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A MultiCenter, Open-Label Phase 1 Study of DS-1205c in Combination with GEFITINIB in SUBJECTS with Metastatic or Unresectable egfr mutant Non Small Cell Lung Cancer

A MULTICENTER, OPEN-LABEL PHASE 1 STUDY OF DS-1205c IN COMBINATION WITH GEFITINIB IN SUBJECTS WITH METASTATIC OR UNRESECTABLE EGFR-MUTANT NON-SMALL CELL LUNG CANCER

20

All of the 20 subjects in the FAS were Japanese. There were 4 males and 16 females. The median age (range) was 68.5 (36 to 82) years, with 14 subjects aged 65 years or older. The median body weight (range) was 47.90 (33.7 to 71.8) kg. All of the 20 subjects had ECOG PS of 0 or 1, in accordance with the inclusion criteria of the study: ECOG PS was 0 in 9 subjects and 1 in 11 subjects. Tumors were histologically and/or cytologically determined to be adenocarcinoma in all subjects. Tumor stage at study entry was IV in 19 subjects. Five subjects had brain metastasis. A total of 7 subjects had EGFR mutation of T790M. In addition, 12 subjects had L858R, 7 subjects had exon 19 deletion, and 1 subject had L861Q. Before the final version of the protocol (version 5.0 published on 29 Jul 2019), subjects after osimertinib treatment could be enrolled in the study regardless of the status of EGFR T790M mutation. Therefore, although the final version of the protocol required absence of EGFR T790M mutation, subjects enrolled in the study before the protocol revision might have T790M mutation.

A total of 20 subjects were enrolled in the study and received DS-1205c. The planned number of subjects was 3 in each cohort at a minimum; the actual number of subjects was 5 in Cohort 1, 4 in Cohort 2, 6 in Cohort 3, 1 in Cohort 4, and 4 in Cohort 5. DLT evaluation in Cohort 4 (1000 mg BID) was completed on 1 subject and discussed at Safety Review Meeting with investigators to initiate Cohort 5 (1200 mg BID). In total, all of the 20 enrolled and treated subjects were included in the FAS, safety analysis set, PK analysis set, and biomarker analysis set. The DLT-evaluable set consisted of 19 subjects. One subject (Subject No. 10301201) in Cohort 1 was excluded from the DLT-evaluable set because the subject was assessed as PD on Cycle 1 Day 17 and did not complete the DLTevaluation period.

Nineteen of the 20 subjects (95.0%) in the safety analysis set had at least 1 TEAE. The most frequently occurring TEAEs were aspartate aminotransferase increased, alanine aminotransferase increased, rash maculopapular, diarrhoea, and white blood cell count decreased. The frequency of the transaminase changes (aspartate aminotransferase increased and alanine aminotransferase increased) tended to increase with the increasing dose of DS-1205c. Grade 3 TEAEs were reported in 6 of the 20 subjects (30.0%): 1 subject in Cohort 1 (nausea), 2 subjects in Cohort 3 (alanine aminotransferase increased in 1 subject, white blood cell count decreased and neutrophil count decreased in 1 subject), and 3 subjects in Cohort 5 (diarrhoea and hepatic function abnormal in 1 subject, nausea in 1 subject, alanine aminotransferase increased in 1 subject). No Grade 4 TEAEs were reported. No serious TEAEs or TEAEs leading to death were reported in the study. One subject in Cohort 5 had a TEAE leading to drug withdrawal (Grade 2 rash). No subjects had TEAEs leading to dose reduction. Seven of the 20 subjects (35.0%) had a TEAE leading to dose interruption. No TEAESIs (hepatic event, QTcF prolongation, or interstitial lung disease) occurred in the study. Fourteen of the 20 subjects (70.0%) in the safety analysis set had at least 1 TEAE during Cycle 0. Most of the Grade 3 TEAEs and TEAEs leading to dose interruption reported in the study occurred during Cycle 0. No clinically relevant changes from baseline or consistent trends were seen in laboratory parameters (hematology, blood chemistry, coagulation, urinalysis, or thyroid function test parameters), except for ALT and AST. The means of ALT and AST tended to increase until Cycle 1 Day 4, and then returned toward the baseline levels. Increases in ALT and AST in each subject were transient. No clinically relevant changes from baseline or consistent trends were seen in vital signs. A QTcF interval of > 480 ms was reported in 1 subject in Cohort 5, and a post-baseline QTcF change of > 30 ms was reported in 1 subject each in Cohorts 2, 3, and 5. Most of these were not considered clinically significant. The data demonstrated that DS-1205c in combination with gefitinib had a generally tolerable and manageable safety profile.

Among the 19 subjects in the DLT-evaluable set, there were 2 DLTs; 1 subject in Cohort 3 (800 mg BID) experienced neutrophil count decreased and 1 subject in Cohort 5 (1200 mg BID) experienced nausea. With all available safety, PK, and tumor response data taken into consideration, the RDE was established to be 800 mg BID.

With regard to the BOR, no subjects achieved CR or PR. SD was observed in 5 of the 20 subjects (25.0%). The DCR (95% confidence interval [CI]) was 25.0% (8.7%, 49.1%). Of the 20 subjects, 18 experienced disease progression. The median (95% CI) PFS was 6.9 (6.1, 7.9) weeks. No reduction in tumor size was observed in any subjects, as assessed by the best percent change in SoD. The mean Cmax and AUC of DS-1205a generally increased with the increasing dose of DS-1205c; however, the increases tended to reach a plateau at high dose levels (800 mg BID to 1200 mg BID). The mean values of Cmax, AUC, and Ctrough were similar among time points on or after Cycle 0 Day 7 within each cohort, suggesting that the plasma DS-1205a concentrations reached the steady state within 7 days of BID dose administration. The PK parameters of DS-1205a on Cycle 2 Day 1 were generally similar to those on Cycle 0 Day 7, suggesting that the PK of DS-1205a was not affected by gefitinib. A dose-exposure relationship analysis using a power model suggested that the increases in exposure of DS-1205a were less than dose proportional. Although the mean Cmax and AUC of gefitinib varied among the cohorts, no specific pattern was observed both on Cycle 1 Day 1 and Cycle 2 Day 1.

DS-1205c was generally safe and well tolerated at all dose levels in Japanese subjects with metastatic or unresectable EGFR-mutant NSCLC; however, the dose of 800 mg BID had a more favorable safety profile compared to 1200 mg BID. The RDE of DS-1205c when administered in combination with gefitinib was determined to be 800 mg BID.

May. 11, 2023

Jan. 09, 2023

https://onlinelibrary.wiley.com/doi/10.1002/cam4.5508

No

-

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Oct. 12, 2018

Interventional

Multicenter, open-label

treatment purpose

1

1. Has histologically or cytologically documented adenocarcinoma NSCLC.
2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation.
3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):
a. 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
b. 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.
4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib.
5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period. Subjects who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day.
6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib.
7. Has at least one measurable lesion per RECIST version 1.1.
8. Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with gefitinib, erlotinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy.
9. Demonstrates absence of EGFR T790M mutation in tumor tissue since progression during gefitinib, erlotinib, afatinib, or osimertinib treatment;
10. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks.

1. 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.
2. 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.
3. Has received treatment with any of the following:
a. 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.
b. Immune checkpoint inhibitor therapy within 30 days of first dose of study treatment.
c. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
d. 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.
4. Has history of other active malignancy within 3 years prior to enrollment, except:
a. Adequately treated non-melanoma skin cancer OR
b. Superficial bladder tumors (Tumor stage "a" [Ta], Tumor stage "is" [Tis], Tumor stage "1" [T1]) OR
c. Curatively treated in situ disease OR
d. Low-risk non-metastatic prostate cancer (with Gleason score < 7 on antiandrogen therapy)
5. 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).
6. 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).
7. Has history of myocardial infarction within the past 6 months.
8. Has symptomatic congestive heart failure (New York Heart Association [NYHA] Classes II-IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment.
9. Has left ventricular ejection fraction (LVEF) < 45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
10. 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).
11. Has a mean corrected QT interval using Fridericia's correction (QTcF) prolongation >470 ms for females and >450 ms for males in three successive Screening measurements.
12. Unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval.
13. 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.
14. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroid treatment, has current ILD/pneumonitis, or has suspected ILD/pneumonitis which cannot be ruled out by imaging at screening.
15. Has history of pancreatitis within the past 6 months.

Both

EGFR mutation-positive non-small cell lung cancer

investigational material(s)
Generic name etc : DS-1205c, gefitinib
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : DS-1205c: orally, Gefitinib: orally

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
Safety, tolerability
Grading of AE is based on CTCAE ver.5.0

efficacy
pharmacokinetics
PK, efficacy
Tumor response measurement is based on RECIST ver 1.1

+81-3-3542-2511

Aug. 01, 2018