| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer, Locally Advanced or Metastatic, with EGFR or HER2 Exon 20 Insertion Mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer, Locally Advanced or Metastatic |
|
| 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 | LLT |
| E.1.2 | Classification code | 10066490 |
| E.1.2 | Term | Progression of 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 |
| Objective Response Rate (ORR) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• Disease Control Rate (DCR)
• Duration of Response (DoR)
• Safety and tolerability
Exploratory Objectives
• Progression-free Survival (PFS)
• Quality of Life (QoL) (Cohorts 1 to 4 only)
• Evaluate alternate poziotinib starting doses and schedules
• Evaluate poziotinib in patients who progressed while on treatment with first-line osimertinib (Cohort 6 only)
• Evaluate poziotinib in patients with EGFR or HER2 activating mutations
• Evaluate overall survival
• Characterize the PK profile of poziotinib
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is at least 18 years of age
2. Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements
3. Patient has histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to treatment with curative intent
4. Prior treatment status:
• Cohorts 1 and 2: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
• Cohorts 3 and 4: Patient is treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with poziotinib as determined by the Investigator. Adjuvant/neo-adjuvant therapies (chemotherapy, radiotherapy, or investigational agents) are permissible as long as they end at least 15 days prior to study entry.
• Cohort 5: Patients who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed
• Cohort 6: Patients with EGFR mutation-positive NSCLC who progressed while on treatment with first-line osimertinib.
• Cohort 7: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
5. Tissue and plasma samples for mutation confirmation:
• Cohorts 1 to 5: Patient has adequate tumor tissue obtained from a biopsy or surgical procedure to enable molecular profiling for retrospective central laboratory confirmation of the mutation. If tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy to provide an appropriate tissue sample prior to receiving treatment in the study.
• Cohort 6: Either tissue or plasma samples after osimertinib progression.
• Cohort 7: Either tissue or plasma samples.
6. Patient is positive for EGFR or HER2 mutations based on:
• Cohorts 1 and 3: Documented EGFR exon 20 insertion mutation (including duplication mutations) using a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, or by an FDA approved test (eg, cobas® EGFR mutation test v2 or therascreen EGFR RGQ PCR kit) performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples
• Cohorts 2 and 4: Documented HER2 exon 20 insertion mutation (including duplication mutations) using a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples
• Cohort 5: Documented EGFR or HER2 exon 20 insertion mutations using tissue samples using the criteria described for Cohorts 1 to 4.
• Cohort 6: Documented acquired EGFR mutation (tested after osimertinib progression) who have progressed while on first-line osimertinib treatment using tissue or plasma tested with a next-generation sequencing assay.
• Cohort 7: Documented EGFR or HER2 activating mutations using tissue or plasma tested with a next-generation sequencing assay.
7. Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).
8. Brain metastases may be allowed if patient’s condition is stable, defined as clinically asymptomatic, no requirement for high dose or increasing dose of systemic corticosteroids, and no need for any anticonvulsant therapy for metastatic brain disease. For the patient who has had radiation therapy, sequential post-treatment MRI tests, at least 4-6 weeks apart, should show no increases in brain lesion size/volume within 4 weeks prior to the study.
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and has a life-expectancy of more than 6 months
10. Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for non-hematologic toxicities (except for Grade ≤2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline, as defined by:
• Leukocytes ≥3.0×10 9/L
• Absolute neutrophil count (ANC) must be ≥1.5×10 9/L
• Platelet count ≥100×10 9/L
• Hemoglobin ≥9.0 g/dL
• Total bilirubin ≤2 mg/dL; if hepatic metastases are present, ≤2.5×ULN
• SGOT (AST) and SGPT (ALT) ≤2.5×ULN with the following exception; Patients with liver metastases AST, ALT ≤5×ULN
• Creatinine clearance ≥50 mL/min
11. Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from study entry until at least 30 days after the last dose of poziotinib
12. Females of childbearing potential must have a negative pregnancy test within 7 days prior to Day 1. Females who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or who are surgically sterilized do not require this test. |
|
| E.4 | Principal exclusion criteria |
1. Patient has:
• All Cohorts: EGFR T790M
• Cohorts 1 to 5: EGFR exon 20 point mutation
• Cohort 7: EGFR Exon 19 deletion and L858R or HER2 T798I mutations, EGFR and HER2 Exon 20 insertion mutation
2. Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible (Cohorts 1 and 2).
3. Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks or 5 half-lives, whichever is longer; local radiation therapy for bone pain may be allowed.
4. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment
5. Patient has a high risk of cardiac disease, as determined by the Investigator, may undergo either echocardiogram (ECHO) or multi-gated acquisition (MUGA) during Screening and has a cardiac ejection fraction <50%.
6. Patient has had other malignancies within the past 3 years, except for stable non-melanoma skin cancer, fully treated and stable early stage prostate cancer or carcinoma in situ of the cervix or breast without need of treatment
7. Patient is confirmed to have clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or coloenteritis as a main symptom (ie, acute enteritis, malabsorption, or Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) Grade 2 or above diarrhea due to other etiologies)
8. Patient has an active Grade ≥2 skin disorder, rash, mucositis, or skin infection that needs medication or therapy or existing Grade ≥2 skin toxicity from previous therapies; Grade >2 neuropathy, Grade ≥2 pneumonitis.
9. Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (eg, Crohn’s disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy
10. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases)
11. Patient has known hypersensitivity to poziotinib or has a history of allergic reactions attributed to chemically similar compounds or other tyrosine kinase inhibitors (TKIs)
12. Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that would not be appropriate for this study
13. Patient has unstable, uncontrolled, active bleeding disorders that the investigator considers that the patient could be at increased risk or not be suitable for treatment in this study
14. Patient is pregnant or breast-feeding.
15. Cohort 5 only: Patient is eligible for treatment in an open cohort (Cohorts 1 to 4) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR, complete response+partial response) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR is defined as the best response recorded from the start of the study until the end of study in patients who received at least 1 dose of poziotinib. The ORR will be based on the primary analysis population. The ORR will be determined by an independent radiologic review committee. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Disease Control Rate (DCR, complete response+partial response+stable disease)
• Duration of Response (DoR)
• Safety and Tolerability
Exploratory Endpoint:
• Progression-free Survival (PFS)
• Quality of Life (QoL) (Cohorts 1 to 4 only)
• Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DCR: from the first dose of poziotinib to the end of study.
DoR: from the date that measurement criteria are first met for CR-complete response or PR-partial response (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.
PFS: the number of days from the treatment start date to the date of documented disease progression or death due to any cause.
QoL: evaluated in Cohorts 1 to 4 only using the EORTC QLQ-C30 and QLQ-LC13 questionnaire at C1D1, at every imaging session, and at the Safety Follow-up Visit. The global health status/QoL, functional scales, symptom scales, and lung cancer related symptoms will be summarized for each evaluation time point.
OS: every three months after patient's EoT, up to 2 years from C1D1. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| Israel |
| United States |
| France |
| Netherlands |
| Spain |
| Italy |
| Belgium |
|
| 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 | 7 |
| 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 | 7 |
| 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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