| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Solid Tumors including EGFR-mutated Non-Small Cell Lung Cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or Metastatic Solid Tumors including EGFR-mutated 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 objectives are to assess anti-tumor activity (objective response rate [ORR]) (Cohorts 1, 2, and 3) and to evaluate the safety (Cohort 4) of amivantamab SC-CF via manual injection. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to assess safety and additional measures of anti-tumor activity (Cohorts 1, 2, and 3) and to characterize the PK of amivantamab-SC-CF (Cohorts 1, 2, and 3). In Cohort 4 only, patient-reported outcomes (PROs) will be utilized to characterize participants’ experience with both formulations. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
Type of Participant and Disease Characteristics
2. Participant must have histologically or cytologically confirmed, locally advanced or metastatic, NSCLC.
Additional Cohort specific disease requirements include:
Cohorts 1 and 3: EGFR Exon19del or Exon21 L858R mutation
Cohort 2: EGFR Exon 20ins mutation
EGFR Exon19del or Exon 21 L858R mutation (Cohort 1 and 3) or EGFR Exon 20 insertion mutation (Cohort 2) must have been identified as determined 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 copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be submitted to the sponsor.
3. Have at least 1 measurable lesion, according to RECIST v1.1. If the only target lesion has been previously irradiated, it must show signs of disease progression since radiation was completed.
Prior Malignancies
4. May have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) (see Appendix 12 of the Protocol on Allowed Recent Second or Prior Malignancies for details).
Prior Therapy Restrictions or Requirements
5. Cohort-specific requirements with regards to prior therapy are as follows:
Cohort 1 and 2:
Participant should not have received any prior systemic therapy for metastatic NSCLC.
Cohort 2: Participant should not have received any prior systemic therapy for metastatic NSCLC. However, prior monotherapy with an approved EGFR TKI targeting common EGFR mutations as first-line therapy for the treatment of locally advanced or metastatic disease is allowed, if: 1) treatment duration did not exceed 8 weeks; 2) lack of disease response was documented radiographically 3) associated toxicities have resolved to baseline; and 4) the EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to treatment initiation at C1D1, whichever is longer. Prior therapy with EGFR TKI agents targeting Exon20ins mutations (eg, TAK788/mobocertinib or poziotinib), is not allowed.
Cohort 3:
Participant should have progressed on or after osimertinib monotherapy as the immediate prior line of systemic therapy. Osimertinib must have been administered as the first EGFR TKI for metastatic disease or as the second TKI after prior treatment with first- or second-generation EGFR TKI.
Cohort 4:
Participants need to currently be on an amivantamab IV Q2W regimen without dose reduction (1,050 mg or 1,600 mg depending on weight) as part of standard of care for at least 3 months, an expanded access program, or as a rollover from a long-term extension prior amivantamab Q2W study. No washout is required between IV and SC-CF administration.
6. Toxicities from prior anticancer therapy, if any, must have resolved to CTCAE Version 5.0 Grade 1 or baseline level (except for other toxicities as indicated in inclusion criteria 8, alopecia [any grade], Grade ≤2 peripheral neuropathy, and Grade <2 hypothyroidism stable on hormone replacement).
For Cohort 4 only:
Amivantamab related toxicities that are stable and deemed tolerable by the investigator and patient are not exclusionary.
Performance Status
7. Participant must have ECOG status of 0 or 1. Refer to Appendix 9 of the Protocol: Eastern Cooperative Oncology Group (ECOG) Performance Status.
Renal, Hepatic and Hematological Function
8. Participant must demonstrate adequate organ and bone marrow function required for safe administration of the cohort-specific regimen, without history of red blood cell transfusion or platelet transfusion within 7 days prior to the date of the laboratory test, as follows:
Cohorts 1 and 4 (chemotherapy-free regimens):
a. Hemoglobin ≥9 g/dL
b. 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
c. Platelets ≥75x109/L
d. ALT and AST ≤3xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases.
e. Total bilirubin ≤1.5xULN (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits)
f. eGFR >50 mL/min as measured or calculated by MDRD (Appendix 11: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in Renal Disease Formula [in mL/min]) |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. Participant has an uncontrolled illness, including but not limited to:
a. Uncontrolled diabetes
b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment] or diagnosed or suspected viral infection).
c. Active bleeding diathesis
d. 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
e. Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements
f. Any ophthalmologic condition that is clinically unstable
2. Participant has a medical history of ILD, including drug induced ILD or radiation pneumonitis
3. Participant has a history of hypersensitivity to any excipients of the investigational products to be used in their enrolment cohort
4. Participant has a history of clinically significant cardiovascular disease including, but not limited to:
a. Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study treatment(s), or any of the following within
6 months prior to the first dose of study treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not
exclusionary.
b. Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate).
c. Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; diastolic blood pressure >100 mmHg
d. Congestive heart failure defined as NYHA class III-IV or hospitalization for CHF (any NYHA class) within 6 months of treatment initiation at C1D1
e. Pericarditis/clinically significant pericardial effusion
f. Myocarditis
g. Baseline LVEF below the institution’s lower limit of normal at screening, as assessed by echocardiogram or MUGA scan.
5. Participant had major surgery (eg, requiring general anesthesia), excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before signing the ICF, 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.
6. Participant has uncontrolled tumor-related pain:
Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated more than 7 days prior to the treatment initiation at C1D1.
Disease Characteristics
7. Participant has received radiotherapy for palliative purposes less than 7 days prior to treatment initiation at C1D1.
8. 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 Screening 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 treatment allocation.
9. Participant has a history of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.
Prior/Concomitant Therapy or Clinical Study Experience
10. Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the planned first dose of study treatment.
11. Participant has received a live or live attenuated vaccine within 3 months before Cycle 1 Day 1. The seasonal influenza vaccine and non-live vaccines against COVID 19 are not exclusionary.
12. Cohorts 1, 3, and 4 (regimens potentially including lazertinib): 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 Cycle 1 Day 1.
Other Exclusions
13. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohorts 1, 2, and 3
- ORR (INV)
Cohort 4
- Incidence and severity of adverse events and clinical laboratory abnormalities |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Cohort 1,2,3: The primary analysis of primary endpoints for Cohorts 1, 2, and 3 will be performed after all participants have completed at least 3 disease assessments (unless they withdrew consent or died prior). Cohort 4: The primary analysis of primary endpoints will be performed 3 months after the last participant in that cohort received the first dose (i.e., once all enrolled patients have completed at least 3 cycles of treatment or discontinued prior). The final analysis of primary and secondary endpoints as well as the analysis of exploratory endpoints will be performed after the last participant in that cohort completed the Follow-up Phase. |
|
| E.5.2 | Secondary end point(s) |
Cohorts 1, 2, and 3
- Incidence and severity of adverse events and clinical laboratory abnormalities
- ORR (ICR)
- DoR
- TTR
- CBR (INV)
- PFS
- OS
- Serum Ctrough of amivantamab on Cycle 2 Day 1
- Serum amivantamab concentrations and serum anti-amivantamab antibodies (Cohorts 1, 2, and 3)
- Plasma lazertinib concentrations (Cohorts 1 and 3)
- The presence or absence of anti-rHuPH20 antibodies
Cohort 4
- Incidence and severity of adverse events and clinical laboratory abnormalities
- Modified TASQ-IV
- Modified TASQ-SC
- PGIC
- PGIS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Cohort 1,2,3: The primary analysis of secondary endpoints for Cohorts 1, 2, and 3 will be performed after all participants have completed at least 3 disease assessments (unless they withdrew consent or died prior). Cohort 4: The primary analysis of secondary endpoints will be performed 3 months after the last participant in that cohort received the first dose (i.e., once all enrolled patients have completed at least 3 cycles of treatment or discontinued prior). The final analysis of primary and secondary endpoints as well as the analysis of exploratory endpoints will be performed after the last participant in that cohort completed the Follow-up Phase. |
|
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Brazil |
| China |
| India |
| Israel |
| Japan |
| Korea, Democratic People's Republic of |
| Malaysia |
| Taiwan |
| United States |
| Spain |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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