A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China

A PHASE 2, MULTI-CENTER, OPEN-LABEL, DUAL-COHORT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LORLATINIB (PF-06463922) MONOTHERAPY IN ALK INHIBITOR-TREATED LOCALLY ADVANCED OR METASTATIC ALK-POSITIVE NON-SMALL CELL LUNG CANCER PATIENTS IN CHINA

A Phase 2, multi center, open label, dual cohort study to evaluate the efficacy and safety of lorlatinib (PF 06463922) monotherapy in ALK inhibitor treated locally advanced or metastatic ALK positive non small cell lung cancer patients in China

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Lorlatinib

Detailed Description

This is a Phase 2, China only, multi center, open label, dual cohort study, in ALK positive locally advanced or metastatic NSCLC patients will be enrolled to receive lorlatinib monotherapy.

• (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor.
• (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100071
    • Fifth Medical Center of PLA General Hospital
  • Beijing, China, 101149
    • Beijing Chest Hospital, Capital Medical University
  • Guangzhou, China, 510000
    • Guangdong Provincial People's Hospital
  • Hangzhou, Zhejiang, China, 310003
    • The First Affiliated Hospital Zhejiang University School of Medicine
  • Nanjing, Jiangsu, China
    • General Hospital of Eastern Theater Command
  • Shanghai, China, 200030
    • Shanghai Chest Hospital
  • Shanghai, China, 200032
    • Fudan University Shanghai Cancer Center
  • Shanghai, China, 200032
    • Zhongshan Hospital, Fudan University
  • Anhui
    • Hefei, Anhui, China, 230088
      • Gaoxin Hospital of The First Affilated Hospital of Anhui Medical University
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350014
      • Fujian Province Oncology Hospital
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Harbin Medical University Cancer Hospital
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Provincial Tumor Hospital/Division of Oncology
  • Jilin
    • Changchun, Jilin, China, 130021
      • The first hospital of Jilin University
    • Changchun, Jilin, China, 130103
      • Jilin Provincial Cancer Hospital
  • Shanxi
    • Xi'an, Shanxi, China, 710000
      • Tangdu Hospital of Fourth Military Medical University
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Sichuan Province Cancer Hospital/Department of Pulmonary Tumor
    • Chengdu, Sichuan, China, 610041
      • West China Hospital, Sichuan University, Cancer center
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • The Second Affiliated Hospital of Zhejiang University College of Medicine
    • Hangzhou, Zhejiang, China, 310016
      • Sir Run Run Shaw Hospital of College of Medicine of Zhejiang University, Center for Oncology
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK positive NSCLC where ALK status has been previously established by the Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), or the EML4 ALK Fusion Gene Detection Kit (AmoyDx).

2. Subject should have:

   1. (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;
   2. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, with or without prior crizotinib.
3. Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study entry.

4. All Subjects must have at least 1 measurable extracranial target lesion according to RECIST v1.1 that has not been previously irradiated. CNS metastases are allowed if:

   1. Asymptomatic: either not currently requiring corticosteroid treatment, or on a stable or decreasing dose of 10 mg QD prednisone or equivalent; or
   2. Previously diagnosed and treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to enrollment, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability.
5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2.
6. Age 18 years (or 20 years as required by local regulation).

7. Adequate bone marrow functions:

   1. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
   2. Platelets 100,000/mm3 or 100 x 109/L;
   3. Hemoglobin 9 g/dL.

8. Adequate pancreatic function:

   1. Serum total amylase 1.5 x upper limit of normal (ULN);*
   2. Serum lipase 1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then subject may be enrolled.

9. Adequate renal function:

   a. Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as calculated using the method standard for the institution.

10. Adequate liver function:

    1. Total serum bilirubin 1.5 x ULN;
    2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 2.5 x ULN (5.0 x ULN in case of liver metastases).
11. Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 except for AEs that in the investigator's judgment do not constitute a safety risk for the subject.

12. Serum or urine pregnancy test (for females of childbearing potential) negative at screening. Female subjects of non childbearing potential must meet at least 1 of the following criteria:

    1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (which may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state if appropriate;
    2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    3. Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
13. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
14. Willing and able to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures.

Exclusion Criteria:

Subjects with any of the following characteristics/conditions will not be included in the study:

1. More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic setting.

   If disease recurred/relapsed within the adjuvant chemotherapy treatment or <=6 months after the completion of the adjuvant chemotherapy, then the adjuvant chemotherapy is considered as the first line systemic chemotherapy to the disease.

2. Systemic anti cancer therapy completed within a minimum of 5 half lives of study enrollment.
3. Prior therapy with an antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways, including, but not limited to, anti programmed cell death protein 1 (anti PD 1), anti programmed cell death protein ligand 1 (anti PD L1), anti PD L2, anti cluster of differentiation 137 (anti CD137), or anti cytotoxic T lymphocyte associated antigen 4 (anti CTLA 4) antibody.
4. Known epidermal growth factor receptor (EGFR) activating mutations; known prior therapy with EGFR TKI(s) (the prior treatment with brigatinib is allowed as an ALK TKI).
5. Major surgery within 4 weeks prior to enrollment. Minor surgical procedures (eg, port insertion) are not excluded, but sufficient time should have passed for adequate wound healing.
6. Radiation therapy within 2 weeks prior to enrollment. Palliative radiation must have been completed at least 48 hours prior to enrollment. Stereotactic or partial brain irradiation must have completed at least 2 weeks prior to enrollment. Whole brain irradiation must have completed at least 4 weeks prior to enrollment.
7. Spinal cord compression unless the subject has good pain control attained through therapy, and there is complete recovery of neurological function for the 4 weeks prior to enrollment.
8. Gastrointestinal abnormalities, including inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection or lap band; active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment for active peptic ulcer disease in the past 6 months; malabsorption syndromes.
9. Known prior or suspected severe hypersensitivity to lorlatinib or any component in the formulation; known prior therapy with lorlatinib.
10. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.

11. Clinically significant cardiovascular disease (both arterial and venous) and non vascular cardiac conditions, (active or within 3 months prior to enrollment, which may include, but not are limited to:

    • Arterial disease such as cerebral vascular accident/stroke (including transient ischemic attack -TIA), myocardial infarction, unstable angina;
    • Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism;
    • Nonvascular cardiac disease such as congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third degree atrioventricular block (unless paced) or any AV block with PR interval >220 msec; or
    • Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless subject is otherwise healthy such as long distance runners, etc.), machine read electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome.
12. Subject with predisposing characteristics for acute pancreatitis according to investigator judgment, including but not limited to uncontrolled hyperglycemia, current gallstone disease, in the last month prior to enrollment.
13. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis.
14. Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or localized and presumed cured prostate cancer or any in situ cancer which does not currently require treatment) within the last 3 years prior to enrollment.

15. Concurrent use of any of the following food or drugs (consult the sponsor if in doubt whether a food or a drug falls into any of the above categories) within 12 days prior to the first dose of administration of lorlatinib:

    1. Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed;
    2. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine) (*withdrawn from US market);
    3. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort);
    4. Known P glycoprotein (P gp) substrates with a narrow therapeutic index (eg, digoxin).
16. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator and/or the sponsor, would make the subject inappropriate for entry into this study.
17. Subject who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
18. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.
19. Pregnant female participants; breastfeeding female participants; fertile male participants and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 97 days if male or 35 days if female, after the last dose of investigational product.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lorlatinib; Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously	Drug: Lorlatinib; ALK inhibitor-treated ALK-positive NSCL treatment; Other Names: PF-06463922

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response (Cohort 1)	Objective response rate (ORR) was defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions. PR was defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Independent Central Radiology (ICR) was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response (Cohort 2)	ORR was defined as the percentage of participants with a best overall confirmed response of CR or PR according to RECIST version 1.1 relative to the total participants in the analysis population. CR was defined as the disappearance of all target lesions. PR was defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. ICR was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)
Progression Free Survival	Progression-free survival (PFS) was defined as the time from first dose to first documentation of objective disease progression or to death due to any cause, whichever came first. ICR was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)
Overall Survival	Overall survival was defined as the time from first dose to the date of death due to any cause. ICR was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)
Percentage of Participants With Intracranial Objective Response	Intracranial objective response(IC-OR) was defined as the same as OR (defined as the percentage of participants with a best overall confirmed response of CR or PR according to RECIST version 1.1 relative to the total participants in the analysis population), but limited to Intra Cranial lesions only on participants with central nervous system metastases. ICR was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)
Duration of Response	Duration of response was defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death due to any cause, whichever occurred first. ICR was used for disease progression assessment.	From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)
Duration of Intracranial Response	Duration of intracranial response was defined the same as duration of response (defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death due to any cause, whichever occurred first), in participants who had at least 1 intracranial lesion. ICR was used for disease progression assessment.	From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)
Time to Tumor Response	Time to tumor response was defined as the time from first dose to first documentation of objective tumor response. ICR was used for disease progression assessment.	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)
Number of Participants With Adverse Events	An Adverse event (AE) was any untoward medical occurrence in a participant. A serious AE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect or that was considered to be an important medical event. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. The grades were defined as follows: Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. The focus of AE summaries was on treatment-emergent AE (TEAE). An AE was considered TEAE if the event occurred during the on-treatment period.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Number of Participants With Central Nervous System-Related Adverse Events	The central-nervous system-related AEs included AEs under the cluster terms of MOOD EFFECTS, COGNITIVE EFFECTS, PSYCHOTIC EFFECTS, SPEECH EFFECTS.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities	Laboratory test results were graded according to NCI CTCAE version 4.03. Laboratory tests included hematology, chemistry, lipids, coagulation and urinalysis. Shifts from Grade <=2 at baseline to Grade 3 or 4 post-baseline were considered clinically significant. The grades were defined as follows: Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria	Vital signs evaluation included sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse rate and weight. The pre-specified criteria included: sitting SBP change >=40 mmHg increase, >=40 mmHg decrease; sitting DBP change >=20 mmHg increase, change >=20 mmHg decrease, or change >=60 mmHg increase; sitting pulse rate value <50 bpm, >120 bpm, change >=30 bpm increase, or change >=30 bpm decrease; weight change >= 10% and <20% increase, change >=20% increase or change >=10% decrease.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria	The QT intervals were corrected for heart rate (QTc) using standard correction factors (ie, QTcF [Fridericia's], QTcB [Bazett's], and possibly a study-specified factor, as appropriate). The pre-specified criteria included: PR interval change >= 50% and baseline <200 msec, change >=25% and baseline >=200 msec; QRS interval change >=50% and baseline <100 msec, change >=25% and baseline >=100 msec; QTcB values <=450 msec, >480 msec and <=500 msec, >500 msec, change <=30 msec, change >30 msec and <=60 msec, change >60 msec; QTcF value <=450 msec, >480 msec and <=500 msec, >=500 msec, change <=30 msec, change >30 msec and <=60 msec, change >60 msec.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Number of Participants With Left Ventricular Ejection Fraction Meeting Pre-specified Criteria	Echocardiogram or multigated acquisition scan were performed, individual left ventricular ejection fraction (LVEF) and its changes from baseline was summarized. The number of participants whose maximum relative decrease from baseline in LVEF greater than 20% was summarized. The number of participants whose LVEF shifted from baseline normal to post-baseline below lower limit of normal (LLN) was also summarized.	From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after the last administration of the investigational product, up to 1.3 years.
Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)	The loratinib Cmax was estimated using non-compartmental analysis.	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1
Cycle 1 Day 1 Time to Cmax (Tmax)	The loratinib Tmax was estimated using non-compartmental analysis.	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1
Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)	The loratinib AUCtau was estimated using non-compartmental analysis.	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1
Steady-State Cmax	The loratinib Cmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1
Steady-State Tmax	The loratinib Tmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1
Steady-State AUCtau	The loratinib AUCtau was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1
Apparent Clearance (CL/F)	The loratinib CL/F was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1
Observed Accumulation Ratio (Rac)	The loratinib Rac was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2019
• Primary Completion (Actual): August 10, 2020
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 5, 2019
• First Submitted That Met QC Criteria: April 8, 2019
• First Posted (Actual): April 10, 2019

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; ALK positive; ALK inhibitor-treated
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: B7461024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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