E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or Metastatic Colorectal Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or Metastatic Colorectal 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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | Colorectal 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 anti-tumor activity of amivantamab as a monotherapy and characterize the safety of amivantamab when added to SoC Chemotherapy in participants with mCRC (Ph2 cohorts), and to assess the recommended phase 2 combination dose (RP2CD) of amivantamab when added to SoC chemotherapy (Ph1b). |
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E.2.2 | Secondary objectives of the trial |
To characterize the safety of amivantamab as a monotherapy and to assess the anti-tumor activity of amivantamab when added to SoC chemotherapy in participants with mCRC. |
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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 been previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum. 3.Participant must have tumor previously characterized as having wildtype KRAS, NRAS, BRAF and without evidence of ERBB2/HER2 amplification. Evaluation of dMMR/MSI-H status is also required in accordance with local guidelines and SoC. 4. For Ph1b-D and Ph1b-E: Participant must have evaluable disease. For Ph 2: Participant must have measurable disease according to RECIST v1.1. If only one measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy. 5. Participant must have ECOG PS 0 or 1. 6. Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, or use of granulocyte colony stimulating factor (G-CSF) within 7 days prior to the date of the laboratory test. 7. Participant must have a tumor lesion amenable for biopsy and agree to mandatory protocol-defined screening biopsies. 8. Human immunodeficiency virus (HIV)-positive participants are eligible if they meet the criteria 9. A female participant 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. 10. A female participant must be either not of childbearing potential, or of childbearing potential and practicing at least 1 highly effective method of contraception. 11. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility. 12. 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 6 months after receiving the last dose of study treatment. If partner is a female of childbearing potential, the male participant must use condoms, and the partner must also be practicing a highly effective method of contraception. A male participant who is vasectomized must still use a condom, but the partner is not required to use contraception. 13. A male participant must agree not to donate sperm for the purposes of reproduction during the study and for 6 months after receiving the last dose of study treatment. Male participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility. 14. 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. 15. Participant must be willing and able to adhere to the lifestyle restrictions specified in this protocol. 16. Participant may have a prior malignancy (other than the disease under study) the natural history or treatment of which is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s). Must be reviewed and agreed to with medical monitor. |
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E.4 | Principal exclusion criteria |
1. Participant with known ERBB2/HER2 amplification based on the local testing results 2. Participant with known dMMR/MSI-H status who has not received immunotherapy treatments per local SoC guidelines. 3. Participant has an uncontrolled illness 4. Participant with symptomatic or untreated brain metastasis 5. History or known presence of leptomeningeal disease 6. Participant has a history of (non-infectious) ILD/pneumonitis/pulmonary fibrosis, or has current ILD/pneumonitis/pulmonary fibrosis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening. 7. Participant has a history of clinically significant cardiovascular disease. 8. Participant has known allergies, hypersensitivity, or intolerance to excipients of: a. amivantamab (refer to the IB, all participants) b. 5-FU or leucovorin (Participants in Ph1b-D, Ph1b-E, and Ph2 Cohorts D and E) c. Oxaliplatin (Participants in Ph1b-D and Ph2 Cohort D) d. Irinotecan (Participants in Ph1b-E and Ph2 Cohort E) 9. Participant has at screening: a. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg) Exception: Participants with a prior history of HBV demonstrated by positive hepatitis B core antibody (HBcAb) are eligible if they have at screening 1) a negative HBsAg and 2) an HBV DNA (viral load) below the lower limit of quantification, per local testing. Participants with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing. b. Positive hepatitis C antibody (anti-HCV [hepatitis C virus]) c. Other clinically active infectious or non-infectious liver disease 10. 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. 11. Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives, whichever is longer, before the first administration of study drug. Participants must not have received any anti-EGFR treatment within 28 days of the first dose of study drug. 12. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less prior to the first dose of study treatment (except for alopecia or postradiation skin changes [any grade], Grade ≤2 peripheral neuropathy, and Grade ≤2 hypothyroidism stable on hormone replacement). 13. Participant has, or will have, any of the following: a. An invasive operative procedure with entry into a body cavity, within 4 weeks or without complete recovery before the first administration of study treatment. Thoracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to the first administration of study treatment, as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator b. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to Day 1) c. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment 14. Participant has received an investigational drug (including investigational vaccines, but not including anti-cancer therapy) or used an invasive investigational medical device within 6 weeks before the planned first dose of study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 8 weeks (±1 week) for the first 30 months, then every 12 weeks (±1 week) until disease progression during the treatment period |
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E.5.2 | Secondary end point(s) |
Duration of response (DoR), clinical benefit rate (CBR), and progression free survival (PFS) as determined by investigator, according to the Response Criteria in Solid Tumors (RECIST) Version 1.1 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 8 weeks (±1 week) for the first 30 months, then every 12 weeks (±1 week) until disease progression during the treatment period |
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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 |
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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) | 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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Korea, Republic of |
Malaysia |
Taiwan |
United States |
France |
Spain |
Germany |
Italy |
Belgium |
United Kingdom |
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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
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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 | 6 |
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 | 6 |