| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Locally Advanced Epidermal Growth Factor Receptor-mutated (EGFRm) Non-small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small Cell Lung Cancer (NSCLC) |
|
| 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 |
| To compare the efficacy of patritumab deruxtecan versus platinum-based chemotherapy, as measured by progression-free survival (PFS), in subjects with metastatic or locally advanced nonsquamous non-small cell lung cancer (NSCLC) with an EGFR-activating mutation (exon 19 deletion or L858R) |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
- To compare the efficacy of patritumab deruxtecan versus platinum-based chemotherapy, as measured by OS, in subjects with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R)
Other Secondary Objectives:
- To further evaluate the efficacy of patritumab deruxtecan compared with platinum-based chemotherapy in subjects with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R)
- To evaluate symptoms, functioning and global health for patritumab deruxtecan compared with platinum-based chemotherapy in subjects with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) based on PROs
Please refer to the protocol for full list of secondary objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Sign and date the main ICF, prior to the start of any study-specific qualification procedures. Consent for the optional samples for EOT tumor biopsy and/or pharmacogenetic analysis will be covered in the main ICF. A separate tissue screening consent will be obtained from all subjects to meet the baseline biopsy requirement.
2. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
3. Has histologically or cytologically documented metastatic or locally advanced nonsquamous NSCLC not amenable to curative surgery or radiation.
4. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
5. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third-generation EGFR TKI (ie, approved therapies designed with higher preferential activity for mutant vs. EGFRwt and that address acquired resistance to first- and second-generation EGFR TKI [eg, osimertinib, lazertinib, aumolertinib, alflutinib, and others in consultation with Medical Monitor]). If a subject has received 2 prior lines of EGRF TKI therapy, administration of the third-generation EGRF TKI must have been in the most recent line and in the setting of NSCLC with a demonstrated T790M substitution. Enrollment of subjects receiving third-generation EGFR TKIs other than osimertinib will be a maximum of approximately 20% of the enrolled population in each treatment arm.
6. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting.
a. To provide an example, a patient who received osimertinib as adjuvant therapy after tumor resection, then progressed to having metastatic disease over a year following completion of adjuvant therapy must have also received a third-generation EGFR TKI as treatment for metastatic disease to be considered eligible for this study.
7. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI).
8. Has documentation of radiographic disease progression while receiving or after a third-generation EGFR TKI for metastatic or locally advanced disease.
9. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
10. Is willing to provide sufficient quantity and quality of tumor tissue content. Required tumor tissue can be provided as either:
a. If medically feasible, a fresh pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy; OR
b. If the tumor is inaccessible or the subject is medically unfit for collection of the pretreatment tumor biopsy, archival tumor tissue not previously irradiated and collected from a biopsy performed on or after treatment with the most recent EGFRTKI systemic treatment regimen.
11. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
12. Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to randomization as described in the protocol.
13. If the subject is a female of childbearing potential, must have a negative serum pregnancy test at Screening and must be willing to use highly effective birth control upon randomization, during the Treatment Period, and for 7 months following the last dose of study drug. A female is considered to be of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) or if permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) with surgery at least 1 month before randomization or confirmed by follicle stimulating hormone (FSH) test.
14. Female subjects must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study Treatment Period and for at least 7 months after the final study drug administration.
15. If male, must be surgically sterile or willing to use highly effective birth control upon randomization, during the Treatment Period, and for at least 4 months following the last dose of study drug.
16. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period and at least 4 months after the final study drug administration.
17. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. |
|
| E.4 | Principal exclusion criteria |
1. Has any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy, or squamous NSCLC histology.
2. Has any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during Screening.
3. Has clinically severe respiratory compromise (based on the Investigator’s assessment) resulting from intercurrent pulmonary illnesses as described in the protocol.
4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to randomization. Subjects who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
5. Has evidence of any leptomeningeal disease.
6. Has evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic and untreated, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive or treated brain metastases who are asymptomatic (i.e., without neurologic signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included in the study but must have a stable neurologic status for at least 2 weeks prior to randomization.
7. Has had inadequate washout period prior to randomization as described in the protocol.
8. Has had prior treatment with the following:
a. Any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase I.
b. HER3 antibody.
c. Any systemic therapies (other than EGFR TKIs) in the metastatic or locally advanced setting, including chemotherapy or any other systemic therapy in combination with an EGFR TKI.
9. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved by the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0), Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities [defined as no worsening to Grade >2 for at least 3 months prior to randomization and managed with standard of care treatment]) that the Investigator deems related to previous anticancer therapy may be randomized.
10. Has history of other active malignancy within 3 years prior to randomization, except the following:
a. Adequately resected nonmelanoma skin cancer.
b. Adequately treated intraepithelial carcinoma of the cervix.
c. Any other curatively treated in situ disease.
11. Has uncontrolled or significant cardiovascular disease prior to randomization as described in the protocol.
12. Has active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of active viral infection within 28 days of randomization.
13. Has a known HIV infection that is not well controlled. All the following criteria are required to define an HIV infection that is well controlled: undetectable viral ribonucleic acid (RNA) load, CD4+ counts/levels of >350 cells/μL, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 3 weeks on same anti-HIV retroviral medications. If an HIV infection meets the above criteria, the subject’s viral RNA load and CD4+ cell count should be monitored per local standard of care (e.g., every 3 months).
14. Has any evidence of severe or uncontrolled diseases (eg, active bleeding diatheses, active infection) psychiatric illness/social situations, geographical factors, substance abuse, or other factors that, in the Investigator’s opinion, make it undesirable for the subject to participate in the study or that would jeopardize compliance with the protocol. Screening for chronic conditions is not required for eligibility.
15. Has known hypersensitivity to either the drug substance or inactive ingredients in any of the drug products.
16. Is a female who is pregnant or breastfeeding or intends to become pregnant during the study.
17. Has prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
18. Has clinically significant corneal disease.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) as assessed by blinded independent central review (BICR) based on RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the time from the date of randomization to the earlier of the dates of the
first documentation of objective progression of disease or death due to any cause. |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Progression-free survival (PFS) as assessed by the Investigator per RECIST v1.1
- Progression-free survival on the next line of therapy (PFS2) as assessed by local standard clinical practice
- Objective response rate (ORR) as assessed by BICR and as assessed by the Investigator per RECIST v1.1
- Duration of response (DoR) as assessed by BICR and as assessed by the Investigator per RECIST v1.1
- Clinical benefit rate (CBR) as assessed by BICR and as assessed by the Investigator per RECIST v1.1
- Disease control rate (DCR) as assessed by BICR and as assessed by the Investigator per RECIST v1.1
- Time to response (TTR) as assessed by BICR and as assessed by the Investigator per RECIST v1.1
- Patient-reported outcome (PRO) of disease-related symptoms, functioning scales, and general health status and
overall quality of life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS is defined as the time from the date of randomization to the date of death due to any cause.
- PFS is defined as the time from the date of randomization to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause.
- ORR must be confirmed at least 4 weeks later (e.g., generally at the next tumor assessment time point).
- DoR, CBR, DCR and TTR must be confirmed from the time of randomization until the date of documented disease progression, death, loss to follow-up, or withdrawal by the subject.
- PRO: Data are collected from before randomization until the date of EOS, death, loss to follow-up, or withdrawal by the subject.
|
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity, biomarker assessments and QOL |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
| Canada |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Sweden |
| Bulgaria |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Portugal |
| Serbia |
| 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 overall EOS will occur when
- all subjects have discontinued treatment and discontinued long-term survival follow-up or have died
- an alternative study becomes available for subjects continuing to derive benefit from treatment with patritumab deruxtecan where the drug is offered to these subjects
- or the study is discontinued by the Sponsor for other reasons (administrative, program-level or class-related). |
|
| 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 years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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