| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced ALK positive non small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific type of advanced lung cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - 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. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare Arm A with Arm B in treatment-naïve advanced ALK-positive NSCLC participants with respect to overall survival (OS);
- To evaluate the antitumor activity in each treatment arm;
- To evaluate the safety and tolerability in each treatment arm;
- 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;
- To evaluate candidate biomarkers of sensitivity or resistance to single-agent crizotinib or lorlatinib in pre-treatment tumor tissue;
- To evaluate candidate biomarkers of sensitivity or resistance to single-agent crizotinib or lorlatinib in peripheral blood.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| - To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamic (PK/PD) relationship for lorlatinib if appropriate |
|
| E.3 | Principal inclusion criteria |
1.Diagnosis:
a.Study Population: Patients 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:
i.Asymptomatic: either not currently requiring corticosteroid treatment, or on a stable or decreasing dose of ≤ 10 mg QD prednisone or equivalent; or
ii.Previously diagnosed and 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
iii.Leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if visualized on MRI (magnetic resonance imaging), 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.No prior systemic NSCLC treatment, including molecularly targeted agents, angiogenesis inhibitors, immunotherapy, or chemotherapy. Adjuvant/neoadjuvant NSCLC treatment only allowed if completed more than 12 months prior to randomization.
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 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.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 patient may be enrolled
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.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.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.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; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
•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.Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
12.Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
|
|
| E.4 | Principal exclusion criteria |
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.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.Radiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Patients 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.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.Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations.
6.Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (e.g., in case of known HBsAg or HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness.
7. Clinically significant vascular (both arterial and venous) and nonvascular
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.Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) in the last month prior to randomization.
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.Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, lobular carcinoma in situ/ductal carcinoma in situ (LCIS/DCIS) of the breast, or localized prostate cancer) within the last 3 years prior to randomization.
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 above 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).
*Due to maximum limit points 12, 13,14,15 are attached in comments. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •PFS based on blinded independent central review (BICR) assessment (RECIST v.1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please, refer to the Schedule of assessments in the Protocol |
|
| E.5.2 | Secondary end point(s) |
•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 ICTTR all by BICR (RECIST v. 1.1) and PFS2;ICOR, IC-TTP, IC-DR, IC-TTR and DR based on the investigator's
assessment.
•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;
•PROs as assessed by EORTC QLC-C30, EORTC QLQ-LC13, EQ-5D-5L;
•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);
•Peripheral blood cfDNA (circulating free Deoxyribonucleic acid) biomarkers including, but not limited to, ALK gene rearrangement and/or ALK kinase domain mutations.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the Schedule of Activities of the Protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| China |
| Hong Kong |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| Singapore |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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