E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-over-expressing or -mutated, unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
HER2-over-expressing or -mutated, unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) |
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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 | 10001246 |
E.1.2 | Term | Adenosquamous cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10001255 |
E.1.2 | Term | Adenosquamous cell lung cancer stage unspecified |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10001253 |
E.1.2 | Term | Adenosquamous cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10001252 |
E.1.2 | Term | Adenosquamous cell lung cancer stage IIIA |
E.1.2 | System Organ Class | 100000004864 |
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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 |
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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 |
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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 |
The primary objective is to evaluate the objective response rate (ORR) of trastuzumab deruxtecan in HER2-over-expressing and/or –HER2 mutated advanced NSCLC subjects. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
The secondary objectives are:
• To evaluate duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS)
• To further evaluate the safety of trastuzumab deruxtecan
• To determine the pharmacokinetics (PK) of trastuzumab deruxtecan
Exploratory Objective:
The exploratory objectives are:
• To evaluate time to response (TTR) and best percent change in the sum of the diameters for all target lesions
• To evaluate potential biomarkers
• To evaluate exposure-response relationships for efficacy and safety endpoints
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Must have provided informed consent for study participation (see Section 15.3) before performance of any study-specific procedure or test.
2. Age ≥20 y old in Japan, ≥18 y old in other countries.
3. Pathologically documented unresectable and/or metastatic nonsquamous NSCLC.
4. Has relapsed from or is refractory to standard treatment or for which no standard treatment is available.
5. For Cohort 1 and Cohort 1a only: HER2-overexpression (IHC 2+ or 3+) status must be assessed and confirmed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent, from an archival tumor tissue sample.
For Cohort 2 only: Documented any known activating HER2 mutation from an archival tumor tissue sample analyzed by CLIA laboratory or equivalent, specifically exon 20 insYVMA (Y772_A775dup), insGSP
(G778_P780dup), insTGT (G776delinsVC), single base pair substitutions L755S, V777L, or S310F or another HER2 mutation listed in the appendix (see Section 17.7). Note: HER2 mutation documented only from a liquid biopsy sample cannot be used for enrollment.
6. Presence of at least 1 measurable lesion assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
7. Is willing and able to provide an adequate archival tumor tissue sample. Fine needle aspirates are not acceptable
8. Is willing to undergo a tissue biopsy, after the completion of the most recent treatment regimen.
9. Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Previously treated with HER2-targeted therapies, except for pan-HER class tyrosine kinase inhibitors.
2. For Cohort 1 and Cohort 1a only: Has known HER2 mutation.
3. Uncontrolled or significant cardiovascular disease, including any of the following:
a. Medical history of myocardial infarction within 6 months prior to enrollment
b. Symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) 28 d prior to enrollment
c. Troponin levels consistent with myocardial infarction (as defined by the manufacturer) 28 d prior to enrollment
d. History of unstable angina, or serious cardiac arrhythmia requiring treatment
e. Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to enrollment
f. Has a corrected QT interval (QTcF) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG).
4. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Has clinically significant corneal disease in the opinion of the Investigator.
6. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated
symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with
corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 wk must have elapsed between the end of whole brain radiotherapy
and study enrollment.
7. Has multiple primary malignancies within 3 y, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
The primary efficacy endpoint (primary outcome measure) is ORR assessed by independent central review (ICR) based on RECIST version 1.1 for each cohort.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
- DoR based on investigator assessment and ICR
- DCR based on investigator assessment and ICR
- PFS based on investigator assessment and ICR
- OS
- ORR based on investigator assessment
Secondary outcome measures include: ORR, DoR, and PFS, and OS.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
every 6 weeks for efficacy, every 3 months for OS for until death or last contact with subject |
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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 | No |
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 | Yes |
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 | No |
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 | 10 |
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 |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |