| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| non-small cell lung cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 compare the progression-free survival (PFS) of pyrotinib versus docetaxel in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring a HER2 exon 20 mutation who progressed after treatment with platinum based chemotherapy). The PFS endpoint will be determined by blinded independent radiology review committee (BIRC). |
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| E.2.2 | Secondary objectives of the trial |
- To compare the efficacy of pyrotinib versus docetaxel in patients with advanced HER2 exon20-mutated non-squamous NSCLC who have progressed after treated with platinum based chemotherapy , through evaluations of overall survival (OS), and objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and time to tumor progression (TTP) assessed by BIRC, and ORR, DCR, DoR, TTP, PFS and PFS2 assessed by investigator;
-To evaluate the safety of pyrotinib versus docetaxel in patients with advanced HER2 exon20-mutated non-squamous NSCLC who have progressed after treated with platinum based chemotherapy;
-To evaluate patient reported outcomes (PRO) in pyrotinib versus docetaxel treatment arms;
-To evaluate pharmacokinetics (PK) of pyrotinib in patients with advanced HER2 exon20-mutated non-squamous NSCLC who have progressed after treated with platinum based chemotherapy; |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent which is approved by IRB/EC, willing and able to comply with scheduled treatment, all examinations at study visits, and other study procedures.
2. Male or female, ≥18 years old.
3. ECOG PS 0-1 (see APPENDIX 2 for ECOG PS criteria).
4. Have histologically or cytologically confirmed locally advanced (must have been evaluated by the investigator that are not amenable to curable surgery or radiotherapy) or metastatic non-squamous NSCLC disease (Stage IIIB – IV, according to the International Association for the Study of Lung Cancer (IASLC) cancer staging system, 8th edition [APPENDIX 3]).
5. Before enrollment, a documented confirmed presence of activating mutations in exon 20 of the HER2 gene must be provided. Sufficient tumor tissue samples should be provided to retrospectively confirm the mutation status of the HER2 gene. For examples of HER2 (ERBB2) exon 20 mutations see APPENDIX 4.
The tumor tissue samples should be: neutral buffered formalin fixed, paraffin-embedded [FFPE] blocks or at least 6-12 unstained (6-10 surgical biopsies, or at least 12 core needle biopsies) tumor tissue slices, fresh or archived (fresh samples are preferred). For patients who cannot provide the required biopsies, their enrollment can be discussed with the sponsor.
6. Must have measureable disease per RECIST v1.1. The definition of CT or MRI measurable lesion as the target lesion: according to RECIST v1.1, the long diameter of such lesion should be ≥10 mm by the spiral CT scan or the short diameter of enlarged lymph nodes ≥15 mm; lesions that have previously received local treatment can be used as target lesions after the confirmation of progress according to the RECIST v1.1 standard.
7. For advanced NSCLC, patients must have had progressive disease on or after a platinum based chemotherapy, with or without immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) and/or anti-angiogenic drugs. No more than 2 prior lines of systemic therapy are allowed. Two scenarios of neoadjuvant/adjuvant therapy are allowed: a) subjects who received adjuvant or neoadjuvant platinum based chemotherapy and developed recurrent or metastatic disease within 6 months of completing therapy are eligible; b) subjects with recurrent disease > 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum based regimen given to treat the recurrence, are eligible.
8. The laboratory test values must meet the following standards to manifest that the functional level of important organs/systems meets the requirements:
• Hematology (not corrected by blood/blood products transfusion, or transfusion of hematopoietic stimulating factors such as G-CSF/TPO, etc. within 14 days before the test): ANC≥1.5 × 109/L; PLT≥100 × 109/L; Hb≥80 g/L;
• Blood biochemistry (liver function): TBIL ≤ 1.0 × ULN; ALT and/or AST ≤ 1.5 × ULN AND alkaline phosphatase (ALP) ≤2.5×ULN.
• Blood biochemistry (renal function): Cr≤1.5 × ULN and CrCL≥50 mL/min (Cockcroft-Gault formula);
9. Female of childbearing potential must have a serum pregnancy test within 7 days before the first dose and the result is negative. Female patient of childbearing potential (WOCBP) and male patient whose partner is WOCBP must agree to use effective contraception method during the study period and within 8 weeks after the last dose (if receiving docetaxel treatment only, after the last dose, 3 months for male patient whose partner is WOCBP, and 6 months for female patient of childbearing potential). |
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| E.4 | Principal exclusion criteria |
1. Target disease exclusion criteria
1) Malignant tumors with other pathological types, such as mixed cancer, double primary cancers;
2) Medical history of other active malignancies within last 5 years; Exceptions: skin basal cell carcinoma, superficial bladder cancer, skin squamous cell carcinoma, prostate cancer in situ, or cervical carcinoma in situ, for which by the date of the first dose of study drug, at least 2 years of complete remission and no other treatment is needed or expected during the study period.
3) Subjects with active CNS metastases are excluded. Subjects with history or evidence of current leptomeningeal metastases are excluded. Subjects are eligible if CNS metastases are adequately treated (surgery or radiotherapy) and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
4) Previously treated with targeted drugs for HER2 gene mutations (including but not limited to trastuzumab and its conjugated drugs, pertuzumab, lapatinib, pyrotinib, neratinib, afatinib, dacomitinib, poziotinib);
5) Previously treated with docetaxel;
6) By the date of first dose of study treatment, the washout period of previous drug treatment / medical intervention does not meet the following requirements:
• anti-tumor drugs such as platinum drugs, other chemotherapy drugs, immune checkpoint inhibitors, etc. (including the study drugs of the same classes in clinical study) ≥ 3 weeks (or 5 half-lives of the drug, to whichever is shorter);
• anti-tumor traditional Chinese medicine treatment ≥ 2 weeks;
• major surgery (requires hospitalization) ≥ 2 weeks;
• minimally invasive surgery (puncture, biopsy, endoscope, etc.) ≥ 1 week;
• with > 30 Gy non-thoracic radiotherapy ≥4 weeks;
• with > 30 Gy thoracic radiotherapy ≥24 weeks;
• with ≤30 Gy palliative radiotherapy ≥2 weeks.
Furthermore, it is required that the adverse event has resolved from the previous drug treatment/medical interventions (except for alopecia or fatigue within NCI-CTCAE v5.0 Grade 1)
2. Medical history exclusion criteria
1) Patients with active (not medically treated) CNS diseases, such as benign brain tumors, benign meningiomas, other leptomeningeal diseases, and poorly controlled (occurs within 6 months prior to the first dose of study treatment) cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction, etc). Patients are eligible if the above-mentioned disease has been adequately treated and clinically stable prior to the first dose of study treatment (by radiological assessments [preferred enhanced MRI or CT] and maintained for at least 2 weeks, and the relevant symptoms have been resolved to NCI-CTCAE v5.0 Grade ≤1 for at least 2 weeks);
2) Severe cardiac disease, including the following diseases that occur within 12 months prior to the first dose of study treatment: (1) myocardial infarction; (2) heart failure; and disease that occurs within 3 months prior to the first dose of study treatment: (1) severe/unstable angina pectoris; (2) ventricular arrhythmias requiring continuous medication; but controlled atrial arrhythmias after continuous medication is eligible; (3) Grade ≥2 myocardial ischemia; (4) Grade ≥2 cardiac insufficiency according to New York Heart Association (NYHA) Functional Classification (APPENDIX 5); (5)LVEF (left ventricular ejection fraction) <50%; (6) coronary / peripheral artery bypass grafting is experienced or expected; (7) QTcF> 450 ms (male)，QTcF > 470 ms (female) (QTc interval is calculated by Fridericia formula; in case QTc is abnormal, it can be tested for three times at an interval of 2 minutes and the average value will be used); any other heart disease judged by the investigator to be unsuitable for clinical study;
3) Prior to the first dose of study treatment, patients with the following conditions: inability to swallow, chronic diarrhea, intestinal obstruction, gastrointestinal perforation or gastrectomy, or other diseases or special conditions that affect drug administration and absorption;
4) Prior to the first dose of study treatment, patients with severe effusions with clinical symptoms (such as a large amount of pleural effusion, ascites or pericardial effusion) require repeated therapeutic puncture drainers (tube is allowed);
5) Within 2 weeks prior to the first dose of study treatment, symptoms of severe infection or evidence for microbiological/viral diagnosis, including but not limited to hospitalization due to infection, bacteremia or severe pneumonia; oral or intravenous administration of therapeutic antibiotics;
6) Congenital or acquired immunodeficiency (e.g., HIV infection);
7) Patients with active hepatitis infection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS evaluated by the blinded independent review committee (BIRC) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS will be collected on Day 1 of each dosing cycle, at discontinuation of treatment/withdrawal, at safety follow-up: 28 days (±7) after the last dose and at Survival follow-up (comes after safety followup). Every 56 days (±7 days) after the last dose investigators must follow up subject’s survival via phone calls. The definition of the Follow-up period is: in addition to safety follow-up and survival follow-up, in the absence of disease progression evidenced by radiological evaluation, regardless whether subjects discontinue from study treatment or not, subjects still need to receive radiological evaluations according to the scheduled visits, until BIRC assessed progression of disease, death, lost to follow up, consent withdrawal, study termination by the sponsor (whichever occurs first). |
|
| E.5.2 | Secondary end point(s) |
• OS;
• ORR, DCR, DoR, and TTP evaluated by BIRC;
• ORR, DCR, DoR, and TTP evaluated by investigator;
• PFS evaluated by investigator;
• PFS2 evaluated by investigator.
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) judged in accordance with NCI-CTCAE v5.0; vital signs, ECG and abnormal laboratory values.
• Changes from baseline in all PRO-CTC AE GI related items;
• Symptoms related to NSCLC, including cough, dyspnea, and pain, assessed using EORTC QLQ-C30 and the QLQ-LC13 to evaluate the health-related quality of life (HRQoL) and NSCLC-related symptoms. To compare the proportion of subjects with improved status, time to deterioration, and scores (mean value and mean changes from baseline) in pyrotinib versus docetaxel treatment arms.
• Plasma concentrations of pyrotinib. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS will be collected on Day 1 of each dosing cycle, at discontinuation of treatment/withdrawal, at safety follow-up: 28 days (±7) after the last dose and at Survival follow-up (comes after safety followup). Every 56 days (±7 days) after the last dose investigators must follow up subject’s survival via phone calls. The definition of the Follow-up period is: in addition to safety follow-up and survival follow-up, in the absence of disease progression evidenced by radiological evaluation, regardless whether subjects discontinue from study treatment or not, subjects still need to receive radiological evaluations according to the scheduled visits, until BIRC assessed progression of disease, death, lost to follow up, consent withdrawal, study termination by the sponsor (whichever occurs first). |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Under certain circumstances crossover from Docetaxel arm to Pyrotinib arm is allowed. |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Belgium |
| China |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Spain |
| Taiwan |
| United States |
|
| 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
|
| End of Study is defined as the time when it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (ie, Clinical Trial Application [CTA]), namely, after the primary completion date (PCD). |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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