| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| A specific type of lung cancer called "Non-Small Cell Lung Cancer" |
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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 | 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 assess the efficacy of lazertinib, amivantamab, carboplatin, and pemetrexed (LACP/ACP-L), compared with carboplatin and pemetrexed (CP), in participants with locally advanced or metastatic epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R substitution NSCLC.
- To assess the efficacy of ACP, as compared with CP, in participants with locally advanced or metastatic EGFR Exon 19del or Exon 21 L858R substitution NSCLC |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
1. To further assess the clinical benefit of
- LACP/ACP-L vs CP
- ACP vs CP
2. To assess the safety of
- LACP/ACP-L vs CP
- ACP vs CP
3. To assess the relationship between pharmacokinetics or immunogenicity and selected endpoints (including but not limited to efficacy, safety, and/or patient-reported outcomes)
4. To assess health-related quality of life and disease-related symptoms in participants treated with
- LACP/ACP-L vs CP
- ACP vs CP
5.To describe the contribution of lazertinib to the efficacy of LACP/ACP-L (vs ACP)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
2. Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation, by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). A de-identified copy of the initial test report documenting the EGFR mutation must be included in the participant records and must be submitted to the sponsor during the Screening Phase. If provision of this report is not permitted by the site or local policies, then sponsor-approved equivalent documentation must be provided.
3. Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first line treatment for locally advanced or metastatic disease or in the second line setting after prior treatment with first- or second-generation EGFR TKI as a monotherapy. Participants who received either neoadjuvant and/or adjuvant treatment of any type are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting.
Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to randomization (ie, last dose no later than Day -8).
4. Participant must have at least 1 measurable lesion, according to RECIST v1.1, that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 non-irradiated measurable lesion exists, it may undergo the optional diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy.
5. Participants with a history of brain metastases must have had all lesions treated as clinically indicated (ie, no current indication for further definitive local therapy). Any definitive local therapy to brain metastases must have been completed at least 14 days prior to randomization and the participant can be receiving no greater than 10 mg rednisone or equivalent daily for the treatment of intracranial disease.
6. Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
7. Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, erythropoietin stimulating agents, or platelet-boosting treatments within 7 days prior to the date of the laboratory test:
• Hemoglobin ≥10 g/dL
• Absolute neutrophil count ≥1.5×10^9/L, without use of G-CSF within 10 days prior to the date of the test
• Platelets ≥100×10^9/L
• ALT and AST ≤3×upper limit of normal (ULN)
• Total bilirubin ≤1.5×ULN if no liver metastasis, or ≤3×ULN in the presence of liver metastasis (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits)
• Creatinine clearance >50 mL/min as measured or calculated by Cockcroft-Gault formula
8. Any toxicities from prior systemic anticancer therapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade ≤2 peripheral neuropathy, or Grade ≤2 hypothyroidism stable on hormone replacement).
9. Participant must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
10. A woman of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
11. A woman must be either of the following:
a. Not of childbearing potential; or
b. Of childbearing potential and
• practicing true abstinence during the entire period of the study, including up to 7 months after the last dose of study treatment is given;
or
• have a sole partner who is vasectomized; or
• practicing at least 1 highly effective user independent method of contraception.
Participant must agree to continue contraception throughout the study and through 6 months after the last dose of study treatment.
12. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment.
Please refer to pages 33- 35 of the protocol for full inclusion criteria.
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| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. Participant has an uncontrolled illness, including but not limited to:
• Uncontrolled diabetes
• Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics at least 1 week prior to starting study treatment] or diagnosed or suspected viral infection), except as allowed by Exclusion Criterion 17 for HIV
• Active bleeding diathesis
• Impaired oxygenation requiring continuous oxygen supplementation
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment
• Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements
• Any ophthalmologic condition that is clinically unstable
2. Participant received prior systemic anticancer therapy in the locally advanced or metastatic setting, or in the adjuvant setting, for the same nonsquamous NSCLC intended for treatment now, except as allowed by Inclusion Criterion 3.
3. Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization.
4. Participants with symptomatic or progressive brain metastases.
5. Participant previously enrolled in the Sponsor’s study 73841937NSC3003 (NCT04487080).
6. Participant has history of or current evidence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.
7. Participant has known small cell transformation.
8. Participant has uncontrolled tumor-related pain. Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated at least 14 days prior to randomization.
9. Participant has a medical history of ILD, including drug induced ILD or radiation pneumonitis.
10. Participant has a history of hypersensitivity to carboplatin or pemetrexed, or to any excipient of carboplatin, pemetrexed, amivantamab, or lazertinib.
11. Participant has an active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Exceptions include participants who have undergone curative therapy and have no evidence of disease recurrence since completion of that therapy, and those with local cancers that have been apparently cured such as:
a. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured.
b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
c. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
d. Localized prostate cancer (N0M0):
• with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance,
• with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence,
• or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
e. Breast cancer:
• lobular carcinoma in situ or ductal carcinoma in situ that is considered completely cured, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
f. Other malignancy that is considered cured with minimal risk of recurrence.
12. Participant has any contraindication to treatment with pemetrexed or carboplatin or participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid.
13. Participant has a history of clinically significant cardiovascular disease including, but not limited to the following:
• Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization, or any of the following within 24 weeks prior to randomization: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or acute coronary syndrome.
Please refer to pages 35- 39 of the protocol for full exclusion criteria.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free survival (PFS) using RECIST v1.1 guidelines, as assessed by blinded independent central review (BICR)
2. Progression-free survival (PFS) using RECIST v1.1 guidelines, as assessed by blinded independent central review (BICR) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1, 2 : the time from randomization until the date of objective disease progression or death, whichever comes first, based on BICR using RECIST v1.1. |
|
| E.5.2 | Secondary end point(s) |
1. Clinical benefits:
• Objective response (by BICR)
• Overall survival
• Duration of response (by BICR)
• Time to subsequent therapy
• PFS after first subsequent therapy (PFS2)
• Time to symptomatic progression
• Intracranial PFS (by BICR)
2. Safety: Incidence and severity of adverse events and clinical laboratory abnormalities
3. Pharmacokinetics or immunogenicity: Serum amivantamab and plasma lazertinib concentrations, and serum anti-amivantamab antibodies
4. HRQOL and disease related symptoms:
• NSCLC-SAQ
• EORTC-QLQ-C30
• PROMIS-PF
5. Efficacy:
• Intracranial PFS (by BICR)
• Objective response (by BICR)
• Duration of response (by BICR)
• PFS (by BICR)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From randomization until the date of documented progression or death due to any cause, whichever comes first.
2. Throughout the study or as clinically indicated.
3. Arm A- Cycle 1 Day 1 (C1D1): predose, 2 hours (h), 4h; C2D1: predose, 2h, 4h; C3D1, C5D1, C7D1, C9D1, C11D1, C13D1: predose, 30 days after last dose
PK: Arms A and C- C1D1 & C1D2, C2D1 : predose and end of infusion; C3D1, C5D1, C7D1, C10D1, C13D1, C17D1: predose, end of infusion and 30 days after last dose
Immunogenicity: Arms A and C- C1D1, C2D1, C3D1, C5D1, C7D1, C9D1, C11D1, C13D1: predose and 30 days after last dose
4. C1D1, C2D1, C3D1, C4D1, C5+, EOT and follow up
5. From randomization until the date of documented progression or death due to any cause, whichever comes first.
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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 | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Biomarker evaluation, Immunogenicity assessments, Quality of life |
|
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Brazil |
| Canada |
| China |
| Hong Kong |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Puerto Rico |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
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| 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 considered as the last scheduled study assessment shown in the Schedule of Activities for the last participant in the study. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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