臨床研究等提出・公開システム

Phase 1/2, Multicenter, Open-label, Multiple-Dose First-in-human Study of U3-1402, in Subjects with HER3 Positive Metastatic Breast Cancer

Phase I/II Study of U3-1402 in Subjects with HER3 Positive Metastatic Breast Cancer

184

The mean (range) age of the subjects who were received at least one dose of the study drug was 55.6 years (range: 30 to 83). All subjects were female. Asian:142 patients (78.0%), White: 34patients (18.7%), Black or African American: 4 patients (2.2%), Alaska Native: 1 patient (0.5%), Other 1 patient (0.5%). The median number of prior cancer regimen (range) was 6.0 (1 to 14).

184 subjects were enrolled. 182 subjects who were enrolled and received at least one dose of the study drug were included in the efficacy and safety analysis set.

The overall incidence of TEAEs was 99.5% (181 patients). Drug-related TESAEs were 20.9% (38 patients). The major TESAEs were platelet count decreased 4.9% (9 patients), nausea 3.8% (7 patients), vomiting 3.8% (7 patients), decreased appetite 3.8% (7 patients), febrile neutropenia 2.2% (4 patients) and disease progression 2.2% (4 patients). Dose interruption, dose reduction, dose discontinuation, or death due to TEAEs were occured in 100 (54.9%), 35 (19.2%), 18 (9.9%) and 7 (3.8%) patients, respectively. The ILD Independent Adjudication Committee adjudicated 6.6% of patients had treatment-related ILD events. Most were grade 1 and 2 (4.4%). Three events were grade 3 (1.6%). One event was grade 5 (0.5%).

Efficacy Results: Of 182 patients, ORR (Overall Response Rate) : 52 patients (28.6%) (95% CI : 22.1, 35.7), DCR (Disease Control Rate) : 148 patients (81.3%) (95% CI : 74.9, 86.7), DOR (Duration Of Response) (median) : 7.0 months (95% CI : 5.5, 8.5), CBR (Clinical Benefit Rate) : 77 patients (42.3%) (95% CI : 35.0, 49.8), TTR (Time To Response) (median) : 6.1months (95% CI : 4.4, 8.3), PFS (Progression Free Survival) (median) : 5.8 months (95% CI : 5.4, 8.1), OS (Overall Survival) (median) : 14.6 months (95% CI : 12.7, 17.2) Safety Results: Please refer to "Adverse Events" section.

Pharmacokinetic Results: DE/DF Parts - Systemic exposure (Cmax and AUCtau) of U3-1402 increased in a generally dose-dependent manner in Cohorts 1 to 5 (1.6 to 8.0 mg/kg), Cohort 6 (3.2/4.8/6.4 mg/kg), and Cohort 7 (4.2/6.4 mg/kg). - For U3-1402, the estimation of the slope of the dose proportionality analysis in Cycle 1 and Cycle 3 was close to 1 for Cmax but was between 1.26 and 1.71 for AUCtau and AUClast. - The PK parameters of total anti-HER3 antibody were comparable to those of U3-1402, whereas exposure to systemic MAAA-1181a was much lower on a mass weight basis than those to U3 1402 and total anti HER3 antibody. - The Tmax for all analytes was rapid (ie, iv administration); the t1/2 for U3-1402 and total anti HER3 antibody was similar and showed a gradual increase with dose means of approximately 3 days for the 1.6 mg/kg dosed group to approximately 7.3 days for the 6.4 and 8.0 mg/kg dose groups. With the exception of the 1.6 mg/kg dosed subjects, the t1/2 tended to increase from Cycle 1 to Cycle 3. The t1/2 for MAAA-1181a also showed a trend to increase with dose (means from 3.5 to 5.3 days) but did not demonstrate any change from Cycle 1 to Cycle 3. - For MAAA-1181a, the estimated slope of the dose proportionality analysis in Cycle 1 and Cycle 3 was close to 1 for Cmax, AUCtau, and AUClast. DEX Part - The increase in U3-1402 systemic exposure (mean Cmax and AUClast) from HER3-High (4.8 mg/kg) to DEX HER3-High 2 (6.4 mg/kg) was dose dependent in Cycle 1 and Cycle 3. - The Cmax of all 3 analytes (U3-1402, total anti-HER3 antibody, and MAAA-1181a) in the DEX Cohorts (6.4 mg/kg) is comparable to each other in Cycle 1 and in Cycle 3. - The AUCtau all 3 analytes was comparable between the DEX HER3-High 2 (6.4 mg/kg), DEX HER3-Low (6.4 mg/kg), and DEX TNBC Cohorts (6.4 mg/kg) in Cycle 1 and in Cycle 3. - The median Tmax and the mean t1/2 of all 3 analytes were also comparable between DEX HER3-High 2 (6.4 mg/kg), DEX HER3-Low (6.4 mg/kg), and DEX TNBC Cohorts (6.4 mg/kg) in Cycle 1 and in Cycle 3.

HER3-DXd demonstrated clinically meaningful and durable antitumor activity in a heavily pretreated population of patients with HER3-expressing BC. The safety profile was acceptable and manageable.

June. 04, 2022

https://ascopubs.org/doi/10.1200/JCO.23.00882?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

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/

DAIICHI SANKYO Co.,Ltd.

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

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

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

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

completed

Dec. 13, 2016

Interventional

Multicenter, open-label Dose Escalation Part: To assess safety and tolerability, To determine MTD Dose Finding Part: To assess safety and efficacy, To assess the safety of alternative dosing schedule(s) of U3-1402, To determine a recommended doses for Expansion Dose Expansion Part: To assess the safety and evaluate the efficacy at the recommended doses for Expansion in subject with HER2 negative breast cancers (including TNBC).

treatment purpose

1-2

Common Inclusion Criteria
1. Has a pathologically documented advanced/unresectable or metastatic breast cancer.
2. Documented HER3-positive disease measured by immunohistochemistry (IHC) .
3. Refractory to or intolerable with standard treatment, or for which no standard treatment is available.
4. Age >= 20 years in Japan, >= 18 years in the United States.
5. Has an Eastern Cooperative Oncology Group Performance Status 0-1.
6. Has left ventricular ejection fraction >= 50%.
7. Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Additional Inclusion Criteria for Dose Finding Part and Dose Expansion Part
1. Has received >= 2 and =< 6 prior chemotherapeutic regimens for breast cancer, >= 2 of which were administered for treatment of advanced/unresectable or metastatic disease. At least 1 prior chemotherapeutic regimen must have included a taxane administered in the neoadjuvant, adjuvant, or advanced setting. (With exception of Dose Expansion Part TNBC cohort.)

Additional Inclusion Criteria for Dose Expansion Part
1. Is able to submit a fresh tumor biopsy sample prior starting study treatment. (If subjects have already submitted fresh tumor biopsy sample for HER3 expression, they don't need to submit it again.)
2. Has documented hormone (estrogen and/or progesterone) receptor (HR)-positive and HER2 negative expression according to American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines. (With exception of Dose Expansion Part TNBC cohort.)

Additional Inclusion criteria for Dose Expansion Part TNBC cohort:
1. Has documented hormone (estrogen and progesterone) receptor (HR)-negative and HER2 negative expression according to American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines.
2. Has progressed after receiving 1 to 2 prior chemotherapy regimens for advanced/unresectable or metastatic breast cancer.

1. Prior treatment with a HER3 antibody.
2. Prior treatment with an antibody-drug conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201).
3. Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatment.
4. Has a medical history of myocardial infarction or unstable angina.
5. Has a corrected QT prolongation to > 450 millisecond (ms) in males and > 470 ms in females
6. Has any history of interstitial lung disease (pulmonary fibrosis or radiation pneumonitis) or is suspected to have such disease by imaging during screening.
7. Has clinically significant corneal disease.

Additional Exclusion criteria for Dose Expansion Part
Prior treatment with an antibody-drug conjugate (ADC) which consists of govitecan derivative (eg, IMMU-132).

Both

Metastatic Breast Cancer

investigational material(s)
Generic name etc : U3-1402
INN of investigational material : -
Therapeutic category code : 429 Other antitumor 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
Dose Escalation Part: Safety, Tolerability
Dose Finding Part: Safety, Efficacy
Dose Expansion Part: Safety, Efficacy
Assessment of tumor response to U3-1402 using RECIST ver. 1.1

safety
efficacy
pharmacokinetics
pharmacodynamics
Dose Escalation Part: Pharmacokinetics, Efficacy, Incidence of anti-drug antibodies (ADAs) against U3-1402
Dose Finding Part: Pharmacokinetics, Incidence of ADAs against U3-1402
Dose Expansion Part: Pharmacokinetics, Incidence of ADAs against U3-1402 relationship between efficacy of U3-1402 and HER3 expression

+81-3-3542-2511

Nov. 09, 2016