E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 IHC-Positive (IHC 2 + or IHC 3 +), Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Human epidermal growth factor receptor 2 positive (HER2+) lung cancer is a cancer that tests positive for a tumor cell surface protein called HER2 targeted by the study treatment drug. |
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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 | 20.0 |
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) |
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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 |
To evaluate the efficacy of single-agent trastuzumab emtansine in patients with centrally confirmed HER2-immunohistochemistry (IHC) positive (IHC 2 + or IHC 3 +) locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior chemotherapy regimen, as measured by confirmed ORR based on investigator assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (see Appendix 3). |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives for this study are as follows:
• To evaluate progression-free survival (PFS), duration of response (DoR), and clinical benefit rate (CBR) according to RECIST v1.1 (see Appendix 3), based on investigator assessment
• To evaluate overall survival (OS).
The safety objective for this study is to evaluate the safety and tolerability of trastuzumab emtansine administered every 3 weeks (Q3W) as a single agent to patients with HER2 IHC positive (IHC 2 + or IHC 3 +) NSCLC.
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of trastuzumab emtansine and assess the anti-therapeutic antibody (ATA) responses to trastuzumab emtansine in patients with HER2 IHC-positive locally advanced or metastatic NSCLC. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Histologically or cytologically documented diagnosis of Stage IIIB not amenable to radical treatment or Stage IV NSCLC; pathological characterization must determine the non-squamous or squamous histological subtype as well as adenocarcinoma subtype classification.
- HER2 status of IHC 2+ or 3+ as determined by a Sponsor-designated central laboratory
- Prior treatment with at least one regimen of platinum-based (cisplatin or carboplatin) chemotherapy in the locally advanced or metastatic setting/recurrent NSCLC with documented disease progression by investigator assessment
- Patients with a known ALK fusion oncogene (must be documented in the patient's chart) must have also experienced disease progression or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the treatment of ALK fusion oncogene NSCLC (e.g., crizotinib). Disease progression or intolerance must be documented
- Patients with a known mutation in the EGFR gene (must be documented in the patient's chart) must have also experienced disease progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant NSCLC (e.g., gefitinib, erlotinib, afatinib). Disease progression or intolerance must be documented.
- Measurable disease determined as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1
- Life expectancy >= 12 weeks
- Adequate organ function
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- LVEF >= 50% by either echocardiogram (ECHO) or or multiple-gated acquisition (MUGA)
- Use of highly effective contraception |
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E.4 | Principal exclusion criteria |
Cancer-Related Criteria
- Any approved anti-cancer therapy <= 21 days (including chemotherapy or hormonal therapy) before the first study treatment; the following exceptions are allowed: (1) TKIs approved for the treatment of NSCLC must be discontinued > 7 days prior to the first study treatment on Cycle 1, Day 1 (The baseline computed tomography scan must be completed after discontinuation of TKIs); (2) Hormone-replacement therapy or oral contraceptives; (3) Anti-emetics, GCS-F, prophylactic antibiotics are allowed according to local standards
- Investigational therapy participation in another clinical study with therapeutic intent <= 21 days before first study treatment
- Previous irradiation is permitted if >= 14 days since the last fraction of radiotherapy have elapsed before the first study treatment on Day 1 of Cycle 1 as long as a sufficient number of target lesions remain to allow for measurable disease as per RECIST v1.1.
- Patients who have untreated brain metastases or are symptomatic; patients with treated brain metastases must have discontinued corticosteroid therapy and not have any neurological symptoms
- History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any excipient of the product
- History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 500 milligrams per meter square (mg/m2); Epirubicin > 900 mg/m2; Mitoxantrone > 120 mg/m2. If another anthracycline, or more than one anthracycline, has been used, the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.
- Current peripheral neuropathy of Grade >= 3 per the National Cancer Institute Common Toxicity Criteria for Adverse Events v. 4.0
- History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those mentioned above.
Cardiopulmonary Function Criteria
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy
- Clinical history of active hemoptysis
- Evidence of pneumonitis during screening
- Current unstable ventricular arrhythmia requiring treatment
- History of symptomatic congestive heart failure (CHF; New York Heart Association [NYHA] Classes II-IV)
- History of myocardial infarction or unstable angina within 6 months of enrollment
- History of a decrease in LVEF to <50%
General Criteria
- Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)
- Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment
- Current pregnancy or lactation
- Current known active infection with HIV, hepatitis B, or hepatitis C virus |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate, defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments >= 4 weeks apart and based on investigator assessment according to RECIST v. 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After three post-baseline tumor assessments (approximately 4.5 months) after last patient is enrolled |
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E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS), defined as the time from first study treatment to first documented disease progression, by investigator assessment using RECIST v1.1
2. Duration of response (DOR), defined as the time from the initial documentation of objective response (CR or PR) to documented disease progression, using RECIST v1.1, or death from any cause
3. Serum concentrations of trastuzumab emtansine and total trastuzumab
4. Plasma concentration of N2-deacetyl-N2-(3-mercapto-1-oxopropyl)-maytansine (DM1)
5. Incidence of adverse events (AEs)
6. Overall survival (OS)
7. CBR, defined as the proportion of patients with a CR or PR or stable disease (using RECIST v1.1) at 6 months
8. ATA response to trastuzumab emtansine
9. Serum concentration of HER2 extracellular domain (ECD)
10. PK parameters (such as area under the concentration-time curve, maximum concentration, clearance, volume of distribution at steady-state, and half-life) from the patients with intense PK sampling (optional). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From first study treatment to disease progression or death from any cause or study termination, up to approximately 18 months
2. From first documented objective response to disease progression or death from any cause or study termination, up to approximately 18 months
3. and 8. Cycle 1 Day 1 and Cycle 3 Day 1; study treatment discontinuation or early termination visit, up to approximately 18 months
4. Cycle 1 Day 1 and Cycle 3 Day 1
5. and 6. From first study treatment to death from any cause or study termination, up to approximately 18 months
7. 6 months
9. cycle 1 Day 1
10. Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 4 or 5, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 4 Day 1.
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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 | Yes |
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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
European Union |
Korea, Republic of |
Switzerland |
United States |
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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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The end of study is defined when all enrolled patients discontinue the study treatment as described in protocol section 4.6.2. Survival data will be collect every 3 months after treatment discontinuation until death, withdrawal of consent, loss to follow-up, or study termination by the Sponsor. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |