| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Patients with Previously Untreated, Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous non-small cell lung cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 assess the efficacy of furmonertinib compared o platinum-based chemotherapy using progression-free survival (PFS) in previously untreated patients with locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations.
|
|
| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of furmonertinib compared to platinum-based chemotherapy using overall survival (OS), tumor response, and progression in previously untreated patients with locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations.
- To assess the impact of furmonertinib compared to platinum-based chemotherapy on patients’ disease-related symptoms and health-related quality of life.
- To evaluate the safety and tolerability of furmonertinib compared to platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations.
- To characterize the PK of furmonertinib and its major metabolite (AST5902). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Informed Consent Form
2. Age ≥ 18 years at time of signing Informed Consent Form
3. Ability to comply with the study protocol, in the investigator’s judgment
4. Measurable disease per RECIST v1.1.
Note: Measurable lesion can neither be subject to local therapy such as radiotherapy nor used for biopsy in the Screening Period; if there is only 1 measurable lesion, this lesion will be permitted to be biopsied. However, the baseline radiologic examination should be performed for this lesion at least 14 days after biopsy.
5. Histologically or cytologically documented, locally advanced or metastatic non-squamous NSCLC not amenable to curative surgery or radiotherapy
6. Documented validated results confirming the presence of an EGFR exon 20 insertion mutation (i.e., addition of 1 or more amino acids) in tumor tissue or blood from local or central testing via:
• A validated NGS assay or a validated PCR test with confirmation by Sanger sequencing performed at a CLIA or equivalently certified laboratory.
− If local testing does not meet the above criteria, then a central test designated by the Sponsor or a commercially available NGS assay should be performed as specified in the laboratory manual.
7. Consent to provide archival tumor tissue specimen (FFPE tissue block [preferred] or at least 15 unstained, serially cut sections on slides from FFPE tumor specimen). The specimens should be provided during screening or no later than within 30 days of Cycle 1, Day 1 and must be accompanied by a pathology report.
• It is preferred that the specimen is prepared from the most recently collected and available tumor tissue.
8. No prior systemic anticancer therapy regimens received for locally advanced or metastatic NSCLC including prior treatment with any EGFR-targeting agents (e.g., previous EGFR-TKIs, monoclonal antibodies, or bispecific antibodies)
9. Patients who have received prior neo-adjuvant and/or adjuvant chemotherapy, immunotherapy, or chemoradiotherapy for non-metastatic disease must have experienced a treatment-free interval of at least 12 months.
10. ECOG performance status of 0 or 1
11. Life expectancy of ≥ 12 weeks
12. Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
• Absolute neutrophil count ≥ 1500/μL
• Hemoglobin ≥ 9 g/dL
• Platelet count ≥ 100,000/μL
• Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia)
• AST, ALT, and AP ≤ 2.5 × ULN, with the following exceptions:
− Patients with documented liver metastases may have AST, ALT, and/or AP ≤ 5.0 × ULN.
− Patients with documented bone metastases may have AP ≤ 5.0 × ULN.
• Creatinine clearance ≥ 45 mL/min on the basis of the Cockcroft-Gault estimation:
(140 – age) × (weight in kg) × (0.85 if female)
72 × (serum creatinine in mg/dL)
• INR ≤ 1.5 × ULN and aPTT ≤ 1.5 × ULN
13. For WOCBP: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs.
14. For men who are not surgically sterile: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm.
15. Patients with CNS metastases are eligible, provided they meet all of the following criteria:
• Measurable disease outside the CNS
• No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for ≥ 2 weeks prior to enrollment
• No ongoing symptoms attributed to CNS metastases
• No active CNS metastases or spinal cord compression (i.e., progressing or requiring anticonvulsants or corticosteroids for symptomatic control)
• No known or suspected leptomeningeal disease
• Patients with previously treated brain metastases:
− No evidence of interim CNS disease progression between the completion of previous CNS directed therapy and the screening radiographic CNS imaging
- Patients may receive local therapy provided that they meet the washout criteria below for WBRT, SRS, or surgical resection
- Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening may be eligible to enroll if:
− Time since WBRT is ≥ 21 days prior to randomization of study treatment, time since SRS is ≥ 7 days prior to randomization of study treatment, or time since surgical resection is ≥ 28 days. |
|
| E.4 | Principal exclusion criteria |
1. Inability or unwillingness to swallow pills
2. Inability to comply with study and follow-up procedures
3. Malabsorption syndrome or other conditions that would interfere with enteral absorption
4. Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently
• Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable, and has symptomatically improved.
5. Severe acute or chronic infections.
6. In the setting of a pandemic or epidemic, screening for active infections should be considered according to local or institutional guidelines or those of applicable professional societies (e.g., American Society of Clinical Oncology or European Society for Medical Oncology).
7. Previous interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis, or having ILD
8. History of or active clinically significant cardiovascular dysfunction, including the following:
• History of stroke or transient ischemic attack within 6 months prior to first dose of study drug
• History of myocardial infarction within 6 months prior to first dose of study drug
• NYHA Class III or IV cardiac disease or congestive heart failure requiring medication
• Uncontrolled arrhythmias, or history of or active ventricular arrhythmia requiring medication
• Coronary heart disease that is symptomatic or unstable angina
9. Mean resting QTc > 470 msec, obtained from triplicate ECGs, using the screening clinic ECG machine–derived Fridericia’s formula (QTcF) value
10. Clinically significant prolonged QT interval or other arrhythmia or clinical status considered by investigators that may increase the risk of prolonged QT interval (e.g., complete left bundle branch block, third-degree atrioventricular block, second degree heart block, PR interval > 250 msec, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relatives, serious hypokalemia, heart failure) or current use of the drugs that may lead to prolonged QT interval
11. Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
12. Significant traumatic injury or major surgical procedure within 4 weeks prior to Day 1 of Cycle 1
13. Patients with chronic diarrhea, short bowel syndrome or significant upper GI surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis)
14. Any other diseases, pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications (e.g., uncontrolled hypertension, active bleeding)
15. Radiation therapy (other than palliative radiation to bone metastases and radiation to CNS metastases as described above) as cancer therapy within 4 weeks prior to initiation of study treatment
16. Palliative radiation to bone metastases within 2 weeks prior to initiation of study drug
17. Any unresolved toxicities from prior therapy (e.g., adjuvant chemotherapy) > Grade 1 at initiation of study drug, with the exceptions of alopecia and prior platinum therapy-related Grade 2 neuropathy
18. History of other malignancy within 3 years prior to screening, with the exception of patients with a negligible risk of metastases or death and/or treated with expected curative outcome (such as appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, or ductal carcinoma in situ)
19. Pregnant or breastfeeding or intending to become pregnant during the study or within 60 days after the final dose of study drug
20. Use of a strong CYP3A4 inhibitor within 7 days prior to the first dose of investigational product or a strong CYP3A4 inducer within 21 days prior to the first dose of investigational product
21. Use of an herbal medicine (e.g., Chinese medicine or traditional Chinese medicine preparation indicated for cancer, or a traditional Chinese medicine or traditional Chinese medicine preparation with adjuvant anticancer effects) within 2 weeks prior to the first dose of investigational product or is expected to be used during the study
22. History of allergic reactions to any components, including excipients, of the furmonertinib drug product
23. History of allergic reactions to pemetrexed, cisplatin, carboplatin, other platinum-containing compounds, or other components of their preparation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, where PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by BICR using RECIST v1.1, or death from any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Defined within the primary endpoint description |
|
| E.5.2 | Secondary end point(s) |
• OS, defined as the time from randomization to death from any cause
• PFS as determined by investigator assessment using RECIST v1.1
• ORR, defined as the percentage of patients with a CR or PR relative to the total number of patients by BICR and investigator assessment using RECIST v1.1
• DOR, defined as the time from first documented evidence of CR or PR until the first documented evidence of disease progression or death, whichever occurs earlier, as determined by BICR and investigator assessment using RECIST v1.1
• PFS2, defined as the time from randomization to second progression, (i.e., earliest of the subsequent progression events after initiation of new anticancer treatment), or death from any cause, whichever occurs first. PFS2 is evaluated per local standard practice by investigator.
• PFS by BICR and investigator assessment using RECIST v1.1 in patients with a history or presence of brain metastases at baseline
• Time to CNS metastases by BICR and investigator assessment using RECIST v1.1
− Time to CNS metastases is defined as the time from the date of randomization until the date of newly diagnosed CNS lesions by RECIST v1.1.
• CNS ORR, evaluated by BICR per modified RECIST criteria in patients with CNS lesion(s) on baseline brain scan
• CNS DOR, evaluated by BICR per modified RECIST criteria in patients with CNS lesion(s) on baseline brain scan
• CNS PFS, evaluated by BICR per modified RECIST criteria in patients with CNS lesion(s) on baseline brain scan
− CNS PFS is defined as the time from randomization to the first occurrence of CNS progression according to modified RECIST by BICR, or death from any cause, whichever comes first.
• Change from baseline in EORTC QLQ-C30
• Change from baseline in EORTC QLQ-LC13
• Change from baseline in NSCLC-SAQ
• Time to deterioration of lung-related symptoms of dyspnea, cough, and chest pain
• Incidence and severity of AEs, with severity determined according to NCI CTCAE v5.0
• Change from baseline in safety-related clinical laboratory test results
• Plasma concentrations of furmonertinib and its major metabolite (AST5902) at specified time points collected from patients receiving furmonertinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Defined within the secondary endpoints description |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability of furmonertinib compared to platinum-based chemotherapy |
|
| 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 | No |
| 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 | 3 |
| 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 | 27 |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Singapore |
| Taiwan |
| Thailand |
| United States |
| France |
| Netherlands |
| Spain |
| Italy |
| Belgium |
| Hungary |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of this study is defined as the date when the last patient, last visit occurs or the date at which the last data point required for follow-up is received from the last patient, or the last patient is lost to follow-up or has withdrawn consent, whichever occurs later. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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