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

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03909971
• Collaborator: (none)
• Enrollment: 109
• Locations: 21
• Arm: 1
• Anticipated Duration (Months): 39.4
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Lorlatinib	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: N/A
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 28, 2019
• Actual Primary Completion Date: Aug 10, 2020
• Anticipated Study Completion Date: Aug 10, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Objective Response (Cohort 1) [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

Secondary Outcome Measures

1. Percentage of Participants With Objective Response (Cohort 2) [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

2. Progression Free Survival [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

3. Overall Survival [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

4. Percentage of Participants With Intracranial Objective Response [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

5. Duration of Response [From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)]

   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.

6. Duration of Intracranial Response [From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)]

   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.

7. Time to Tumor Response [From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)]

   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.

8. Number of Participants With Adverse Events [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.]

   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.

9. Number of Participants With Central Nervous System-Related Adverse Events [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.]

   The central-nervous system-related AEs included AEs under the cluster terms of MOOD EFFECTS, COGNITIVE EFFECTS, PSYCHOTIC EFFECTS, SPEECH EFFECTS.

10. Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities [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.]

    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.

11. Number of Participants With Vital Signs Data Meeting Pre-specified Criteria [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.]

    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.

12. Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria [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.]

    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.

13. Number of Participants With Left Ventricular Ejection Fraction Meeting Pre-specified Criteria [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.]

    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.

14. Cycle 1 Day 1 Maximum Plasma Concentration (Cmax) [At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1]

    The loratinib Cmax was estimated using non-compartmental analysis.

15. Cycle 1 Day 1 Time to Cmax (Tmax) [At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1]

    The loratinib Tmax was estimated using non-compartmental analysis.

16. Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau) [At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1]

    The loratinib AUCtau was estimated using non-compartmental analysis.

17. Steady-State Cmax [At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1]

    The loratinib Cmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

18. Steady-State Tmax [At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1]

    The loratinib Tmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

19. Steady-State AUCtau [At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1]

    The loratinib AUCtau was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

20. Apparent Clearance (CL/F) [At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1]

    The loratinib CL/F was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

21. Observed Accumulation Ratio (Rac) [At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1]

    The loratinib Rac was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

3. (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;

4. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, with or without prior crizotinib.

5. Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study entry.

6. 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.

3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2.

4. Age 18 years (or 20 years as required by local regulation).

5. Adequate bone marrow functions:

6. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;

7. Platelets 100,000/mm3 or 100 x 109/L;

8. Hemoglobin 9 g/dL.

9. Adequate pancreatic function:

10. Serum total amylase 1.5 x upper limit of normal (ULN);*

11. 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.

12. Adequate renal function:

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

1. Adequate liver function:

2. Total serum bilirubin 1.5 x ULN;

3. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 2.5 x ULN (5.0 x ULN in case of liver metastases).

4. 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.

5. 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:

6. 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;

7. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

8. Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.

9. 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.

10. 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.

1. Systemic anti cancer therapy completed within a minimum of 5 half lives of study enrollment.

2. 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.

3. 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).

4. 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.

5. 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.

6. 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.

7. 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.

8. Known prior or suspected severe hypersensitivity to lorlatinib or any component in the formulation; known prior therapy with lorlatinib.

9. 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.

10. 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.

1. 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.

2. 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.

3. 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.

4. 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:

5. 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;

6. 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);

7. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort);

8. Known P glycoprotein (P gp) substrates with a narrow therapeutic index (eg, digoxin).

9. 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.

10. 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.

11. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.

12. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects 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 21 days if female, after the last dose of investigational product

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gaoxin Hospital of The First Affilated Hospital of Anhui Medical University	Hefei	Anhui	China	230088
2	Beijing Cancer Hospital	Beijing	Beijing	China	100142
3	Fujian Province Oncology Hospital	Fuzhou	Fujian	China	350014
4	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China	150081
5	Hunan Provincial Tumor Hospital/Division of Oncology	Changsha	Hunan	China	410013
6	The first hospital of jilin university	Changchun	Jilin	China	130021
7	Jilin Provincial Cancer Hospital	Changchun	Jilin	China	130103
8	Tangdu Hospital of Fourth Military Medical University	Xi'an	Shanxi	China	710000
9	Sichuan Province Cancer Hospital/Department of Pulmonary Tumor	Chengdu	Sichuan	China	610041
10	West China Hospital, Sichuan University, Cancer center	Chengdu	Sichuan	China	610041
11	The Second Affiliated Hospital of Zhejiang University College of Medicine	Hangzhou	Zhejiang	China	310009
12	Sir Run Run Shaw Hospital of College of Medicine of Zhejiang University, Center for Oncology	Hangzhou	Zhejiang	China	310016
13	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China	310022
14	Fifth Medical Center of PLA General Hospital	Beijing		China	100071
15	Beijing Chest Hospital, Capital Medical University	Beijing		China	101149
16	Guangdong Provincial People's Hospital	Guangzhou		China	510000
17	The First Affiliated Hospital Zhejiang University School of Medicine	Hangzhou, Zhejiang		China	310003
18	General Hospital of Eastern Theater Command	Nanjing, Jiangsu		China
19	Shanghai Chest Hospital	Shanghai		China	200030
20	Fudan University Shanghai Cancer Center	Shanghai		China	200032
21	Zhongshan Hospital, Fudan University	Shanghai		China	200032

Sponsors and Collaborators

• Pfizer

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Oct 11, 2019
• Statistical Analysis Plan - Sep 11, 2020

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03909971
• Other Study ID Numbers: B7461024
• First Posted: Apr 10, 2019
• Last Update Posted: Oct 26, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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
• Keywords provided by Pfizer: ALK positive; ALK inhibitor-treated; NSCLC
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Pre-assignment Detail	The study enrolled 109 participants, with 67 in Cohort 1 and 42 in Cohort 2.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Period Title: Overall Study
STARTED	67	42
COMPLETED	57	20
NOT COMPLETED	10	22

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Total
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Total of all reporting groups
Overall Participants	67	42	109
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.4 (10.85)	52.1 (13.36)	51.0 (11.84)
Age, Customized (Count of Participants)
<18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	61 91%	35 83.3%	96 88.1%
>65 years	6 9%	7 16.7%	13 11.9%
Sex: Female, Male (Count of Participants)
Female	33 49.3%	23 54.8%	56 51.4%
Male	34 50.7%	19 45.2%	53 48.6%
Race/Ethnicity, Customized (Count of Participants)
Chinese	67 100%	42 100%	109 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Objective Response (Cohort 1)
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of lorlatinib.

Arm/Group Title	Cohort 1
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67
Number (95% Confidence Interval) [Percentage of participants]	70.1 104.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Percentage of Participants With Objective Response (Cohort 2)
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 2
Arm/Group Description	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	42
Number (95% Confidence Interval) [Percentage of participants]	47.6 71%

3. Secondary Outcome

Title	Progression Free Survival
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
Median (95% Confidence Interval) [Months]	NA	5.6

4. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
Median (95% Confidence Interval) [Months]	NA	NA

5. Secondary Outcome

Title	Percentage of Participants With Intracranial Objective Response
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had intracranial response. Only included participants for whom the brain lesions have been chosen as RECIST target or non-target lesions at baseline

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	36	21
Number (95% Confidence Interval) [Percentage of participants]	80.6 120.3%	47.6 113.3%

6. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	47	20
Median (95% Confidence Interval) [Months]	NA	11.2

7. Secondary Outcome

Title	Duration of Intracranial Response
Description	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.
Time Frame	From first documentation of CR or PR to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had at least 1 intracranial lesion. Only included participants for whom the brain lesions have been chosen as RECIST target or non-target lesions at baseline.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	29	10
Median (95% Confidence Interval) [Months]	NA	NA

8. Secondary Outcome

Title	Time to Tumor Response
Description	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.
Time Frame	From Cycle 1 Day 1 to documented progression of disease by ICR (up to 67 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	47	20
Median (Full Range) [Months]	1.4	1.4

9. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
All-causality TEAEs	67 100%	42 100%
Treatment-related TEAEs	67 100%	42 100%
All-causality serious AEs	9 13.4%	14 33.3%
Treatment-related serious AEs	4 6%	5 11.9%
All-causalities maximum Grade 3 or 4 AEs	39 58.2%	20 47.6%
Treatment-related Grade 3 or 4 AEs	36 53.7%	17 40.5%
All-causality Grade 5 AEs	1 1.5%	7 16.7%
Treatment-related Grade 5 AEs	0 0%	0 0%

10. Secondary Outcome

Title	Number of Participants With Central Nervous System-Related Adverse Events
Description	The central-nervous system-related AEs included AEs under the cluster terms of MOOD EFFECTS, COGNITIVE EFFECTS, PSYCHOTIC EFFECTS, SPEECH EFFECTS.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
COGNITIVE EFFECTS	2 3%	1 2.4%
MOOD EFFECTS	0 0%	2 4.8%
SPEECH EFFECTS	0 0%	1 2.4%
PYSCHOTIC EFFECTS	1 1.5%	0 0%

11. Secondary Outcome

Title	Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
Anemia	2 3%	3 7.1%
Hemoglobin increased	0 0%	1 2.4%
Lymphocyte count decreased	0 0%	0 0%
Lymphocyte count increased	0 0%	0 0%
Neutrophil count decreased	0 0%	0 0%
Platelet count decreased	0 0%	1 2.4%
White blood cell decreased	0 0%	0 0%
Alanine aminotransferase increased	3 4.5%	0 0%
Alkaline phosphatase increased	0 0%	0 0%
Aspartate aminotransferase increased	2 3%	1 2.4%
Blood bilirubin increased	0 0%	1 2.4%
Creatine phosphokinase increased	1 1.5%	0 0%
Creatinine increased	0 0%	1 2.4%
Gamma-glutamyl transferase increased	1 1.5%	2 4.8%
Hypercalcemia	0 0%	1 2.4%
Hyperglycemia	2 3%	1 2.4%
Hyperkalemia	0 0%	0 0%
Hypermagnesemia	1 1.5%	1 2.4%
Hypernatremia	0 0%	0 0%
Hypoalbuminemia	0 0%	0 0%
Hypocalcemia	0 0%	1 2.4%
Hypoglycemia	0 0%	0 0%
Hypokalemia	1 1.5%	2 4.8%
Hypomagnesemia	1 1.5%	0 0%
Hyponatremia	0 0%	2 4.8%
Hypophosphatemia	1 1.5%	0 0%
Lipase increased	2 3%	3 7.1%
Serum amylase increased	2 3%	1 2.4%
Cholesterol high	9 13.4%	3 7.1%
Hypertriglyceridemia	23 34.3%	8 19%
Activated partial thromboplastin time prolonged	0 0%	0 0%
International normalized ratio increased	0 0%	0 0%
Proteinuria	0 0%	0 0%

12. Secondary Outcome

Title	Number of Participants With Vital Signs Data Meeting Pre-specified Criteria
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
Sitting SBP change >=40 mmHg increase	5 7.5%	0 0%
Sitting SBP change >=40 mmHg decrease	1 1.5%	0 0%
Sitting DBP change >=20 mmHg increase	20 29.9%	8 19%
Sitting DBP change >=20 mmHg decrease	5 7.5%	6 14.3%
Sitting DBP change >=60 mmHg increase	0 0%	0 0%
Sitting pulse rate value <50 bpm	0 0%	0 0%
Sitting pulse rate value >120 bpm	5 7.5%	3 7.1%
Sitting pulse rate change >=30 mmHg increase	17 25.4%	4 9.5%
Sitting pulse rate change >=30 mmHg decrease	4 6%	6 14.3%
Weight change >=10% and <20% increase	34 50.7%	16 38.1%
Weight change >=20% increase	10 14.9%	6 14.3%
Weight change >=10% decrease	0 0%	1 2.4%

13. Secondary Outcome

Title	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	42
PR interval change >=50 and baseline <200 msec	0 0%	0 0%
PR interval change >=25% and baseline >=200 msec	0 0%	0 0%
QRS interval change >=50% and baseline<100	1 1.5%	1 2.4%
QRS interval change >=25% and baseline >=100	0 0%	0 0%
QTcB value <=450 msec	38 56.7%	28 66.7%
QTcB value >450 and <=480 msec	22 32.8%	10 23.8%
QTcB value >480 and <=500 msec	3 4.5%	2 4.8%
QTcB value >500 msec	4 6%	2 4.8%
QTcB change <=30 msec	43 64.2%	27 64.3%
QTcB change >30 and <=60 msec	17 25.4%	13 31%
QTcB change >60 msec	7 10.4%	2 4.8%
QTcF value <=450 msec	59 88.1%	36 85.7%
QTcF value >450 and <=480 msec	7 10.4%	6 14.3%
QTcF value >480 and <=500 msec	0 0%	0 0%
QTcF value >500 msec	1 1.5%	0 0%
QTcF change <=30 msec	53 79.1%	31 73.8%
QTcF change >30 and <=60 msec	11 16.4%	8 19%
QTcF change >60 msec	3 4.5%	3 7.1%

14. Secondary Outcome

Title	Number of Participants With Left Ventricular Ejection Fraction Meeting Pre-specified Criteria
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and who had at least 1 result of the LVEF value.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	67	40
LVEF change from baseline normal to post-baseline below LLN	3 4.5%	0 0%
LVEF >=20-point decrease from baseline	1 1.5%	0 0%

15. Secondary Outcome

Title	Cycle 1 Day 1 Maximum Plasma Concentration (Cmax)
Description	The loratinib Cmax was estimated using non-compartmental analysis.
Time Frame	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	1004 (42)	1074 (58)

16. Secondary Outcome

Title	Cycle 1 Day 1 Time to Cmax (Tmax)
Description	The loratinib Tmax was estimated using non-compartmental analysis.
Time Frame	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Median (Full Range) [hour]	1.02	1.45

17. Secondary Outcome

Title	Cycle 1 Day 1 Area Under the Plasma Concentration Versus Time Profile Within A Dose Interval (AUCtau)
Description	The loratinib AUCtau was estimated using non-compartmental analysis.
Time Frame	At pre-dose, 0.5, 1, 2, 3, 4, 6 ,8, 9 and 24 hours on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng.hr/mL)]	7310 (17)	7778 (39)

18. Secondary Outcome

Title	Steady-State Cmax
Description	The loratinib Cmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Time Frame	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	643.9 (50)	795.9 (40)

19. Secondary Outcome

Title	Steady-State Tmax
Description	The loratinib Tmax was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Time Frame	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Median (Full Range) [hour]	1.53	1.88

20. Secondary Outcome

Title	Steady-State AUCtau
Description	The loratinib AUCtau was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Time Frame	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	5388 (37)	6801 (40)

21. Secondary Outcome

Title	Apparent Clearance (CL/F)
Description	The loratinib CL/F was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Time Frame	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [Liter per hour (L/hr)]	18.55 (37)	14.71 (40)

22. Secondary Outcome

Title	Observed Accumulation Ratio (Rac)
Description	The loratinib Rac was estimated using non-compartmental analysis. Steady-state was reached on Cycle 1 Day 15.
Time Frame	At Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

The analysis population included all enrolled participants who received at least 1 dose of loratinib and had sufficient information to estimate at least 1 of the pharmacokinetic parameters of interest.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.	Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.7371 (47)	0.9578 (33)

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	The same event may appear as both an AE and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study. AE reporting, including suspected unexpected serious adverse reactions, was carried out in accordance with applicable local regulations.
Arm/Group Title	Cohort 1		Cohort 2
Arm/Group Description	Participants whose disease had progressed after crizotinib as the only anaplastic lymphoma kinase (ALK) inhibitor were enrolled in Cohort 1 to receive lorlatinib 100 mg orally once daily (QD) continuously until confirmed disease progression by Independent Central Radiology (ICR) (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.		Participants whose disease had progressed after one ALK inhibitor treatment other than crizotinib, with or without prior crizotinib were enrolled in Cohort 2 to receive lorlatinib100 mg QD continuously until confirmed disease progression by ICR (unless clinical benefit is still achievable), global deterioration of health status requiring permanent discontinuation, unacceptable toxicity, pregnancy, significant protocol violation, patient lost to follow-up, or patient refusal, study terminated by the sponsor, or death, whichever comes first. Each cycle duration was 21 days.
All Cause Mortality
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/67 (3%)		6/42 (14.3%)
Serious Adverse Events
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/67 (13.4%)		14/42 (33.3%)
General disorders
Death	0/67 (0%)		1/42 (2.4%)
Pyrexia	0/67 (0%)		1/42 (2.4%)
Sudden death	0/67 (0%)		1/42 (2.4%)
Hepatobiliary disorders
Cholecystitis	1/67 (1.5%)		0/42 (0%)
Cholelithiasis	1/67 (1.5%)		0/42 (0%)
Drug-induced liver injury	1/67 (1.5%)		0/42 (0%)
Hepatic function abnormal	1/67 (1.5%)		0/42 (0%)
Liver injury	0/67 (0%)		1/42 (2.4%)
Infections and infestations
Infection	0/67 (0%)		1/42 (2.4%)
Pneumonia	2/67 (3%)		3/42 (7.1%)
Injury, poisoning and procedural complications
Ulna fracture	1/67 (1.5%)		0/42 (0%)
Investigations
Platelet count decreased	0/67 (0%)		1/42 (2.4%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	0/67 (0%)		1/42 (2.4%)
Hypokalemia	1/67 (1.5%)		0/42 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/67 (0%)		1/42 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	0/67 (0%)		1/42 (2.4%)
Neoplasm progression	1/67 (1.5%)		0/42 (0%)
Psychiatric disorders
Mental disorder	0/67 (0%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Bronchial haemorrhage	1/67 (1.5%)		0/42 (0%)
Pulmonary embolism	0/67 (0%)		1/42 (2.4%)
Pneumonitis	1/67 (1.5%)		0/42 (0%)
Respiratory failure	0/67 (0%)		2/42 (4.8%)
Vascular disorders
Embolism	1/67 (1.5%)		0/42 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/67 (100%)		42/42 (100%)
Blood and lymphatic system disorders
Anaemia	19/67 (28.4%)		12/42 (28.6%)
Cardiac disorders
Atrioventricular block first degree	4/67 (6%)		2/42 (4.8%)
Sinus bradycardia	5/67 (7.5%)		5/42 (11.9%)
Sinus tachycardia	6/67 (9%)		3/42 (7.1%)
Pericardial effusion	5/67 (7.5%)		2/42 (4.8%)
Ear and labyrinth disorders
Tinnitus	0/67 (0%)		3/42 (7.1%)
Eye disorders
Vision blurred	4/67 (6%)		1/42 (2.4%)
Gastrointestinal disorders
Vomiting	1/67 (1.5%)		3/42 (7.1%)
Diarrhea	4/67 (6%)		2/42 (4.8%)
General disorders
Oedema peripheral	13/67 (19.4%)		9/42 (21.4%)
Peripheral swelling	7/67 (10.4%)		1/42 (2.4%)
Pain	4/67 (6%)		2/42 (4.8%)
Pyrexia	5/67 (7.5%)		5/42 (11.9%)
Infections and infestations
Pneumonia	4/67 (6%)		1/42 (2.4%)
Upper respiratory tract infection	7/67 (10.4%)		2/42 (4.8%)
Investigations
Alanine aminotransferase increased	31/67 (46.3%)		16/42 (38.1%)
Amylase increased	9/67 (13.4%)		3/42 (7.1%)
Aspartate aminotransferase increased	30/67 (44.8%)		14/42 (33.3%)
Blood alkaline phosphatase increased	4/67 (6%)		6/42 (14.3%)
Blood cholesterol increased	29/67 (43.3%)		14/42 (33.3%)
Blood creatine phosphokinase increased	4/67 (6%)		4/42 (9.5%)
Blood creatinine increased	6/67 (9%)		4/42 (9.5%)
Blood triglycerides increased	11/67 (16.4%)		5/42 (11.9%)
Electrocardiogram QT prolonged	14/67 (20.9%)		7/42 (16.7%)
Gamma-glutamyltransferase increased	19/67 (28.4%)		12/42 (28.6%)
Haemoglobin decreased	2/67 (3%)		4/42 (9.5%)
High density lipoprotein increased	6/67 (9%)		3/42 (7.1%)
Lipase increased	6/67 (9%)		5/42 (11.9%)
Low density lipoprotein increased	12/67 (17.9%)		10/42 (23.8%)
Neutrophil count decreased	5/67 (7.5%)		1/42 (2.4%)
Platelet count decreased	6/67 (9%)		2/42 (4.8%)
Weight increased	43/67 (64.2%)		16/42 (38.1%)
Albumin urine present	1/67 (1.5%)		3/42 (7.1%)
Blood albumin decreased	2/67 (3%)		5/42 (11.9%)
Blood glucose increased	5/67 (7.5%)		2/42 (4.8%)
Blood pressure increased	2/67 (3%)		4/42 (9.5%)
Blood uric acid increased	2/67 (3%)		3/42 (7.1%)
Lymphocyte count decreased	1/67 (1.5%)		3/42 (7.1%)
Blood phosphorus decreased	1/67 (1.5%)		3/42 (7.1%)
Metabolism and nutrition disorders
Hypercholesterolaemia	36/67 (53.7%)		26/42 (61.9%)
Hyperglycaemia	18/67 (26.9%)		2/42 (4.8%)
Hyperlipidaemia	4/67 (6%)		0/42 (0%)
Hypertriglyceridaemia	58/67 (86.6%)		31/42 (73.8%)
Hyperuricaemia	13/67 (19.4%)		5/42 (11.9%)
Hypoalbuminemia	16/67 (23.9%)		8/42 (19%)
Hypokalemia	7/67 (10.4%)		5/42 (11.9%)
Hyponatremia	2/67 (3%)		7/42 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/67 (17.9%)		3/42 (7.1%)
Nervous system disorders
Hypoaesthesia	10/67 (14.9%)		3/42 (7.1%)
Renal and urinary disorders
Proteinuria	6/67 (9%)		2/42 (4.8%)
Hematuria	5/67 (7.5%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Cough	6/67 (9%)		2/42 (4.8%)
Dyspnea	2/67 (3%)		3/42 (7.1%)
Skin and subcutaneous tissue disorders
Rash	6/67 (9%)		0/42 (0%)
Vascular disorders
Hypertension	9/67 (13.4%)		4/42 (9.5%)

Limitations/Caveats

The study is still ongoing. This report reflects data collected up to 10 Aug 2020, and will be updated after completion of the whole study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Restriction Description: Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclosure previously undisclosed confidential information other than study results.