Study with investigational drug PF-06463922 and comparator crizotinib in patients with a specific type of advanced lung cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Jul 2017 → ongoing

Decision date (initial)

2024-06-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509169-19-00

EudraCT number

2016-003315-35

ClinicalTrials.gov

NCT03052608

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Efficacy

To demonstrate that lorlatinib as a single agent (Arm A) is superior to crizotinib alone (Arm B) in prolonging Progression Free Survival (PFS) in advanced ALK positive NSCLC participants who are treatment naïve.

Secondary objectives 6

1. To compare Arm A and Arm B in treatment naïve advanced ALK positive NSCLC participants with respect to Overall Survival (OS)
2. To evaluate the antitumor activity in each treatment arm
3. To evaluate the safety and tolerability in each treatment arm
4. To evaluate participant reported outcomes (PROs) of health related quality of life, disease/treatment related symptoms of lung cancer, and general health status for each treatment arm
5. To evaluate candidate biomarkers of sensitivity or resistance to single agent crizotinib or lorlatinib in pre treatment tumor tissue
6. To evaluate candidate biomarkers of sensitivity or resistance to single agent crizotinib or lorlatinib in peripheral blood.

Conditions and MedDRA coding

Advanced ALK positive non-small cell lung cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Diagnosis: a. Study Population: Participants with histologically or cytologically confirmed diagnosis of locally advanced [(Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) by American Joint Committee on Cancer (AJCC) v 7.0] ALK positive NSCLC where ALK status is determined by the FDA approved (for use in US), CE (Conformité Européene) marked (for EU and other countries that accept CE marking), and PMDA(Pharmaceuticals and Medical Devices Agency) approved (for use in Japan) Ventana ALK (D5F3) Companion Diagnostic (CDx) IHC test performed on the Ventana ULTRA or XT platforms (refer to Section 6.1.1.1 for any prescreening activity related to ALK determination); b. Tumor Requirements: At least 1 extracranial measurable target lesion per RECIST v. 1.1 that has not been previously irradiated. CNS metastases are allowed if asymptomatic and: 1. Either untreated and not currently requiring corticosteroid treatment, or on a stable or decreasing dose of ≤10 mg QD prednisone or equivalent; or 2. Local treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to randomization, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability; or 3. In case of leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if visualized on magnetic resonance imaging (MRI), or if baseline CSF positive cytology is available. c. Tissue Requirements: All participants must have an archival formalin fixed, paraffin embedded (FFPE) tissue specimen available and collected prior to randomization. If archived tissue is unavailable, then a mandatory de novo biopsy must be performed.
2. 2. No prior systemic NSCLC treatment for advanced (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) disease, including molecularly targeted agents (eg, ALK TKIs), angiogenesis inhibitors, immunotherapy, or chemotherapy. Prior treatment for earlier Stages of the NSCLC only allowed if completed more than 12 months prior to randomization.
3. 3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2.
4. 4. Age ≥18 years (or ≥20 years as required by local regulation).
5. 5. Adequate Bone Marrow Function, including: a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥1.5 x 109/L; b. Platelets ≥100,000/mm3 or ≥100 x 109/L; c. Hemoglobin ≥9 g/dL.
6. 6. Adequate Pancreatic Function, including: a. Serum total amylase ≤1.5 x upper limit of normal (ULN)*; b. Serum lipase ≤1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then participant may be enrolled.
7. 7. Adequate Renal Function, including: a. Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.
8. 8. Adequate Liver Function, including: a. Total serum bilirubin ≤1.5 x ULN; b. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN (≤5.0 x ULN in case of liver metastases).
9. 9. Acute effects of prior radiotherapy resolved to baseline severity or to CTCAE Grade ≤1 except for AEs that in the investigator’s judgment do not constitute a safety risk for the participant.
10. 10. Serum pregnancy test (for females of childbearing potential) negative at screening. Female participants of non childbearing potential must meet at least 1 of the following criteria: • 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); • Have undergone a documented hysterectomy and/or bilateral oophorectomy; • Have medically confirmed ovarian failure. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential.
11. 11. Evidence of a personally signed and dated informed consent document indicating that the participant (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
12. 12. Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion criteria 15

1. 1. Spinal cord compression unless the participant has good pain control attained through therapy, and there is stabilization or recovery of neurological function for the 4 weeks prior to randomization.
2. 2. Major surgery within 4 weeks prior to randomization. Minor surgical procedures (eg, port insertion) are not excluded, but sufficient time should have passed for adequate wound healing.
3. 3. Radiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Participants who complete whole brain irradiation within 4 weeks prior to randomization or palliative radiation therapy outside of the CNS within 48 hours prior to randomization will also not be included in the study.
4. 4. 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.
5. 5. Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations.
6. 6. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known HBsAg or HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
7. 7. Clinically significant vascular (both arterial and venous) and non vascular cardiac conditions, (active or within 3 months prior to enrollment), which may include, but are not 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; • Non vascular cardiac disease such as congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third degree AV block (unless paced) or any AV block with PR >220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless participant is otherwise healthy such as long distance runners, etc.), machine read Electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome.
8. 8. Participants with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) in the last month prior to randomization.
9. 9. 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.
10. 10. Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or localized prostate cancer or any in situ cancer which does not currently require treatment) within the last 3 years prior to randomization.
11. 11. 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 below categories) within 12 days prior to the first dose of lorlatinib or crizotinib. a. 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. b. 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). c. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort). d. Known P gp substrates with a narrow therapeutic index (eg, digoxin).
12. 12. 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, would make the participant inappropriate for entry into this study.
13. 13. Participants 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 participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.
14. 14. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.
15. 15. 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 if under lorlatinib or 90 days if under crizotinib.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • PFS based on blinded independent central review (BICR) assessment (RECIST v.1.1).

Secondary endpoints 5

1. • Efficacy: OS, PFS based on Investigator’s assessment, OR based on BICR and on Investigator’s assessment; intracranial OR (IC OR), IC TTP, DR and IC-DR, TTR and IC-TTR all by BICR (RECIST v. 1.1) and PFS2; IC-OR, IC-TTP, IC-DR, IC-TTR and DR based on the investigator’s assessment.
2. • Safety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate) and body weight; electrocardiograms (ECGs); echocardiogram or MUGA scan; ophthalmologic data.
3. • PROs as assessed by EORTC QLC C30, EORTC QLQ LC13, EQ 5D 5L.
4. • Tumor tissue biomarkers including, but not limited to, ALK gene rearrangement and/or mutation as measured by next generation sequencing (NGS) and/or immunohistochemistry (IHC).
5. • Peripheral blood cfDNA (circulating free Deoxyribonucleic acid) biomarkers including, but not limited to, ALK gene rearrangement and/or ALK kinase domain mutations.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 4

Locations

8 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 110 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications