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

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03383692
• Collaborator: AstraZeneca (Industry)
• Enrollment: 40
• Locations: 10
• Arms: 2
• Anticipated Duration (Months): 62.6
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Neoplasm Metastasis	Drug: DS-8201a; Drug: Ritonavir; Drug: Itraconazole	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jan 12, 2018
• Actual Primary Completion Date: Sep 26, 2018
• Anticipated Study Completion Date: Mar 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
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	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 Names: Norvir
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	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: Itraconazole; Itraconazole is a CYP3A inhibitor; an antifungal tablet for oral administration; Other Names: Sporanox Orungal

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Ritonavir - Cohort 1 [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.

2. Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) For MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1 [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.

3. Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Ritonavir - Cohort 1 [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.

4. Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1 [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.

5. Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Itraconazole - Cohort 2 [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.

6. Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2 [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.

7. Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Itraconazole - Cohort 2 [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.

8. Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2 [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.

Secondary Outcome Measures

1. Best Objective Response as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [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.

2. Objective Response Ratio (ORR) as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [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.

3. Objective Response Rate as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hokkaido Cancer Center	Sapporo	Hokkaido	Japan	003-0804
2	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
3	Kobe University Hospital	Kobe	Hyogo	Japan	650-0017
4	Hamamatsu University Hospital	Hamamatsu	Shizuoka	Japan	431-3125
5	Shizuoka Cancer Center	Nagaizumicho	Shizuoka	Japan	411-0934
6	National Cancer Center Hospital	Chuo Ku	Tokyo	Japan	104-0045
7	The Cancer Institute Hospital of JFCR	Koto-Ku	Tokyo	Japan	135-8550
8	Seoul National University Hospital	Seoul		Korea, Republic of	03080
9	Samsung Medical Center	Seoul		Korea, Republic of	06351
10	National Taiwan University Hospital	Taipei		Taiwan	100

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.
• AstraZeneca

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 3, 2020

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Co., Ltd.
• ClinicalTrials.gov Identifier: NCT03383692
• Other Study ID Numbers: DS8201-A-A104; 173790
• First Posted: Dec 26, 2017
• Last Update Posted: Mar 14, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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
• Keywords provided by Daiichi Sankyo Co., Ltd.: Unresectable or metastatic solid malignant tumors; Solid malignant tumors; Oncology; HER2; Antibody drug conjugate; ADC
• Additional relevant MeSH terms: Neoplasm Metastasis; Neoplasms; Ritonavir; Itraconazole

Study Results

Participant Flow

Recruitment Details	A total of 40 participants who met all inclusion criteria and no exclusion criteria were enrolled and received treatment at 10 study centers in Japan, South Korea, and Taiwan.
Pre-assignment Detail	Based on the pharmacokinetic parameters of DS-8201a assessed in an earlier Phase 1 trial, 5.4 mg/kg DS-8201a was chosen to assess drug interactions.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Period Title: Overall Study
STARTED	17	23
COMPLETED	11	19
NOT COMPLETED	6	4

Baseline Characteristics

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir	Cohort 2: DS-8201a + Itraconazole	Total
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily on Day 17 of Cycle 2 until Day 21 of Cycle 3.	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole BID on Day 17 of Cycle 2 followed by 200 mg QD until Day 21 of Cycle 3.	Total of all reporting groups
Overall Participants	17	23	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.5 (9.45)	53.5 (12.91)	56.5 (11.96)
Age, Customized (Count of Participants)
<65 years	10 58.8%	18 78.3%	28 70%
≥65 years	7 41.2%	5 21.7%	12 30%
Sex: Female, Male (Count of Participants)
Female	12 70.6%	10 43.5%	22 55%
Male	5 29.4%	13 56.5%	18 45%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	17 100%	23 100%	40 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Ritonavir - Cohort 1
Description	Maximum concentration (Cmax) was assessed for DS-8201a and total Anti-HER2 antibody.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.
Measure Participants	12
DS-8201a, Cycle 2: DS-8201a only	133 (25.5)
DS-8201a, Cycle 3: DS-8201a + ritonavir	140 (23.0)
Total Anti-HER2 antibody, Cycle 2: DS-8201a only	121 (22.2)
Total Anti-HER2 antibody, Cycle 3: DS-8201a + ritonavir	126 (23.1)

2. Primary Outcome

Title	Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) For MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1
Description	Maximum concentration (Cmax) was assessed for MAAA-1181a.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.
Measure Participants	12
MAAA-1181a, Cycle 2: DS-8201a only	8.98 (2.83)
MAAA-1181a, Cycle 3: DS-8201a + ritonavir	8.95 (3.68)

3. Primary Outcome

Title	Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Ritonavir - Cohort 1
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.
Measure Participants	12
DS-8201a, Cycle 2 (DS-8201a only): AUC17d	650 (168.0)
DS-8201a, Cycle 2 (DS-8201a only): AUCtau	701 (185)
DS-8201a, Cycle 3 (DS-8201a + ritonavir): AUC17d	754 (137.0)
DS-8201a, Cycle 3 (DS-8201a + ritonavir): AUCtau	810 (153.0)
Total Anti-HER2 antibody, Cycle 2 (DS-8201a only): AUC17d	723 (191)
Total Anti-HER2 antibody, Cycle 2 (DS-8201a only): AUCtau	791 (217)
Total Anti-HER2 antibody, Cycle 3 (DS-8201a + ritonavir): AUC17d	796 (155)
Total Anti-HER2 antibody, Cycle 3 (DS-8201a + ritonavir): AUCtau	860 (170)

4. Primary Outcome

Title	Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Ritonavir - Cohort 1
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.
Measure Participants	12
MAAA-1181a, Cycle 2 (DS-8201a only): AUC17d	32.7 (7.45)
MAAA-1181a, Cycle 2 (DS-8201a only): AUCtau	35.0 (8.10)
MAAA-1181a, Cycle 3 (DS-8201a + ritonavir): AUC17d	37.2 (6.93)
MAAA-1181a, Cycle 3 (DS-8201a + ritonavir): AUCtau	39.2 (7.98)

5. Primary Outcome

Title	Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) Following Treatment With DS-8201a and Itraconazole - Cohort 2
Description	Maximum concentration (Cmax) was assessed for DS-8201a and total Anti-HER2 antibody.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	14
DS-8201a, Cycle 2: DS-8201a only	139 (23.6)
DS-8201a, Cycle 3: DS-8201a + ritonavir	142 (23.9)
Total Anti-HER2 antibody, Cycle 2: DS-8201a only	119 (19.1)
Total Anti-HER2 antibody, Cycle 3: DS-8201a + ritonavir	130 (18.2)

6. Primary Outcome

Title	Pharmacokinetic Parameter of Maximum (Peak) Observed Serum Concentration (Cmax) of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2
Description	Maximum concentration (Cmax) was assessed for MAAA-1181a.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	14
MAAA-1181a, Cycle 2: DS-8201a only	8.65 (2.03)
MAAA-1181a, Cycle 3: DS-8201a + ritonavir	8.93 (1.77)

7. Primary Outcome

Title	Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve Following Treatment With DS-8201a and Itraconazole - Cohort 2
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	14
DS-8201a, Cycle 2 (DS-8201a only): AUC17d	644 (188)
DS-8201a, Cycle 2 (DS-8201a only): AUCtau	706 (211)
DS-8201a, Cycle 3 (DS-8201a + ritonavir): AUC17d	710 (187)
DS-8201a, Cycle 3 (DS-8201a + ritonavir): AUCtau	789 (217)
Total Anti-HER2 antibody, Cycle 2 (DS-8201a only): AUC17d	707 (194)
Total Anti-HER2 antibody, Cycle 2 (DS-8201a only): AUCtau	790 (224)
Total Anti-HER2 antibody, Cycle 3 (DS-8201a + ritonavir): AUC17d	781 (196)
Total Anti-HER2 antibody, Cycle 3 (DS-8201a + ritonavir): AUCtau	883 (238)

8. Primary Outcome

Title	Pharmacokinetic Parameter of Area Under the Serum Concentration-time Curve of MAAA-1181a Following Treatment With DS-8201a and Itraconazole - Cohort 2
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Arm/Group Title	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	14
MAAA-1181a, Cycle 2 (DS-8201a only): AUC17d	29.9 (8.31)
MAAA-1181a, Cycle 2 (DS-8201a only): AUCtau	32.4 (9.21)
MAAA-1181a, Cycle 3 (DS-8201a + ritonavir): AUC17d	34.8 (8.04)
MAAA-1181a, Cycle 3 (DS-8201a + ritonavir): AUCtau	37.7 (8.87)

9. Secondary Outcome

Title	Best Objective Response as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors
Description	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.
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

Outcome Measure Data

Analysis Population Description

Response was assessed in the Efficacy Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	17	19
Complete response (CR)	0 0%	0 0%
Partial response (PR)	9 52.9%	10 43.5%
Stable disease (SD)	8 47.1%	8 34.8%
Non-CR/Non-PR	0 0%	0 0%
Progressive disease (PD)	0 0%	1 4.3%
Non evaluable	0 0%	0 0%

10. Secondary Outcome

Title	Objective Response Ratio (ORR) as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors
Description	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.
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

Outcome Measure Data

Analysis Population Description

Response was assessed in the Efficacy Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	17	19
Count of Participants [Participants]	9 52.9%	10 43.5%

11. Secondary Outcome

Title	Objective Response Rate as Confirmed By The Investigator's Assessment in Participants With HER2-Expressing Advanced Solid Malignant Tumors
Description	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.
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

Outcome Measure Data

Analysis Population Description

Response was assessed in the Efficacy Analysis Set.

Arm/Group Title	Cohort 1: DS-8201a + Ritonavir	Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3.	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole twice daily (BID) on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3.
Measure Participants	17	19
Count of Participants [Participants]	8 47.1%	7 30.4%

Adverse Events

Time Frame	Adverse event data were collected from baseline up to approximately 9 months post-dose.
Arm/Group Title	Cohort 1: DS-8201a + Ritonavir		Cohort 2: DS-8201a + Itraconazole
Arm/Group Description	Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg ritonavir twice daily on Day 17 of Cycle 2 until Day 21 of Cycle 3.		Participants who received 5.4 mg/kg DS-8201a as an intravenous infusion once every 3 weeks and 200 mg itraconazole BID on Day 17 of Cycle 2 followed by 200 mg QD until Day 21 of Cycle 3.
All Cause Mortality
	Cohort 1: DS-8201a + Ritonavir		Cohort 2: DS-8201a + Itraconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		0/23 (0%)
Serious Adverse Events
	Cohort 1: DS-8201a + Ritonavir		Cohort 2: DS-8201a + Itraconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)		3/23 (13%)
Gastrointestinal disorders
Diarrhoea	0/17 (0%)		1/23 (4.3%)
Ileus	0/17 (0%)		1/23 (4.3%)
Nausea	0/17 (0%)		1/23 (4.3%)
Vomiting	0/17 (0%)		1/23 (4.3%)
General disorders
Disease progression	1/17 (5.9%)		0/23 (0%)
Pyrexia	0/17 (0%)		1/23 (4.3%)
Infections and infestations
Sepsis	0/17 (0%)		1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/17 (5.9%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: DS-8201a + Ritonavir		Cohort 2: DS-8201a + Itraconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/17 (100%)		22/23 (95.7%)
Blood and lymphatic system disorders
Anaemia	6/17 (35.3%)		5/23 (21.7%)
Neutropenia	5/17 (29.4%)		1/23 (4.3%)
Thrombocytopenia	4/17 (23.5%)		1/23 (4.3%)
Leukopenia	2/17 (11.8%)		0/23 (0%)
Lymphopenia	1/17 (5.9%)		0/23 (0%)
Cardiac disorders
Atrioventricular block first degree	1/17 (5.9%)		0/23 (0%)
Palpitations	1/17 (5.9%)		0/23 (0%)
Eye disorders
Eye discharge	1/17 (5.9%)		0/23 (0%)
Gastrointestinal disorders
Nausea	17/17 (100%)		15/23 (65.2%)
Constipation	8/17 (47.1%)		7/23 (30.4%)
Diarrhoea	8/17 (47.1%)		5/23 (21.7%)
Vomiting	3/17 (17.6%)		8/23 (34.8%)
Stomatitis	4/17 (23.5%)		2/23 (8.7%)
Haemorrhoids	1/17 (5.9%)		1/23 (4.3%)
Ileus	0/17 (0%)		2/23 (8.7%)
Abdominal discomfort	1/17 (5.9%)		0/23 (0%)
Abdominal pain	1/17 (5.9%)		0/23 (0%)
Abdominal pain upper	1/17 (5.9%)		0/23 (0%)
Mouth haemorrhage	1/17 (5.9%)		0/23 (0%)
General disorders
Fatigue	5/17 (29.4%)		4/23 (17.4%)
Malaise	4/17 (23.5%)		1/23 (4.3%)
Pyrexia	1/17 (5.9%)		1/23 (4.3%)
Disease progression	1/17 (5.9%)		0/23 (0%)
Oedema peripheral	1/17 (5.9%)		0/23 (0%)
Peripheral swelling	1/17 (5.9%)		0/23 (0%)
Hepatobiliary disorders
Hepatic function abnormal	1/17 (5.9%)		0/23 (0%)
Infections and infestations
Nasopharyngitis	3/17 (17.6%)		0/23 (0%)
Paroncyhia	1/17 (5.9%)		1/23 (4.3%)
Cystitis	1/17 (5.9%)		0/23 (0%)
Infected dermal cyst	1/17 (5.9%)		0/23 (0%)
Influenza	1/17 (5.9%)		0/23 (0%)
Osteomyelitis	1/17 (5.9%)		0/23 (0%)
Upper respiratory tract infection	1/17 (5.9%)		0/23 (0%)
Vulvovaginal candidiasis	1/17 (5.9%)		0/23 (0%)
Investigations
Neutrophil count decreased	6/17 (35.3%)		8/23 (34.8%)
White blood cell count decreased	7/17 (41.2%)		7/23 (30.4%)
Platelet count decreased	9/17 (52.9%)		4/23 (17.4%)
Aspartate aminotransferase increased	6/17 (35.3%)		5/23 (21.7%)
Alanine aminotransferase increased	7/17 (41.2%)		3/23 (13%)
Blood alkaline phosphatase increased	4/17 (23.5%)		0/23 (0%)
Weight decreased	2/17 (11.8%)		2/23 (8.7%)
Blood creatinine increased	2/17 (11.8%)		1/23 (4.3%)
Troponin I increased	1/17 (5.9%)		1/23 (4.3%)
Alanine aminotransferase decreased	1/17 (5.9%)		0/23 (0%)
Aspartate aminotransferase decreased	1/17 (5.9%)		0/23 (0%)
Blood bilirubin increased	1/17 (5.9%)		0/23 (0%)
Blood lactate dehydrogenase increased	1/17 (5.9%)		0/23 (0%)
Gamma-glutamyltransferase increased	1/17 (5.9%)		0/23 (0%)
Ophthalmological examination abnormal	1/17 (5.9%)		0/23 (0%)
Protein total decreased	1/17 (5.9%)		0/23 (0%)
Metabolism and nutrition disorders
Decreased appetite	13/17 (76.5%)		9/23 (39.1%)
Hypoalbuminaemia	1/17 (5.9%)		1/23 (4.3%)
Hypokalaemia	1/17 (5.9%)		0/23 (0%)
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw	2/17 (11.8%)		1/23 (4.3%)
Arthralgia	2/17 (11.8%)		0/23 (0%)
Back pain	0/17 (0%)		2/23 (8.7%)
Musculoskeletal pain	1/17 (5.9%)		0/23 (0%)
Myalgia	1/17 (5.9%)		0/23 (0%)
Nervous system disorders
Headache	4/17 (23.5%)		2/23 (8.7%)
Dysgeusia	1/17 (5.9%)		1/23 (4.3%)
Akathisia	1/17 (5.9%)		0/23 (0%)
Hyperaesthesia	1/17 (5.9%)		0/23 (0%)
Neuropathy peripheral	1/17 (5.9%)		0/23 (0%)
Peripheral sensory neuropathy	1/17 (5.9%)		0/23 (0%)
Somnolence	1/17 (5.9%)		0/23 (0%)
Renal and urinary disorders
Dysuria	1/17 (5.9%)		0/23 (0%)
Renal impairment	1/17 (5.9%)		0/23 (0%)
Reproductive system and breast disorders
Atrophic vulvovaginitis	1/17 (5.9%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/17 (11.8%)		4/23 (17.4%)
Oropharyngeal pain	1/17 (5.9%)		1/23 (4.3%)
Hypoxia	1/17 (5.9%)		0/23 (0%)
Organising pneumonia	1/17 (5.9%)		0/23 (0%)
Pneumonitis	1/17 (5.9%)		0/23 (0%)
Rhinitis allergic	1/17 (5.9%)		0/23 (0%)
Upper-airway cough syndrome	1/17 (5.9%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Alopecia	6/17 (35.3%)		7/23 (30.4%)
Rash	1/17 (5.9%)		2/23 (8.7%)
Dry skin	2/17 (11.8%)		0/23 (0%)
Rash maculo-papular	2/17 (11.8%)		0/23 (0%)
Dermatitis acneiform	1/17 (5.9%)		0/23 (0%)
Night sweats	1/17 (5.9%)		0/23 (0%)
Palmar-plantar erythrodysaesthesia syndrome	1/17 (5.9%)		0/23 (0%)
Rash erythematous	1/17 (5.9%)		0/23 (0%)
Vascular disorders
Hot flush	1/17 (5.9%)		0/23 (0%)

Limitations/Caveats

[Not Specified]

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.