A Study of Tucatinib (MK-7119) in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Carcinoma (MK-7119-001)

A Phase 2 Open-label, Single Arm Study of MK-7119 in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic HER2+ Breast Carcinoma

The goal of this study is to evaluate the efficacy and safety of tucatinib in combination with trastuzumab and capecitabine in participants with unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with taxane anti-cancer agent, trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1). The primary hypothesis is that the confirmed objective response rate (cORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as determined by independent central review (ICR) for the combination of tucatinib, trastuzumab and capecitabine, is greater than 20%.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Tucatinib; Biological: Trastuzumab; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center ( Site 1009)
  • Fukushima, Japan, 960-1295
    • Fukushima Medical University Hospital ( Site 1012)
  • Hiroshima, Japan, 730-8518
    • Hiroshima City Hiroshima Citizens Hospital ( Site 1024)
  • Kagoshima, Japan, 892-0833
    • Social medical corporation Hakuaikai Sagara Hospital ( Site 1008)
  • Kumamoto, Japan, 862-8655
    • Kumamoto Shinto General Hospital ( Site 1007)
  • Osaka, Japan, 540-0006
    • National Hospital Organization Osaka National Hospital ( Site 1001)
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute ( Site 1004)
  • Tokyo, Japan, 104-0045
    • National Cancer Center Hospital ( Site 1003)
  • Tokyo, Japan, 113-0033
    • Juntendo University Hospital ( Site 1025)
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR ( Site 1015)
  • Tokyo, Japan, 142-8666
    • Showa University Hospital ( Site 1023)
  • Tokyo, Japan, 160-0023
    • Tokyo Medical University Hospital ( Site 1006)
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 464-8681
      • Aichi Cancer Center Hospital ( Site 1013)
    • Nagoya, Aichi-ken, Japan, 466-8560
      • Nagoya University Hospital ( Site 1021)
  • Chiba
    • Kashiwa, Chiba, Japan, 2778577
      • National Cancer Center Hospital East ( Site 1002)
  • Ehime
    • Matsuyama, Ehime, Japan, 791-0280
      • National Hospital Organization Shikoku Cancer Center ( Site 1014)
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 003-0804
      • National Hospital Organization Hokkaido Cancer Center ( Site 1017)
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital ( Site 1022)
  • Hyōgo
    • Akashi, Hyōgo, Japan, 673-8558
      • Hyogo Cancer Center ( Site 1005)
    • Nishinomiya, Hyōgo, Japan, 663-8501
      • Hyogo College of Medicine Hospital ( Site 1019)
  • Ibaraki
    • Tsukuba, Ibaraki, Japan, 305-8576
      • University of Tsukuba Hospital ( Site 1020)
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 241-8515
      • Kanagawa Cancer Center ( Site 1010)
  • Okinawa
    • Naha, Okinawa, Japan, 901-0154
      • Medical Corporation Nahanishikai Nahanishi Clinic ( Site 1016)
  • Saitama
    • Kitaadachi-gun, Saitama, Japan, 362-0806
      • Saitama Cancer Center ( Site 1018)
• South Korea
  • Seoul, South Korea, 03080
    • Seoul National University Hospital ( Site 2003)
  • Seoul, South Korea, 03722
    • Severance Hospital ( Site 2001)
  • Seoul, South Korea, 06351
    • Samsung Medical Center ( Site 2002)
• Taiwan
  • Tainan
    • Dawan, Tainan, Taiwan, 704
      • National Cheng Kung University Hospital ( Site 3000)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has histologically confirmed HER2+ breast carcinoma
• Has received previous treatment with taxane anti-cancer agent, trastuzumab, pertuzumab, and T-DM1 with the exception of when the use of taxanes is contraindicated or judged not to be the best treatment at the investigator's discretion
• Has radiographically and/or histologically confirmed disease progression on last systemic anticancer treatment
• Has adequate organ function
• Female participant is not pregnant or breastfeeding and is not a woman of childbearing potential (WOCBP) or is a WOCBP and using contraception or abstinent from heterosexual intercourse during the intervention period and for at least 30 days after receiving the last dose of tucatinib, 80 days after receiving the last dose of trastuzumab, or 180 days after receiving the last dose of capecitabine, whichever occurs last and agrees to not donate eggs during this period
• Male participants refrain from donating sperm and are either abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after receiving the last dose of tucatinib and 90 days after receiving the last dose of capecitabine, whichever occurs last
• Previously treated brain metastasis is stable or progressed, provided there is no clinical indication for immediate re-treatment

Exclusion Criteria:

• Has been previously treated with lapatinib within 12 months of starting study treatment
• Has been previously treated with neratinib, afatinib, tucatinib or capecitabine
• Has a history of exposure to doxorubicin, epirubicin, mitoxantrone, idarubicin, liposomal doxorubicin
• Has had treatment with any systemic anti-cancer therapy including hormonal therapy, non-central nervous system (CNS) radiation or experimental agent ≤3 weeks before first dose of study treatment
• Has any toxicity related to prior cancer therapies that has not resolved with the exception of alopecia, congestive heart failure, anemia
• Has clinically significant cardiopulmonary disease
• Has known myocardial infarction or unstable angina within 6 months prior to the first dose of study treatment
• Has any uncontrolled viral, bacterial or fungal infection within 14 days prior to the first dose of study treatment
• Is positive for Hepatitis B, Hepatitis C or has known chronic liver disease
• Is known to be positive for human immunodeficiency virus (HIV)
• Has evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
• Has ongoing use of systemic corticosteroids for control of symptoms of brain metastases
• Has any brain lesion thought to require immediate local therapy
• Has known or suspected leptomeningeal disease (LMD)
• Has poorly controlled generalized or complex partial seizures or manifest neurologic progression due to brain metastases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tucatinib + Trastuzumab + Capecitabine; Participants will receive tucatinib plus trastuzumab plus capecitabine. Tucatinib 300 mg will be administered orally twice daily (BID). Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg maintenance dose thereafter, will be administered intravenously (IV) on Day 1 of each 21-day cycle. Capecitabine 1000 mg/m^2 will be administered orally BID on Days 1-14 of each 21-day cycle. Tucatinib, trastuzumab and capecitabine treatment will continue until unacceptable toxicity, disease progression, death, withdrawal of consent or study closure.

Drug: Tucatinib; Tucatinib 300 mg administered BID via oral tablet; Other Names: MK-7119; Tukysa; Biological: Trastuzumab; Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg maintenance dose, administered via IV infusion; Other Names: Herceptin; Herceptin Hylecta; Drug: Capecitabine; Capecitabine 1000 mg/m^2 administered BID via oral tablet; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Objective Response Rate(cORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Determined by Independent Central Review (ICR): Japanese Participants	cORR was defined as percentage of participants with confirmed complete response (CR) or partial response (PR), per RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 millimeter(mm). PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented progressive disease(PD) or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study(included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Participants with missing data were considered non-responders. cORR was determined by ICR. Two-sided 90% exact confidence interval was based on Clopper-Pearson method.	From date of first dose until first documented disease progression or start of new anticancer therapy, whichever occurred first (maximum up to 17.8 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Objective Response Rate(cORR) Per RECIST Version 1.1 Determined by ICR: All Participants	cORR was defined as percentage of participants with confirmed CR or PR, per RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Participants with missing data were considered non-responders. cORR was determined by ICR. Two-sided 90% exact confidence interval was based on Clopper-Pearson method.	From date of first dose until first documented disease progression or start of new anticancer therapy, whichever occurred first
Confirmed Objective Response Rate(cORR) Per RECIST Version 1.1 Determined by Investigator Assessment (INV): Japanese Participants	cORR was defined as percentage of participants with confirmed CR or PR, per RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Participants with missing data were considered non-responders. cORR was determined by INV. Two-sided 90% exact confidence interval was based on Clopper-Pearson method.	From date of first dose until first documented disease progression or start of new anticancer therapy, whichever occurred first
Confirmed Objective Response Rate(cORR) Per RECIST Version 1.1 Determined by INV: All Participants	cORR was defined as percentage of participants with confirmed CR or PR, per RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Participants with missing data were considered non-responders. cORR was determined by ICR. Two-sided 90% exact confidence interval was based on Clopper-Pearson method.	From date of first dose until first documented disease progression or start of new anticancer therapy, whichever occurred first
Duration of Response (DOR) Per RECIST Version 1.1 Determined by INV: All Participants	DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST version 1.1 or death from any cause, whichever occurred first. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Only those participants who achieved a confirmed response will be included in the analysis. DOR was determined by INV.	From date of first objective response (CR or PR that is subsequently confirmed) to documented PD, or death from any cause whichever occurred first
Duration of Response (DOR) Per RECIST Version 1.1 Determined by INV: Japanese Participants	DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST version 1.1 or death from any cause, whichever occurred first. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Only those participants who achieved a confirmed response will be included in the analysis. DOR was determined by INV.	From date of first objective response (CR or PR that is subsequently confirmed) to documented PD, or death from any cause whichever occurred first
Duration of Response (DOR) Per RECIST Version 1.1 Determined by ICR: All Participants	DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST version 1.1 or death from any cause, whichever occurred first. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Only those participants who achieved a confirmed response will be included in the analysis. DOR was determined by ICR.	From date of first objective response (CR or PR that is subsequently confirmed) to documented PD, or death from any cause whichever occurred first
Duration of Response (DOR) Per RECIST Version 1.1 Determined by ICR: Japanese Participants	DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST version 1.1 or death from any cause, whichever occurred first. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: a >=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented PD or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Only those participants who achieved a confirmed response will be included in the analysis. DOR was determined by ICR.	From date of first objective response (CR or PR that is subsequently confirmed) to documented PD, or death from any cause whichever occurred first
Progression Free Survival (PFS) Per RECIST Version 1.1 Determined by ICR: All Participants	PFS time was defined as the time from the first date of study treatment to the date of documented disease progression using RECIST v1.1 or death from any cause, whichever occurred first. Participants who were alive and had not progressed at the time of the analysis were censored at the time of their last tumor assessment documenting absence of PD. Participants lacking an evaluation of tumor response after their start of study treatment had their event time censored at 1 day. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. PFS was determined by ICR.	From date of first dose to the date of documented disease progression or death from any cause whichever occurred first or censoring date
Progression Free Survival (PFS) Per RECIST Version 1.1 Determined by ICR: Japanese Participants	PFS time was defined as the time from the first date of study treatment to the date of documented disease progression using RECIST v1.1 or death from any cause, whichever occurred first. Participants who were alive and had not progressed at the time of the analysis were censored at the time of their last tumor assessment documenting absence of PD. Participants lacking an evaluation of tumor response after their start of study treatment had their event time censored at 1 day. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. PFS was determined by ICR.	From date of first dose to the date of documented disease progression or death from any cause whichever occurred first or censoring date
Progression Free Survival (PFS) Per RECIST Version 1.1 Determined by INV: All Participants	PFS time was defined as the time from the first date of study treatment to the date of documented disease progression using RECIST v1.1 or death from any cause, whichever occurred first. Participants who were alive and had not progressed at the time of the analysis were censored at the time of their last tumor assessment documenting absence of PD. Participants lacking an evaluation of tumor response after their start of study treatment had their event time censored at 1 day. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. PFS was determined by INV.	From date of first dose to the date of documented disease progression or death from any cause whichever occurred first or censoring date
Progression Free Survival (PFS) Per RECIST Version 1.1 Determined by INV: Japanese Participants	PFS time was defined as the time from the first date of study treatment to the date of documented disease progression using RECIST v1.1 or death from any cause, whichever occurred first. Participants who were alive and had not progressed at the time of the analysis were censored at the time of their last tumor assessment documenting absence of PD. Participants lacking an evaluation of tumor response after their start of study treatment had their event time censored at 1 day. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. PFS was determined by INV.	From date of first dose to the date of documented disease progression or death from any cause whichever occurred first or censoring date
Overall Survival: All Participants	OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. Participants lacking data beyond their start of study treatment had their survival time censored at 1 day.	From start of study treatment to date of death from any cause or censoring date
Overall Survival: Japanese Participants	OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. Participants lacking data beyond their start of study treatment had their survival time censored at 1 day.	From start of study treatment to date of death from any cause or censoring date
Number of Participants With Adverse Events, Serious Adverse Events and Treatment Related Adverse Events and Serious Adverse Events: All Participants	An adverse event was defined as any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Serious adverse event was any untoward medical occurrence at any dose that resulted in death; life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect or that was considered as an important medical event. Treatment related adverse events and serious adverse events was judged by investigator.	From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Adverse Events, Serious Adverse Events and Treatment Related Adverse Events and Serious Adverse Events: Japanese Participants	An adverse event was defined as any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. t intervention indicated and Grade 5 indicates death related to AE. Participants who discontinued treatment due to AEs were captured under AEs leading to treatment discontinuation. SAE was any untoward medical occurrence at any dose that resulted in death; life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect or that was considered as an important medical event. Treatment related adverse events and serious adverse events was judged by investigator.	From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Abnormalities in Laboratory Parameters: All Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Abnormalities in Laboratory Parameters: Japanese Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Dose Modifications and Treatment Discontinuations: All Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Dose Modifications and Treatment Discontinuations: Japanese Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Clinically Significant Changes in Vital Signs: All Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment
Number of Participants With Clinically Significant Changes in Vital Signs: Japanese Participants		From date of first dose of study treatment to up to 30 days after last dose of study treatment

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2021
• Primary Completion (Actual): July 17, 2023
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: January 20, 2021
• First Submitted That Met QC Criteria: January 20, 2021
• First Posted (Actual): January 25, 2021

Study Record Updates

• Last Update Posted (Actual): January 9, 2026
• Last Update Submitted That Met QC Criteria: December 16, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Trastuzumab; Capecitabine; tucatinib
• Other Study ID Numbers: 7119-001; MK-7119-001 (Other Identifier: Merck); jRCT2051200152 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes