| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| left-sided metastatic colorectal cancer (mCRC) |
| cancro metastatico del colon-retto (mCRC) sinistro |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic colorectal cancer |
| cancro metastatico del colon-retto |
|
| 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 | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Safety Run-in:
To confirm the recommended Phase II dose (RP2D) of tepotinib when used in combination with cetuximab
Overall Study:
To evaluate the preliminary efficacy of tepotinib (RP2D) in combination with cetuximab in terms of tumor response |
Run-in di sicurezza:
Confermare la dose raccomandata per la fase II (Recommended Phase II Dose, RP2D) di tepotinib utilizzato in combinazione con cetuximab
Studio generale:
Valutare l’efficacia preliminare di tepotinib (RP2D) in combinazione con cetuximab in termini di risposta tumorale |
|
| E.2.2 | Secondary objectives of the trial |
1) To further evaluate the efficacy of the combination of tepotinib (RP2D) and cetuximab in terms of:
- a)duration of response (DoR)
- b) progression-free survival (PFS)
- c)overall survival (OS)
2) To evaluate the safety and tolerability of tepotinib in combination with cetuximab
3) To characterize the immunogenicity of cetuximab |
1) Valutare ulteriormente l’efficacia della combinazione di tepotinib (RP2D) e cetuximab in termini di:
- durata della risposta (Duration of Response, DoR)
- Sopravvivenza libera da progressione (Progression-Free Survival, PFS
- Sopravvivenza complessiva (Overall Survival, OS)
2) Valutare la sicurezza e la tollerabilità di tepotinib in combinazione con cetuximab
3) Caratterizzare l’immunogenicità di cetuximab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Are = 18 years of age (or having reached the age of majority according to local laws and regulations, if the age of majority is > 18 years of age) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Advanced (locally advanced or metastatic) left sided CRC with RAS/BRAF wild-type at study entry confirmed prior to enrollment, with previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR monoclonal antibody therapy (panitumumab or cetuximab) by radiological documentation of disease progression according to RECIST Version 1.1.
3. MET amplification detected by a positive liquid biopsy and/or tissue with appropriate regulatory status (collected after disease progression of the previous anti-EGFR therapy).
4. Measurable disease by Investigator in accordance with RECIST Version 1.1.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
6. Life expectancy > 3 months.
7. Participants having at least one systemic treatment for mCRC including 1 anti-EGFR monoclonal antibody therapy as the most recent line of therapy for mCRC before study treatment and must have shown a radiologically confirmed by RECIST Version 1.1 complete response (CR) or partial response (PR), both for at least 4 months or stable disease (SD) for at least 6 months to that therapy prior to disease progression.
a. For Cohort A in sites outside of US, participants must only have had one prior systemic treatment for mCRC.
b. For Cohort B in sites in the US only, participants must have had at least two prior systemic treatments for mCRC.
8. Less than 2 months between the last administration of the most recent EGFR containing regimen and first dosing in this study.
9. Adequate hematological function in the absence of transfusions in 7 days before testing defined by white blood cell count = 3 × 109/L with absolute neutrophil count, = 1.5 × 109/L, platelet count = 100 × 109/L, and hemoglobin = 8.5 g/dL.
10. Adequate hepatic function defined by a total bilirubin level = 1.5 × upper limit of normal (ULN), AST = 3 × ULN, and ALT = 3 × ULN. For participants with liver metastases: total bilirubin = 1.5 × ULN, AST/ALT
= 5 × ULN.
11. Adequate renal function defined by an estimated glomerular filtration rate > 30 mL/min according to the 4-component Modification of Diet in Renal Disease (MDRD) equation. (GFR [mL/min/1.73 m2] = 175
× serum creatinine (Scr)-1.154 × age 0.203 × 1.212 [if African American] × 0.742 [if female]).
Sex
12. Are male or female
Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
Informed Consent
13. Capable of giving signed informed consent |
Age
1. Are = 18 years of age (or having reached the age of majority according to local laws and regulations, if the age of majority is > 18 years of age) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Advanced (locally advanced or metastatic) left sided CRC with RAS/BRAF wild-type at study entry confirmed prior to enrollment, with previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR monoclonal antibody therapy (panitumumab or cetuximab) by radiological documentation of disease progression according to RECIST Version 1.1.
3. MET amplification detected by a positive liquid biopsy and/or tissue with appropriate regulatory status (collected after disease progression of the previous anti-EGFR therapy).
4. Measurable disease by Investigator in accordance with RECIST Version 1.1.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
6. Life expectancy > 3 months.
7. Participants having at least one systemic treatment for mCRC including 1 anti-EGFR monoclonal antibody therapy as the most recent line of therapy for mCRC before study treatment and must have shown a radiologically confirmed by RECIST Version 1.1 complete response (CR) or partial response (PR), both for at least 4 months or stable disease (SD) for at least 6 months to that therapy prior to disease progression.
a. For Cohort A in sites outside of US, participants must only have had one prior systemic treatment for mCRC.
b. For Cohort B in sites in the US only, participants must have had at least two prior systemic treatments for mCRC.
8. Less than 2 months between the last administration of the most recent EGFR containing regimen and first dosing in this study.
9. Adequate hematological function in the absence of transfusions in 7 days before testing defined by white blood cell count = 3 × 109/L with absolute neutrophil count, = 1.5 × 109/L, platelet count = 100 × 109/L, and hemoglobin = 8.5 g/dL.
10. Adequate hepatic function defined by a total bilirubin level = 1.5 × upper limit of normal (ULN), AST = 3 × ULN, and ALT = 3 × ULN. For participants with liver metastases: total bilirubin = 1.5 × ULN, AST/ALT
= 5 × ULN.
11. Adequate renal function defined by an estimated glomerular filtration rate > 30 mL/min according to the 4-component Modification of Diet in Renal Disease (MDRD) equation. (GFR [mL/min/1.73 m2] = 175
× serum creatinine (Scr)-1.154 × age 0.203 × 1.212 [if African American] × 0.742 [if female]).
Sex
12. Are male or female
Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
Informed Consent
13. Capable of giving signed informed consent |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS metastases. Also excluded are participants with carcinomatous meningitis.
2. Participants who have brain metastasis as the only measurable lesion.
Prior/Concomitant Therapy
3. Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study intervention, except for the anti-EGFR containing regimen including associated chemotherapy if applicable, which may be continued until enrollment of
the participant in the study.
Prior/Concurrent Clinical Study Experience 4. Any unresolved toxicity Grade 2 or more according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) Version 5.0, from previous anticancer therapy excluding neuropathy, alopecia and rash.
Other Exclusions
5. Known severe hypersensitivity reactions to monoclonal antibodies (Grade = 3 NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more occurrences of partially controlled asthma).
6. Discontinuation of the most recent cetuximab or panitumumab containing therapy due to an adverse event.
7. Prior treatment with other agents targeting the HGF/MET pathway.
8. Impaired cardiac function:
a. Left ventricular ejection fraction < 45% defined by echocardiography (a screening assessment not required for participants without a history of congestive heart failure unless clinically indicated)
b. Serious arrhythmia
c. Unstable angina pectoris
d. New York Heart Association heart failure Class III and IV
e. Myocardial infarction within the last 12 months prior to study entry
f. Symptomatic pericardial effusion
9. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
10. Past or current history of neoplasm other than mCRC, except for curatively treated nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years.
11. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test products.
12. Major surgery within 28 days prior to Day 1 of study intervention.
13. Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus.
14. Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of Investigators.
15. IMP use in another study within 3 weeks of the first dose of study intervention. |
Medical Conditions
1. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS metastases. Also excluded are participants with carcinomatous meningitis.
2. Participants who have brain metastasis as the only measurable lesion.
Prior/Concomitant Therapy
3. Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study intervention, except for the anti-EGFR containing regimen including associated chemotherapy if applicable, which may be continued until enrollment of
the participant in the study.
Prior/Concurrent Clinical Study Experience 4. Any unresolved toxicity Grade 2 or more according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) Version 5.0, from previous anticancer therapy excluding neuropathy, alopecia and rash.
Other Exclusions
5. Known severe hypersensitivity reactions to monoclonal antibodies (Grade = 3 NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more occurrences of partially controlled asthma).
6. Discontinuation of the most recent cetuximab or panitumumab containing therapy due to an adverse event.
7. Prior treatment with other agents targeting the HGF/MET pathway.
8. Impaired cardiac function:
a. Left ventricular ejection fraction < 45% defined by echocardiography (a screening assessment not required for participants without a history of congestive heart failure unless clinically indicated)
b. Serious arrhythmia
c. Unstable angina pectoris
d. New York Heart Association heart failure Class III and IV
e. Myocardial infarction within the last 12 months prior to study entry
f. Symptomatic pericardial effusion
9. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
10. Past or current history of neoplasm other than mCRC, except for curatively treated nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years.
11. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test products.
12. Major surgery within 28 days prior to Day 1 of study intervention.
13. Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus.
14. Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of Investigators.
15. IMP use in another study within 3 weeks of the first dose of study intervention. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Run-in:
Occurrence of dose limiting toxicities (DLTs)
Overall Study:
Objective response (OR, confirmed complete response [CR] or partial response [PR]) determined according to RECIST Version 1.1 assessed by the Investigators |
Run-in di sicurezza:
Insorgenza di tossicità dose-limitanti (Dose Limiting Toxicities, DLT)
Studio generale:
Risposta obiettiva ([Objective Response, OR], risposta completa [Complete Response, CR] o risposta parziale [Partial Response, PR]) confermata valutata dagli sperimentatori secondo i criteri RECIST versione 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety Run-In, Overall Study: Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15 and subsequently every 4 cycles until study closure or disease progression |
| Safety Run-In, Overall Study: Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15 and subsequently every 4 cycles until study closure or disease progression |
|
| E.5.2 | Secondary end point(s) |
Overall Study:
1)
a) DoR (months) according to RECIST Version 1.1 assessed by the Investigators.
b) PFS (months) according to RECIST Version 1.1 assessed by the Investigators.
c) OS (months) assessed by the Investigators.
2)
- Occurrence of Adverse Events (AE) and treatment related AEs
- Occurrence of clinically significant changes in vital signs, laboratory parameters and 12-lead electrocardiogram (ECG) findings
3)
Immunogenicity of cetuximab as measured by antidrug antibody (ADA) assays on Day 1 Cycle 1 and End of Treatment Visit |
Studio generale:
1)
a) DoR (in mesi) valutata dagli sperimentatori secondo i criteri RECIST versione 1.1
b) PFS (in mesi) valutata dagli sperimentatori secondo i criteri RECIST versione 1.1
c) OS (in mesi) valutata dagli sperimentatori
2)
- Insorgenza di eventi avversi (Adverse Event, AE) e AE correlati al trattamento
- Insorgenza di variazioni clinicamente significative dei segni vitali, dei parametri di laboratorio e dei risultati dell’elettrocardiogramma (ECG) a 12 derivazioni
3) Immunogenicità di cetuximab misurata mediante test degli anticorpi anti-farmaco (Antidrug Antibody, ADA) al Giorno 1 del Ciclo 1 e alla Visita di fine trattamento |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Survival Follow -Up and End of Treatment Visits |
| Survival Follow -Up and End of Treatment Visits |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| biomarker research, Immunogenicity Assessments |
| biomarker research, Immunogenicity Assessments |
|
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 1 |
| 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 | 8 |
| 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 | Information not present in EudraCT |
| 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 |
| Russian Federation |
| Turkey |
| United States |
| Belgium |
| Czechia |
| France |
| Italy |
| Spain |
| United Kingdom |
|
| 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 the study is defined as the date when the last participant has completed the last visit in the Survival Follow-up. |
| The end of the study is defined as the date when the last participant has completed the last visit in the Survival Follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 9 |
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