| Cycle 0: Day 7 |
376
(143)
|
460
(219)
|
688
(631)
|
816
(NA)
|
| Cycle 2: Day 1 |
359
(137)
|
576
(275)
|
722
(406)
|
903
(NA)
|
| Title | Terminal Half-life (t1/2) Following Administration of DS-1205c Alone and in Combination With Osimertinib |
|---|---|
| Description | The terminal half-life (t1/2) of DS-1205c alone and in combination with osimertinib was assessed. Pharmacokinetic (PK) parameters for each participant were estimated using non-compartmental analysis. Descriptive statistics are provided for all plasma concentration data by analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as appropriate. |
| Time Frame | Predose, 1, 2, 4, 6, 8, and 12 hours of Cycle 0 (7-day cycle; DS-1205c alone), Day 1; Predose, 1, 2, 4, 6, 8, and 10 hours of Cycle 0, Day 7 (DS-1205c alone); Predose, 1, 2, 4, 6, 8, 10, and 12 hours of Cycle 2 (21-day cycle), Day 1 (DS-1205c+osimertinib) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic parameter of terminal half-life (t1/2) was assessed in the Pharmacokinetic Analysis Set, except for 1 patient (Cohort 1) who did not have an available sample. |
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib |
|---|---|---|---|---|
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. |
| Measure Participants | 5 | 3 | 3 | 1 |
| Cycle 0: Day 1 |
6.98
(1.89)
|
5.3
(1.0)
|
4.7
(0.6)
|
3.3
(NA)
|
| Cycle 0: Day 7 |
11.6
(6.7)
|
7.1
(1.0)
|
6.9
(NA)
|
|
| Cycle 2: Day 1 |
9.8
(3.3)
|
7.9
(0.8)
|
7.0
(1.3)
|
11.7
(NA)
|
Adverse Events
| Time Frame | Treatment-emergent adverse events (TEAEs) were collected at Screening, Cycle 0 (7-day cycle), Days -1, 1, 2, 4, 6, and 7; Cycle 1 (21-day cycle), Days 4, 8, and 15; Cycle 2 (21-day cycle), Days 1, 2, and 8; Cycle 3 and beyond (21-day cycles), Day 1; and end-of-treatment, 30 days after last dose, up to 1 year. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | A TEAE is defined as an adverse event that occurs, having been absent before the first dose of study drug, or has worsened in severity after the initiation of the study drug until 30 days after last dose of the study drug. | |||||||
| Arm/Group Title | DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib | ||||
| Arm/Group Description | Participants who received DS-1205c 200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 400 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 400 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 800 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 800 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | Participants who received DS-1205c 1200 mg twice daily (BID) at Cycle 0 monotherapy of a 7-day cycle and DS-1205c 1200 mg BID in combination with 80 mg oral dose of osimertinib daily (QD) at Cycle 1 and beyond of a 21-day cycle. | ||||
All Cause Mortality |
||||||||
| DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
Serious Adverse Events |
||||||||
| DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/6 (33.3%) | 1/3 (33.3%) | 2/3 (66.7%) | 1/1 (100%) | ||||
| Cardiac disorders | ||||||||
| Cardiac failure | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Coronary artery disease | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Dysphagia | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pancreatitis | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Infections and infestations | ||||||||
| Pneumonia | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 1/1 (100%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Aspartate aminotransferase increased | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Metastases to Meninges | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Pneumonia aspiration | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| DS-1205c 200 mg + Osimertinib | DS-1205c 400 mg + Osimertinib | DS-1205c 800 mg + Osimertinib | DS-1205c 1200 mg + Osimertinib | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 3/3 (100%) | 3/3 (100%) | 1/1 (100%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 1/1 (100%) | ||||
| Haematuria | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Lymph node pain | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | 1/1 (100%) | ||||
| Splenomegaly | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Cardiac disorders | ||||||||
| Cardiac failure | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Coronary artery disease | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Ear and labyrinth disorders | ||||||||
| Tinnitus | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Endocrine disorders | ||||||||
| Hyperthyroidism | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Eye disorders | ||||||||
| Conjunctival haemorrhage | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Conjunctivitis | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Cornea verticillata | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Dry eye | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Vomiting | 3/6 (50%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Diarrhoea | 0/6 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 0/1 (0%) | ||||
| Constipation | 2/6 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Abdominal pain | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Dysphagia | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Gastric polyps | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Gastric ulcer | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Gastritis | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Nausea | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pancreatitis | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Stomatitis | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| General disorders | ||||||||
| Fatigue | 1/6 (16.7%) | 2/3 (66.7%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pyrexia | 0/6 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/1 (0%) | ||||
| Mucosal inflammation | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Infections and infestations | ||||||||
| Upper respiratory tract infection | 2/6 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Urinary tract infection | 2/6 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pneumonia | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 1/1 (100%) | ||||
| Herpes simplex | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Nasopharyngitis | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Paronychia | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Tinea capitis | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Overdose | 0/6 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/1 (0%) | ||||
| Contusion | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Traumatic haematoma | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | 1/1 (100%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 1/6 (16.7%) | 0/3 (0%) | 1/3 (33.3%) | 1/1 (100%) | ||||
| Aspartate aminotransferase increased | 1/6 (16.7%) | 0/3 (0%) | 1/3 (33.3%) | 1/1 (100%) | ||||
| Blood creatinine phosphokinase increased | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 1/1 (100%) | ||||
| Blood creatinine increased | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Ejection fraction decreased | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Lipase increased | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/1 (100%) | ||||
| Blood bilirubin increased | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Electrocardiogram QT prolonged | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| International normalised ratio increased | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Neutrophil count decreased | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Platelet count decreased | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| White blood cell count decreased | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Hypoalbuminaemia | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Hyponatraemia | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Back pain | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pain in extremity | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Spondylolisthesis | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Metastases to meninges | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Headache | 1/6 (16.7%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Facial paralysis | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Hypoaesthesia | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Lethargy | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Peripheral motor neuropathy | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Psychiatric disorders | ||||||||
| Insomnia | 1/6 (16.7%) | 2/3 (66.7%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Anxiety | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Depression | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Dyspnoea | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Haemopytsis | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Breath sounds abnormal | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Dysphonia | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Oropharyngeal pain | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pleural effusion | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Pneumonia aspiration | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Productive cough | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Wheezing | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Rash | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Decubitus ulcer | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Dry skin | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
| Onychomadesis | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Pruritus | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Rash maculo-papular | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | 0/1 (0%) | ||||
| Skin exfoliation | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Vascular disorders | ||||||||
| Hypertension | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/1 (0%) | ||||
| Hypotension | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/1 (0%) | ||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Contact for Clinical Trial Information |
|---|---|
| Organization | Daiichi Sankyo |
| Phone | 908-992-6400 |
| CTRinfo@dsi.com |
- DS1205-A-U101