E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
EGFR Exon 20ins-mutated 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 |
The primary objective is to compare the efficacy, as demonstrated by PFS, in participants treated with amivantamab in combination with chemotherapy, versus chemotherapy alone |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are: 1. To further assess the clinical benefit achieved with amivantamab in combination with chemotherapy, versus chemotherapy alone 2. To assess the safety in participants treated with amivantamab in combination with chemotherapy, versus chemotherapy alone 3. To assess the relationship between pharmacokinetics or immunogenicity and selected endpoints (including but not limited to efficacy, safety and/or PRO) 4. To assess health-related quality of life and disease related symptoms in participants treated with amivantamab in combination with chemotherapy, versus chemotherapy alone |
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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 histologically or cytologically confirmed, locally advanced or metastatic, nonsquamous NSCLC with documented primary EGFR Exon 20ins activating mutation (a copy of the mutation analysis must be submitted during screening) performed by a Clinical Laboratory Improvement Amendments (CLIA) certified (US sites) or an accredited (outside of the US) local laboratory. 3. Participant must have measurable disease according to RECIST v1.1. If only one measurable lesion exists, it may be used for the screening biopsy (if required for submission of tumor tissue) if the baseline tumor assessment scans are performed ≥14 days after the biopsy. 4. Participant must have ECOG performance status 0 or 1. 5. Participant must agree to genetic characterization of tumor status through the required pretreatment tumor biopsy (or submission of equivalent archival material), as well as baseline and periodic blood samples for analysis of tumor mutations in the bloodstream. 6. Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion or platelet transfusion within 7 days prior to the date of the laboratory test. • Hemoglobin ≥10 g/dL • Absolute neutrophil count ≥1.5x109/L, without use of granulocyte colony stimulating factor (G-CSF) within 10 days prior to the date of the test • Platelets ≥100x109/L • ALT and aspartate aminotransferase (AST) ≤3×upper limit of normal (ULN) • Total bilirubin ≤1.5xULN (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits) • Creatinine clearance >50 mL/min as measured or calculated by Cockroft Gault formula 7. Participant must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. 8. A female participant of childbearing potential must have a negative serum or urine 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. 9. A female participant must be (as defined in Appendix 4: Contraceptive and Barrier Guidance) either of the following: a. Not of childbearing potential b. Of childbearing potential and practicing 2 methods of contraception, including 1 highly effective, user independent method. Examples of highly effective methods of contraception are located in Appendix 4: Contraceptive and Barrier Guidance. 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 2 methods of birth control, as described above. 10. A female participant 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. 11. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 6 months after receiving the last dose of study treatment. 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. A male participant 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]). 12. 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. 13. Participant must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
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E.4 | Principal exclusion criteria |
1. Participant has received any prior systemic treatment for locally advanced or metastatic disease, with exceptions noted in section 5.2 of the protocol. 2. Participant has evidence of synchronous NSCLC disease (as suggested by genetic characterization or radiographic appearance). 3. Participant has untreated brain metastases (a participant with definitively, locally treated metastases who is clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomization is eligible). If brain metastases are diagnosed on Screening imaging, the participant may be rescreened for eligibility after definitive treatment. 4. Participant has a history of leptomeningeal disease. 5. Participant has history of spinal cord compression that has not been treated definitively with surgery or radiation. 6. Participant has uncontrolled tumor-related pain (symptomatic lesions amenable to palliative radiotherapy [eg, bone metastases or metastases causing nerve impingement] should be treated prior to Screening). 7. Participant has a medical history of ILD, including drug-induced ILD, or radiation pneumonitis. 8. Participant has an active malignancy (ie, ongoing, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study.Exceptions noted in section 5.2. of the protocol. 9. Participant has a history of clinically significant cardiovascular disease. Examples noted in section 5.2 of the protocol. 10. 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 11. Participant is known to be positive for human immunodeficiency virus (HIV) and meets one of the following criteria: • Not receiving highly active antiretroviral therapy (ART) •Had a change in antiretroviral therapy within 6 months of the start of screening • Receiving antiretroviral therapy that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment) • CD4 count <350 at screening •AIDS-defining opportunistic infection within 6 months of start of screening • Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled). 12. Participant has an uncontrolled illness, including but not limited to the following: • Diabetes • Ongoing or active bacterial infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week before randomization]), symptomatic viral infection, or any other clinically significant infection • Active bleeding diathesis • Impaired oxygenation requiring supplemental oxygen • Psychiatric illness/social situation that would limit compliance with study requirements 13. Participant had major surgery (eg, requiring general anesthesia) or significant traumatic injury within 4 weeks of randomization, 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. 14. Participant has a contraindication to the use of carboplatin or pemetrexed (refer to local prescribing information for each agent2,5). Participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid. 15. Participant has a history of hypersensitivity to the excipients of amivantamab (refer to the IB12). 16. Participant has received a live or live attenuated vaccine within 3 months before randomization. 17. Participant has received an investigational intervention (including investigational vaccines) within 6 weeks before randomization. 18. 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. 19. Participant plans to father a child while enrolled in this study or within 6 months after the last dose of study treatment. 20. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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 |
From randomization, until the date of objective disease progression based on BICR using RECIST v1.1 or death (by any cause) in the absence of progression, whichever comes first. |
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E.5.2 | Secondary end point(s) |
1. Objective response rate 2. Duration of response 3. Overall survival 4. Time to subsequent therapy 5. PFS after first subsequent therapy 6. Time to symptomatic progression 7. Incidence and severity of adverse events and laboratory abnormalities, assessment of vital signs, and physical examination abnormalities 8. a. Pharmacokinetic sample: Serum amivantamab concentrations • Ceoi: end of infusion serum concentration • Ceoi,ss: end of infusion serum concentration at steady state • Ctrough: serum concentration immediately prior the next study treatment administration • Ctrough,ss: serum concentration immediately prior the next study treatment administration at steady state • Cmax: maximum serum concentration b. Immunogenecity sample: anti-amivantamab antibodies 9. EORTC-QLQ-C30 10. PROMIS PF
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. to 6. From randomization until the date of documented progression or death, whichever comes first 7. Throughout study 8.a. Day 1 (D1) of Cycle 1(C1), C2, C3, C5, C7, C9, C11, C13 and C1D2, and End of Treatment visit (ETV) b. D1 of C1, C2, C3, C5, C7, C9, C11, C13 and ETV 9 and 10. EORTC-QLQ-C30: D1 of C1, C3, C5, C7, C9 etc, EOT, Follow-up every 12 weeks
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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 | 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 |
Immunogenecity, Tolerability, Biomarker evaluation, Quality of life |
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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 | Yes |
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 | 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 |
Malaysia |
Ukraine |
Taiwan |
Australia |
Brazil |
Canada |
China |
India |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Thailand |
Turkey |
United Kingdom |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Portugal |
Spain |
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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
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Last visit of the last subject |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |