臨床研究等提出・公開システム

Phase 1 study of DS-8201a in subjects with advanced solid malignant tumors

Phase 1 study of DS-8201a in subjects with advanced solid malignant tumors

292

Overall, the majority of subjects were female, <65 years of age, Asian from Japan with an ECOG PS of 0, and treated with 5 or more prior regimens for locally advanced/metastatic cancer . In the Enrolled Analysis Set, those who assigned to receive 5.4 or 6.4 mg/kg, 105/277 (37.9%) subjects were treated with the ATC class anthracyclines and related substances as part of a prior cancer therapy . Among the tumor types, gastric/GEJ cancer subjects had the highest proportion of male subjects, Asian subjects, as well as the shortest mean time from initial diagnosis. Compared to the 5.4 mg/kg dose group, the 6.4 mg/kg group had a higher proportion of male subjects, Asian subjects, and subjects from Japan. Per protocol, subjects were enrolled into the study based on historical HER2 status. HER2 IHC was later assessed retrospectively by central laboratory testing of submitted archival samples. Among HER2-positive BC subjects: -Of the 32 evaluable subjects with IHC 2+ HER2 expression by the study site, 16 (13.6%) had IHC 2+ HER2 expression by the central laboratory (50.0% concordance) and 7 (5.9%) had IHC 3+ HER2 expression by central laboratory -Of the 70 evaluable subjects with IHC 3+ HER2 expression by the study site, 48 (40.7%) had IHC 3+ HER2 expression by the central laboratory (68.6% concordance) and 12 (10.2%) had IHC 2+HER2 expression by central laboratory Among HER2-low BC subjects: - Of the 24 subjects with IHC 1+ HER2 expression by the study site, 17 (31.5%) had IHC 1+ HER2 expression by the central laboratory (70.8%) concordance and 4 (7.4%) had IHC 2+ HER2 expression by the central laboratory - Of the 25 subjects with IHC 2+ HER2 expression by the study site, 10 (18.5%) had IHC 2+ HER2 expression by the central laboratory (40.0% concordance) and 13 (24.1%) had IHC 2+ HER2 expression by the central laboratory In the Enrolled Analysis Set, central testing results of HER2 expression were missing for 32 subjects (12 subjects at 5.4 mg/kg, 19 subjects at 6.4 mg/kg, and 1 subject at 0.8 mg/kg in Part 1) Tissue samples of 19 subjects were submitted but were not evaluable or had no tumor tissue. For 13 subjects, informed consent was obtained but no tumor tissue sample was available. One subject withdrew consent before starting study drug.

A total of 292 participants who met all inclusion and no exclusion criteria were enrolled at 8 centers in the US and 6 centers in Japan. A total of 27 participants started the Dose Escalation phase and a total of 265 participants in the Dose Expansion phase. Enrolled Analysis Set (ITT) included 292 patricipants. n=292, of whom 3 were not dosed. Safety Analysis Set (SAS) included 289 participants. The Dose Escalation was intended to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of DS-8201a with at least 3 participants evaluable for assessment of dose-limiting toxicity per dose level. Since the MTD was not reached, doses of 5.4 mg/kg and 6.4 mg/kg were chosen for evaluation in the Dose Expansion phase.

Overall, T DXd demonstrated an acceptable and generally manageable safety profile, with the results from 289 treated subjects considered in the evaluation of common TEAEs overall and by subgroup. No DLT was reported and the MTD was not reached in the Dose Escalation Phase. Among the 289 subjects in the Safety Analysis Set: - 288 (99.7%) subjects experienced at least 1 TEAE, with most of the common TEAEs being gastrointestinal or hematological in nature, which is in line with the known nonclinical and pharmacological profile and the currently established safety profile of T DXd and/or of this class of drugs, and were manageable via dose modification and routine clinical practice. Gastrointestinal: nausea was most commonly reported, was predominantly Grade 1 or Grade 2, occurred early in the treatment (the majority occurring in the first 1 to 3 cycles), and was manageable under routine clinical practice. Hematological: events were predominantly Grade 1 or Grade 2, occurred early in treatment (the majority occurring in the first 1 to 3 cycles), and were manageable under routine clinical practice. - 175 (60.6%) subjects had a >=Grade 3 TEAE, which included the following grouped TEAEs that are hematological in nature: anemia (21.5%), platelet count decrease (11.8%), neutrophil count decrease (18.7%), white blood cell count decrease (13.1%), and lymphocyte count decrease (4.2%). - 68 (23.5%) subjects discontinued study drug due to TEAE, with the most common TEAEs associated with being investigator reported ILD. 134 (46.4%) subjects had at least 1 dose interruption due to TEAEs, with the most common TEAEs associated with being neutrophil count decrease and anemia. 67 (23.2%) subjects had at least 1 dose reduction due to TEAEs, with the most common TEAEs associated with being decreased appetite and platelet count decrease. - TEAEs associated with an outcome of death were reported in 15 (5.2%) subjects. 14 of these subjects each had a single TEAE with an outcome of death: 4 (1.4%) had a PT of pneumonitis, 3 (1.0%) respiratory failure, 3 (1.0%) disease progression, 1 (0.3%) acute respiratory failure, 1 (0.3%) ILD, 1 (0.3%) pneumonia aspiration, 1 (0.3%) mechanical ileus. - All events of potential ILD/pneumonitis defined by the 44 PTs in the ILD AC Charter were adjudicated by an independent AC. Of the 72 (24.9%) subjects with potential ILD events submitted, 55 (19.0%) subjects had events that were adjudicated as drug related ILD. Most of the events adjudicated as drug related ILD were either Grade 1 (18 [6.2%]) or Grade 2 (24 [8.3%]), fewer were Grade 3 (4 [1.4%]), no was Grade 4, and few were Grade 5 (9 [3.1%]). A higher frequency of events adjudicated as drug related ILD was observed in the following subgroups: subjects treated with 6.4 mg/kg (40/183 [21.9%]) vs. 5.4 mg/kg (13/91 [14.3%]) and subjects in Japan (40/178 [22.5%]) vs. subjects in US (15/111 [13.5%]).

Median duration of follow up for all subjects at doses of 5.4 mg/kg or 6.4 mg/kg in the Dose Escalation and Dose Expansion phases across all tumor types was 17.3 months (range = 0.1 to 87.6). As described below, clinically meaningful and durable responses were seen across multiple tumor types at doses of 5.4 mg/kg or 6.4 mg/kg. Confirmed ORR by ICR of 54.2% (95% CI = 44.8 to 63.4) was seen among the 118 subjects with HER2 positive BC, with confirmed ORR of 51.0% (95% CI = 36.6 to 65.2) for the 51 subjects in the 5.4 mg/kg dose group and confirmed ORR 56.7% (95% CI = 44.0 to 68.8) for the 67 subjects in the 6.4 mg/kg dose group. The median confirmed DoR by ICR was 13.3, 10.8, and 13.6 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. The median PFS by ICR was 13.7, 13.7, and 14.7 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Median OS was 33.7, 33.7, and 32.6 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Similar results were seen regardless of the hormone receptor status of the subject. Confirmed ORR by ICR of 38.9% (95% CI = 25.9 to 53.1) was seen among the 54 subjects with HER2 low BC, with confirmed ORR of 38.1% (95% CI = 18.1 to 61.6) for the 21 subjects in the 5.4 mg/kg dose group and confirmed ORR of 39.4% (95% CI = 22.9 to 57.9) for the 33 subjects in the 6.4 mg/kg dose group. Median confirmed DoR by ICR was 9.6, 9.6, and 10.4 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Median PFS by ICR was 10.9, 10.8, and 11.1 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Median OS was 19.7, 17.8, and 19.7 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Confirmed ORR by ICR of 29.5% (95% CI = 16.8 to 45.2) was seen among the 44 subjects with HER2 positive gastric/GEJ cancer, with confirmed ORR of 26.3% (95% CI = 9.1 to 51.2) for the 19 subjects in the 5.4 mg/kg dose group and confirmed ORR of 32.0% (95% CI = 14.9 to 53.5) for the 25 subjects in the 6.4 mg/kg dose group. Median confirmed DoR by ICR was 5.8, 5.6, and 6.9 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Median PFS by ICR was 5.4, 4.3, and 8.2 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Median OS was 20.2, 18.9, and 26.2 months for the pooled, 5.4 mg/kg, and 6.4 mg/kg dose groups, respectively. Subjects with prior irinotecan also showed high ORR (50.0% [95% CI = 29.1 to 70.9]). Confirmed ORR by ICR of 29.5% (95% CI = 18.5 to 42.6) was seen among the 61 subjects with other cancers, including 1 subject with no study drug administration, 1 subject dosed with 5.4 mg/kg, and 59 subjects dosed with 6.4 mg/kg. Median confirmed DoR by ICR was 13.4 months (95% CI = 7.0 to not estimable). Median PFS by ICR was 7.2 months (95% CI = 4.8 to 11.1) and median OS was 21.9 months (95% CI = 15.8 to 29.1).

Pharmacokinetics: Dose escalation part After intravenous (iv) administration of DS-8201a, median time to reach maximum concentration (Tmax) of DS-8201a was from 1.95 to 4.12 h and mean elimination half-life (t1/2) was from 2.18 to 7.33 day, across a dose level range of 0.8 to 8.0 mg/kg. the t1/2 increased with dose between 0.8 and 3.2 mg/kg but remained approximately constant within a dose range of 5.4 to 8.0 mg /kg. DS-8201a systemic exposure (maximum concentration; Cmax and area under the concentration-versus-time curve from time 0 to the last quantifiable concentration; AUClast) increased in a generally dose-dependent manner. DS-8201a Cmax was dose- proportional across the dose range of 0.8 to 8.0 mg/kg. DS-8201a AUClast demonstrated greater-than-dose-proportional increases across the wide dose range of 0.8 to 8.0 mg/kg but increased dose-proportionally at doses at or above 3.2 mg/kg. The PK parameters of total anti-HER2 antibody were comparable to those of DS-8201a. After iv administration of DS-8201a, free payload (DXd) concentrations in serum gradually increased and reached peak concentrations with longer median Tmax (range of median Tmax: 5.38 to 6.98 h) compared to those for DS-8201a. The t1/2 of DXd ranged from 2.50 to 6.45 day, with similar to that of DS-8201a. The systemic exposure (Cmax and AUClast) of DXd was much lower than that of DS-8201a, where DS-8201a exposure was >10 ,000-fold to that of DXd. The AUClast of DXd was generally constant over 5.4 mg/kg. Dose expansion part The Cmax and AUC of DS-8201a were numerically higher for the 6.4 mg/kg dose than for the 5.4 mg/kg dose across cohorts. PK parameters of total anti-HER2 antibody were comparable to those of DS-8201a. The DXd serum exposures were similar across parts, and >10 ,000-fold lower than those seen for DS-8201a for Cmax and AUC. The mean t1/2 appeared to be similar to that of DS-8201a. For DS-8201a, all parameters were similar between HER2-positive and HER2-low BC, with lower values for HER2-positive gastric /GEJ cancer. The DXd serum exposures appeared to be similar across all tumor types. Between FL-DP1 and FL-DP2 drug products, PK parameters by drug product were comparable for each analyte. Formation of anti-drug antibody (ADA): Five (2.4%) subjects were positive for ADA at baseline, with 1 (0.5%) of these subjects ADA- positive after dosing. In the subject with an ADA-positive result after dosing, AUClast was comparable to that of the ADA negative subjects. No subject who was ADA-negative at baseline was ADA-positive after dosing.

At the 5.4 and 6.4 mg/kg doses that were chosen for the Dose Expansion phase, T-DXd demonstrated clinical activity in terms of clinically meaningful and durable responses. ILD/pneumonitis is an important identified risk of T-DXd. Although cases with fatal outcomes have been reported, most events were Grade 1 or 2 and were manageable by modifying the dose and following the established ILD management guidelines.

Oct. 13, 2017

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(17)30604-6.pdf

Yes

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Information: - Study Protocol - Statistical Analysis Plan (SAP) - Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

completed

Sept. 04, 2015

Interventional

Multicenter, non-randomized, open-label Part 1: dose escalation, Part 2: dose expansion

treatment purpose

1

1. Age >= 20 years in Japan, >= 18 years in the United States.
2. Eastern Cooperative Oncology Group performance status(PS) of 0 or 1.
3. Left ventricular ejection fraction (LVEF) >= 50%
Part 1:
1. Advanced/unresectable or metastatic breast cancer or gastric or gastroesophageal junction adenocarcinoma that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
Part 2a:
1. Advanced breast cancer with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
2.Treated with T-DM1
Part 2b:
1. Advanced gastric or gastroesophageal junction adenocarcinoma with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
2. Treated with trastuzumab
Part 2c:
1. Advanced breast cancer with HER2 low expression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
Part 2d:
Satisfy at least one of the following criteria
1. Advanced/unresectable or metastatic solid malignant tumor with HER2 expression other than breast cancer and gastric or gastroesophageal junction adenocarcinoma that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
2. Advanced/unresectable or metastatic tumor with HER2 mutation that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
Part 2e
1. Advanced breast cancer with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
2. Treated with ado-trastuzumab emtansine (T-DM1) (patients with HER2 overexpression only)

1. Has a medical history of symptomatic CHF (New York Heart Association; NYHA classes II-IV) or serious cardiac arrhythmia.
2. Has a medical history of myocardial infarction or unstable angina.
3. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females.
4. Has a medical history of clinically significant lung diseases

Both

advanced solid malignant tumors

investigational material(s)
Generic name etc : DS-8201a
INN of investigational material : trastuzumab deruxtecan
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Intravenous

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

safety
efficacy
Part 1: Safety
Part 2: Safety, Efficacy

Assessment of tumor response to DS-8201a using RECIST ver. 1.1

pharmacokinetics
exploratory
Part 1: Pharmacokinetics, Incidence of human anti-human antibodies (HAHA) against DS-8201a, Efficacy
Part 2: Pharmacokinetics, Incidence of human anti-human antibodies (HAHA) against DS-8201a

Aug. 10, 2015