| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EGFR-mutated locally advanced or metastatic Non Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific type of lung cancer called "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 | 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) |
|
| 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 assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with EGFR mutation (Exon 19del or Exon 21 L858R substitution) positive, locally advanced or metastatic NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess:
1. The clinical benefit achieved using the amivantamab and lazertinib combination compared with osimertinib in participants with EGFR mutation positive, locally advanced or metastatic NSCLC
2. The safety and tolerability of the amivantamab and lazertinib combination compared with osimertinib
3. The pharmacokinetics or immunogenicity for amivantamab and pharmacokinetics for lazertinib and assess their relationship to selected endpoints
4.The health-related quality of life and disease related symptoms in participants treated with the amivantamab and lazertinib combination compared with osimertinib
5. The efficacy of the amivantamab and lazertinib combination, compared with lazertinib monotherapy, in participants with EGFR mutation positive, locally advanced or metastatic NSCLC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
2. Participant must have newly diagnosed, histologically or cytologically confirmed, locally advanced or metastatic NSCLC that is treatment naïve and not amenable to curative therapy including surgical resection or chemoradiation.
3. The tumor (meeting criteria described in Inclusion Criterion no. 2) harbors Exon 19del or Exon 21 L858R substitution, as detected by an FDA-approved or other validated test in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US) in accordance with site standard of care. (Note: A copy of the test report documenting the EGFR mutation must be included in the participant records and must also be submitted to the sponsor.)
4.Mandatory submission of unstained tissue from tumor meeting criteria described in Inclusion Criterion no. 2 (in a quantity sufficient to allow for central analysis of EGFR mutation status) and blood (for ctDNA, digital droplet polymerase chain reaction
[ddPCR], and pharmacogenomic analysis).
5. Any toxicities from prior anticancer therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline level.
6. 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 a diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy.
7. Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, or granulocyte colony-stimulating factor (G-CSF) within 7 days prior to the date of the test.
8. Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
9. Participant must sign an ICF (or their legally acceptable representative must sign) indicating that he or she 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 (as defined in Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information) either of the following:
a. Not of childbearing potential
b. Of child-bearing potential and practicing true abstinence during the entire period of the study, including up to 6 months after the last dose of study treatment is given
c. Of childbearing potential and practicing 2 methods of contraception, including 1 highly effective user independent method and a second method (examples of highly effective methods of contraception are located in Appendix 4: Contraceptive
Guidance and Collection of Pregnancy Information).
Participant must agree to continue contraception throughout the study and through 6 months after the last dose of study treatment.
Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin birth control, as described above.
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.
13. A man must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment. A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (ie, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine hormone-releasing system [IUS]).
If the participant is vasectomized, he must still use a condom (with or without spermicide) for prevention of passage of exposure through ejaculation, but his female partner is not required to use contraception.
14. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment.
15. Participant must be willing and able to adhere to the lifestyle restrictions specified in this protocol.
Full details of inclusion criteria can be found in section 5.1 of the study protocol. |
|
| E.4 | Principal exclusion criteria |
1. Participant has received any prior systemic treatment at any time for locally advanced Stage III or metastatic Stage IV disease (adjuvant or neoadjuvant therapy for Stage I or II disease is allowed, if administered more than 12 months prior to the development of locally advanced or metastatic disease).
2. Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before randomization are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (≤10 mg/day prednisone or equivalent) for at least 2 weeks prior to randomization.
3. Participant has an active or past medical history of leptomeningeal disease.
4. Participant with untreated spinal cord compression. A participant that has been definitively treated with surgery or radiation and has a stable neurological status for at least 2 weeks prior to randomization is eligible provided they are off corticosteroid
treatment or receiving low-dose corticosteroid treatment ≤10 mg/day prednisone or equivalent.
5. Participant has uncontrolled tumor-related pain.
6. Participant has an active or past medical history of ILD/pneumonitis, including drug-induced or radiation ILD/pneumonitis.
7. Participant has an uncontrolled illness
8. Participant has an active malignancy other than the disease being treated under study
9. Participant has active cardiovascular disease
10. Participant has known allergy, hypersensitivity, or intolerance to the excipients used in formulation of amivantamab, lazertinib, or osimertinib, or any contraindication to the use of osimertinib.
11.Participant is currently receiving medications or herbal supplements known to be potent CYP3A4/5 inducers and is unable to stop use for an appropriate washout period prior to randomization
12. Participant has received any prior treatment with an EGFR TKI.
13. Participant has received an investigational medication within 12 months before randomization or is currently enrolled in an investigational study.
14. Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
15. Participant plans to father a child while enrolled in this study or within 6 months after the last dose of study treatment.
16. Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
17. Participant has at Screening:
• Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg)
• Positive hepatitis C (hepatitis C virus [HCV]) antibody (anti-HCV)
• Other clinically active infectious liver disease
18. Participant is positive for human immunodeficiency virus (HIV)
19. Participant had major surgery excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before randomization, or will not have fully recovered from surgery, or has surgery planned during the time the
participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.
Full details of exclusion criteria can be found in section 5.2 of the study protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) according to RECIST v1.1 by blinded independent central review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A futility analysis based on PFS will be conducted when approximately 150 PFS events have occurred overall (all treatment arms combined). |
|
| E.5.2 | Secondary end point(s) |
Arm A vs Arm B:
1. Overall survival
2. Objective response rate
3. Duration of response
4. PFS after first subsequent therapy (Arm A vs Arm B)
5. Time to symptomatic progression
6. Intracranial PFS
7. Incidence of severity of adverse events and clinical laboratory abnormalities, assessment of vital signs, and physical examination abnormalities
8. Serum amivantamab and lazertinib concentrations, and anti-amivantamab antibodies
9. NSCLC-SAQ
10. EORTC-QLQ-C30
Arm A vs Arm C:
11. PFS
12. Overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From randomization until the date of objective disease progression or death,whichever comes first |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity, Quality of Life and Biomarker evaluation |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 |
| Malaysia |
| Philippines |
| Singapore |
| Ukraine |
| Hong Kong |
| Taiwan |
| Australia |
| Belarus |
| Brazil |
| Canada |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Thailand |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Türkiye |
|
| 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
|
| last visit of the last Patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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