| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| C-Met overexpressing EGFR wildtype, non-squamous non-small cell lung cancer |
|
| 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 |
The primary objective is to evaluate the efficacy of telisotuzumab vedotin compared with docetaxel on the basis of progression-free survival and/or overall survival in the following nested
populations:
- Subjects with c-Met high overexpressing, EGFR wildtype, non-squamous NSCLC
and
- All subjects with c-Met overexpressing, EGFR wildtype, non-squamous NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
1. Objective Response Rate (ORR) by ICR.
2. Duration of Response (DoR) by ICR.
3. Progression Free Survival per investigator assessment.
4. Time to deterioration in cough, pain or dyspnea as measured by the cough, pain and dyspnea items of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module 13 (EORTC QLQ-LC13).
5. Time to deterioration of physical functioning as measured by the physical functioning domain of the EORTC-QLQ-Core 30 (EORTC QLQ-C30).
6. Change from baseline in quality of life as measured by the global health status/quality of life domain of the EORTC QLQ-C30. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subject must have c-Met overexpressing NSCLC as assessed by an AbbVie designated IHC laboratory using the VENTANA MET (SP44) RxDx assay
• Archival or fresh tumor material must be submitted for assessment of c-Met levels by an AbbVie designated IHC laboratory during the Pre-Screening period. Tumor material from the primary tumor site and/or metastatic sites are allowed. If archival tissue is negative for c-Met overexpression, fresh biopsy material may be submitted for reassessment of c-Met expression.
- If a subject was prescreened for Study M14-239 but did not enroll, tumor material previously submitted for Study M14-239 may be used for Study M18-868 Pre-Screening upon confirmation from AbbVie that sufficient evaluable tumor material is available
• Subject has adequate bone marrow, renal, and hepatic function
• Subject must have histologically documented non-squamous cell NSCLC that is locally advanced or metastatic.
• Subjects must have a known EGFR activating mutation status.
-Subjects with actionable EGFR activating mutations are not eligible.
• Subjects with actionable alterations in genes other than EGFR are eligible.
• Subject must have measurable disease per RECIST version 1.1.
• Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
• Subject must have received no more than 1 line of prior systemic cytotoxic chemotherapy in the locally advanced or metastatic setting.
-Neoadjuvant and adjuvant systemic cytotoxic chemotherapy would count as a prior line for eligibility purposes if progression occurred within 6 months of the end of therapy.
• Subject must have progressed on at least 1 line of prior therapy for locally advanced/metastatic NSCLC:
- Subjects WITHOUT an actionable gene alteration: subjects must have progressed on (or be considered ineligible for) platinum-based chemotherapy and immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy).
- Subjects WITH an actionable gene alteration for which immune checkpoint inhibitor therapy is not standard of care (e.g., anaplastic lymphoma kinase [ALK] translocation): subjects must have progressed on (or be considered ineligible for) anti-cancer therapy targeting driver gene alterations and platinum-based chemotherapy.
- Subjects with actionable gene alterations for which immune checkpoint inhibitor is standard of care must have also progressed on (or be considered ineligible for) immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy).
• Subject must be considered appropriate for docetaxel therapy based on the assessment of the treating physician.
• No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., polymerase chain reaction [PCR]) test or 2 negative antigen test
results at least 24 hours apart. Subject must not have had any serious SARS-CoV-2 infection that required mechanical ventilation/endotracheal intubation or extracorporeal membrane oxygenation (ECMO) support in the past 6 months, or long-term complications from SARS-CoV-2 infection that are not resolved at the time of prescreening.
• Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen for the study after they meet the SARS-CoV-2 infection viral clearance criteria listed in the protocol. |
|
| E.4 | Principal exclusion criteria |
• Subject has adenosquamous histology.
• Subject has received prior c-Met-targeted antibodies, prior telisotuzumab vedotin, or prior antibody-drug conjugates either targeting c-Met or consisting of monomethylauristatin E.
• Subject has received prior docetaxel therapy.
• Subjects with metastases to the central nervous system (CNS) are eligible only after definitive therapy (such as surgery or radiotherapy) is provided and:
- There is no evidence of progression of CNS metastases at least 2 weeks after definitive therapy.
- They are asymptomatic and off or on a stable or reducing dose of systemic steroids and/or anticonvulsants for at least 2 weeks prior to first dose of telisotuzumab vedotin.
• Subjects with a history of other malignancies except:
- Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated carcinoma in situ without current evidence of disease.
