Study of DS-8201a for Participants With Advanced Solid Malignant Tumors

• ClinicalTrials.gov Identifier: NCT03383692
• Recruitment Status: Completed
• First Posted: December 26, 2017
• Results First Posted: June 14, 2021
• Last Update Posted: December 11, 2023
• Sponsor: Daiichi Sankyo Co., Ltd.
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Daiichi Sankyo ( Daiichi Sankyo Co., Ltd. )

Tracking Information

• First Submitted Date: December 7, 2017
• First Posted Date: December 26, 2017
• Results First Submitted Date: May 18, 2021
• Results First Posted Date: June 14, 2021
• Last Update Posted Date: December 11, 2023
• Actual Study Start Date: January 12, 2018
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 18, 2021)

• Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Ritonavir - Cohort 1 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Maximum concentration (Cmax) was assessed for DS-8201a and total Anti-HER2 antibody.
• Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) For MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Maximum concentration (Cmax) was assessed for MAAA-1181a.
• Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Ritonavir - Cohort 1 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Area under the serum concentration-time curve from time zero to 17 days (AUC17d) and during the dosing interval (AUCtau) for DS-8201a and total anti-HER2 antibody were assessed.
• Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Area under the serum concentration-time curve from time zero to 17 days (AUC17d) and during the dosing interval (AUCtau) were assessed for MAAA-1181a.
• Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Itraconazole - Cohort 2 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Maximum concentration (Cmax) was assessed for DS-8201a and total Anti-HER2 antibody.
• Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Maximum concentration (Cmax) was assessed for MAAA-1181a.
• Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Itraconazole - Cohort 2 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Area under the serum concentration-time curve from time zero to 17 days (AUC17d) and during the dosing interval (AUCtau) were assessed for DS-8201a and total anti-HER2 antibody.
• Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2 [ Time Frame: Cycle 1: Day 1, pre-dose and end of infusion (EOI); Cycles 2 and 3: Day 1, pre-dose, EOI, 2 hours, 4 hours, 7 hours; Day 2, 4, 8, 12, 17, and 22; Cycles 4, 6 and 8: Day 1, pre-dose and EOI (each cycle is 22 days) ]
  Area under the serum concentration-time curve from time zero to 17 days (AUC17d) and during the dosing interval (AUCtau) were assessed for MAAA-1181a.

Original Primary Outcome Measures (submitted: December 19, 2017)

• Cohort 1: Maximum concentration (Cmax) [ Time Frame: within 3 months ]
  Categories: DS-8201a and MAAA-1181a, with and without ritonavir
• Cohort 1: Area under the drug-time concentration curve from 0 to 17 days (AUC0-17d) [ Time Frame: within 3 months ]
  Categories: DS-8201a and MAAA-1181a, with and without ritonavir
• Cohort 2: Maximum concentration (Cmax) [ Time Frame: until the end of the trial (approximately 8.5 months) ]
  Categories: DS-8201a and MAAA-1181a, with and without itraconazole
• Cohort 2: Area under the drug-time concentration curve from 0 to 17 days (AUC0-17d) [ Time Frame: until the end of the trial (approximately 8.5 months) ]
  Categories: DS-8201a and MAAA-1181a, with and without itraconazole

Current Secondary Outcome Measures (submitted: May 18, 2021)

• Best Objective Response as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [ Time Frame: Baseline up to disease progression, death, lost to follow up, or study discontinuation (whichever comes first), up to approximately 9 months post-dose ]
  Best objective response (BOR) was assessed by the investigator based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Completed response (CR) was defined as a disappearance of all target lesions, 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 Ratio (ORR) as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [ Time Frame: Baseline up to disease progression, death, lost to follow up, or study discontinuation (whichever comes first), up to approximately 9 months post-dose ]
  Objective response ratio (ORR) was defined as the proportion of participants who achieved CR and PR as assessed by the investigator based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
• Objective Response Rate as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [ Time Frame: Baseline up to disease progression, death, lost to follow up, or study discontinuation (whichever comes first), up to approximately 9 months post-dose ]
  Objective response rate (defined as participants who achieved CR and PR) was assessed by the investigator based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. ORR with confirmation is Objective Response Rate applying a confirmed response of CR/PR in RECIST version 1.1.

Original Secondary Outcome Measures (submitted: December 19, 2017)

• Number of participants who discontinued because of adverse events (AEs) [ Time Frame: after all subjects have either discontinued the study or completed at least 4 cycles of the study drug (approximately 8.5 months) ]
  AEs include serious AEs, non-serious treatment-emergent AEs (TEAEs) and AEs of special interest (AESIs) Clinically significant changes in physical examination findings, vital sign measurements, standard clinical laboratory parameters, 12-lead electrocardiogram (ECG) parameters, ECHO cardiography or multiple-gated acquisition (MUGA) scan, ophthalmologic findings and anti-drug antibodies will be recorded as AEs.
• Objective response rate (ORR) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  ORR is defined as the percentage of participants who achieve a best overall response of complete response (CR) or partial response (PR)
• Disease control rate (DCR) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  DCR is defined as the percentage of participants who achieve the sum of CR rate, PR rate, and stable disease (SD) rate for a minimum of 5 weeks from the first dosing date
• Duration of Response (DoR) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  DoR is defined as the length of time response of CR or PR or SD lasted
• Duration of stable disease (SD) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  Duration of stable disease is defined as the length of time SD lasted
• Clinical benefit ratio (CBR) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  BR is defined as the number of participants who achieved a best overall response of CR or PR or more than 6 months SD
• Time to response (TTR) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  TTR is defined as the time it took for the participants to have a response
• Progression free survival (PFS) [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  Progression-free survival is defined as the length of time the participant survived without the disease getting worse, based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Number of participants with anti-drug antibodies against DS-8201a [ Time Frame: through the end of the trial (approximately 8.5 months) ]
  A reaction to the drug by the immune system leads to production of antibodies against the drug, called an anti-drug antibody (ADA)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of DS-8201a for Participants With Advanced Solid Malignant Tumors
• Official Title: A Phase 1, Multicenter, Open-label, Single Sequence Crossover Study to Evaluate Drug-drug Interaction Potential of OATP1B/CYP3A Inhibitor on the Pharmacokinetics of DS-8201a in Subjects With HER2-expressing Advanced Solid Malignant Tumors

Brief Summary

HER2-positive cancer is a cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). HER2 promotes the growth of certain cancer cells. This study will test an experimental drug called DS-8201a that has not been approved by the health authorities yet.

DS-8201a will be tested for safety in patients with advanced solid malignant tumors that test positive for HER2. It also will test how DS-8201a moves within the body (pharmacokinetics).

Detailed Description

The expected time from the first subject's enrollment until the last subject's enrollment is approximately 8.5 months. The screening period is 28 days and each cycle of treatment is 21 days.

The data for the primary analysis will cutoff after all subjects have either discontinued the study or completed at least 3 cycles, whichever comes first. After the primary analysis, the main study will be closed and transition to the extension period.

Depending on the preliminary results of Cohort 1, Sponsor may decide whether Cohort 2 will be opened or not.

The number of treatment cycles is not fixed in this study. Subjects who continue to derive clinical benefit from the study drug in the absence of withdrawal of consent, progressive disease (PD), or unacceptable toxicity may continue the study drug.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasm Metastasis

Intervention

• Drug: DS-8201a
  DS-8201a is provided as a sterile lyophilized powder of DS-8201a in a glass vial, which will be dissolved and administered as an intravenous (IV) solution
• Drug: Ritonavir
  Ritonavir is a OATP1B inhibitor; an antiretroviral tablet for oral administration
  Other Name: Norvir
• Drug: Itraconazole
  Itraconazole is a CYP3A inhibitor; an antifungal tablet for oral administration
  Other Names:

  • Sporanox
  • Orungal

Study Arms

• Experimental: Cohort 1: DS-8201a + Ritonavir
  DS-8201a will be administered as an intravenous (IV) solution once every 3 weeks (Q3W) + Ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3
  Interventions:

  • Drug: DS-8201a
  • Drug: Ritonavir
• Experimental: Cohort 2: DS-8201a + Itraconazole
  DS-8201a will be administered as an intravenous (IV) solution once every 3 weeks (Q3W) + Itraconazole BID on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3
  Interventions:

  • Drug: DS-8201a
  • Drug: Itraconazole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 30, 2018): 40
• Original Estimated Enrollment (submitted: December 19, 2017): 32
• Actual Study Completion Date: September 11, 2023
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Has a pathologically documented unresectable or metastatic solid malignant tumor, with HER2 expression [immunohistochemistry (IHC) 3+, 2+, or 1+ and/or in situ hybridization (ISH) +], Next Generation Sequencing, or other analysis techniques as appropriate] that is refractory to or intolerable with at least one prior systemic chemotherapy regimen, or for which no standard treatment is available
• Has a left ventricular ejection fraction (LVEF) ≥ 50%
• Has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1

Exclusion Criteria:

• Has a contraindication for receiving ritonavir or itraconazole according to the prescribing information
• Has a medical history of myocardial infarction within 6 months before enrollment or symptomatic congestive heart failure

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, Korea, Republic of, Taiwan

Administrative Information

• NCT Number: NCT03383692
• Other Study ID Numbers: DS8201-A-A104; 173790 ( Registry Identifier: JAPIC CTI )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) 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 Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Studies 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 from 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/

• Current Responsible Party: Daiichi Sankyo ( Daiichi Sankyo Co., Ltd. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: AstraZeneca

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: September 2023