• Subject with a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• History of prior radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Subject with unresolved AE ≥ Grade 2 from prior anticancer therapy, except for alopecia or anemia.
• Subject has had major surgery within 21 days prior to the first dose of telisotuzumab vedotin.
• Subjects with the following:
- Known human immunodeficiency virus (HIV) infection. Note: HIV testing is not required for eligibility for this protocol unless mandated by local regulatory authority or ethics committee/institutional review board.
- Active hepatitis B virus (HBV) infection, defined by HBV DNA ≥ 500 IU/mL or hepatitis B surface antigen (HBsAG) positivity associated with HBV DNA ≥ 500 IU/mL. In subjects with known HBV infection, the presence of active infection must be tested locally. If HBV status is unknown, it must be tested locally at screening if required by local regulatory authority or ethics committee/institutional review board.
- Active hepatitis C virus (HCV) infection, defined by HCV RNA positivity. Subjects cured of HCV infection may be included in the study. In subjects with known HCV infection, the presence of active infection must be tested locally. If HCV status is unknown, it must be tested locally at screening if required by local regulatory authority or ethics committee/institutional review board.
- Uncontrolled autoimmune disease.
• Subject has clinically significant condition(s) including but not limited to the following:
- Clinically significant vascular disease, including:
- Myocardial infarction within 1 year or stroke within 6 months prior to first dose of study drug, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV), cardiac arrhythmia (CTCAE Version 5 Grade 2 or higher), or clinically
significant electrocardiogram (ECG) abnormalities.
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) > 470 msec.
- Clinically significant liver disease, including hepatitis, current alcohol abuse, or cirrhosis.
- Grade ≥ 2 edema or lymphedema.
- Grade ≥ 2 ascites or pleural effusion.
- Grade ≥ 2 neuropathy.
- Active uncontrolled bacterial or viral infection.
- Active corneal disorder
• Subject has a history of major immunologic reaction to any immunoglobulin G (IgG)-containing agent. Subject has hypersensitivity to docetaxel or polysorbate 80.
• Subjects have received any live vaccine within 30 days of the first dose of study drug.
• Treatment with any of the following therapies within the noted time intervals prior to the first dose of telisotuzumab vedotin:
- Within 2 weeks (14 days): radiation not involving the lungs.
- Within 4 weeks (28 days) or 5 half-lives (whichever is shorter): systemic cytotoxic chemotherapy; small molecule targeted agents with half-life ≥ 7 days; monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies.
• Subjects must not have had radiation therapy to the lung within 6 months prior to the first dose of study drug and until study drug is permanently discontinued. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary endpoints are:
- Progression-Free Survival (PFS) per independent central review (ICR).
- Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS will be defined as the time from randomization to the first occurrence of radiographic progression based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 per ICR or death from any cause. Subjects with no PFS event will be censored at the last evaluable radiographic assessment per ICR. For subjects without baseline disease assessment or any post-baseline disease assessments who did not die, PFS will be censored at the date of randomization.
OS will be defined as the time from randomization to the event of death from any cause. Subjects with no documented death will be censored at the last known alive date. |
|
| E.5.2 | Secondary end point(s) |
• Objective Response Rate (ORR) by ICR
• Duration of Response (DoR) by ICR
• PFS per investigator assessment
• Time to deterioration in cough, pain or dyspnea as measured by the cough, pain and dyspnea items of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module 13 (EORTC QLQ-LC13).
• Time to deterioration of physical functioning as measured by the physical functioning domain of the EORTC-QLQ-Core 30 (EORTC QLQ-C30).
• Change from baseline in quality of life as measured by the global health status/quality of life domain of the EORTC QLQ-C30. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• ORR: defined as the proportion of subjects with a complete response (CR) or partial response (PR) based on RECIST, version 1.1 .
• DOR: defined for responders as the time from response (CR or PR) to the first occurrence of radiographic progression per RECIST v1.1, or death from any cause.
• PFS: defined as the time from randomization to the first occurrence of radiographic progression based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 per investigator or death from any cause. Subjects with no PFS event will be censored at the last evaluable radiographic assessment per investigator. Subjects with no event and no evaluable post-baseline assessment will be censored at randomization. |
|
| 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 | No |
| 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 | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| South Africa |
| Taiwan |
| United States |
| Switzerland |
| Russian Federation |
| Turkey |
| Ukraine |
| 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-study is defined as the date of end of study participation by the last subject in the last country where the study was conducted. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 34 |
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