| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic colorectal 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 | 21.0 |
| 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 |
• Cohorts A (2L), B (3L), and C (>3L)
− Efficacy: To evaluate the antitumor activity of etruma-based treatment combinations
• All Cohorts (including Safety Run-in Cohort)
− Safety: To evaluate the safety and tolerability of etruma-based treatment combinations |
|
| E.2.2 | Secondary objectives of the trial |
• Cohorts A (2L), B (3L), and C (>3L)
− To evaluate clinical activity of etruma-based treatment combinations
• All Cohorts (including Safety Run-in Cohort)
− To determine the pharmacokinetic (PK) profile for components of etruma-based treatment combinations
• All Cohorts (including Safety Run-in Cohort)
− To assess immunogenicity of the biologic component(s) of combination therapy where appropriate |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
2.Male and female participants ≥18 years of age inclusive, at the time of signing the informed consent
3.Ability to comply with the study protocol in the Investigator’s judgment
4.Histologically confirmed metastatic colorectal adenocarcinoma
5.Measurable (at least one target lesion) disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
Note: Inclusion Criterion 5 is not required for participants entering into the Safety Run-in Cohort.
6.Participants with measurable disease and accessible tumor will undergo a pre-treatment biopsy (unless an archived specimen is available) and on-treatment fresh tumor biopsy. The biopsy must not put participants at undue risk and the procedure must not be more invasive than a core biopsy as documented in the medical record by the Investigator. Fresh biopsy of a tumor lesion not previously irradiated should be obtained. Tumors progressing in a prior site of radiation may be considered after Sponsor consultation.
• Participants for biopsy should have at least two measurable lesions at baseline: one for tissue sampling and one for radiographic response assessment.
7.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8.Life expectancy ≥3 months as determined by the Investigator
9.Adequate hematologic and end-organ function defined by the following laboratory test results at screening:
a. Absolute neutrophil count ≥1.5 x 10^9/L (1500/μL) without granulocyte colony-stimulating factor support
b. White blood cell counts ≥2.5x 10^9/L (2500/μL)
c. Lymphocyte count ≥0.5 x 10^9/L (500/μL)
d. Platelet count ≥100 x 10^9/L (100,000/μL) without transfusion
e. Hemoglobin ≥90 g/L (9.0 g/dL)
Participants must not have been transfused within 2 weeks prior to screening to meet minimum platelet and hemoglobin parameters.
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN), with the following exception:
i. Participants with documented liver metastases: AST and ALT ≤5 x ULN
ii. Participants with documented liver or bone metastases: alkaline phosphatase (ALP) ≤5 x ULN
g. ALP ≤5 x ULN
i. If ALP >5 × ULN, then gamma-glutamyl transpeptidase must be within normal limits
h. Total bilirubin ≤1.5 x ULN, with the following exception:
i. Participants with known Gilbert syndrome: serum bilirubin level ≤3 x ULN
i. Albumin ≥25 g/L (2.5 g/dL)
j. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥30 mL/min as determined by Cockcroft-Gault equation (Cockcroft and Gault, 1976)
10.Negative human immunodeficiency virus (HIV) test at screening. Due to safety concerns related to viral activation, development of a secondary malignancy, as well as the potential for increased treatment related toxicity, eligible participants must not have evidence of chronic HIV infection at screening
11.Negative hepatitis B surface antigen (HBsAg) and core antibody (HBcAb) tests, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV test will be performed only for participants who have a positive total HBcAb test. Due to safety concerns related to viral activation, development of a secondary malignancy, as well as the potential for increased treatment related toxicity, eligible participants must not have evidence of chronic viral hepatitis infection at screening
12.Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening. The HCV RNA test will be performed only for participants who have a positive HCV antibody test. Due to safety concerns related to viral activation, development of a secondary malignancy, as well as the potential for increased treatment related toxicity, eligible participants must not have evidence of chronic viral hepatitis infection at screening
13.Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment cohort in Section 18 of the protocol.
Due to limited space, for Study Treatment-Specific Inclusion Criteria please refer to section 7.2 of the protocol |
|
| E.4 | Principal exclusion criteria |
1.Prior anticancer treatment for the disease under study, including approved agents, systemic radiotherapy, or investigational therapy, within 4 weeks (or 5 half-lives) whichever is shorter prior to initiation of study treatment. Prior focal radiotherapy must be completed at least 2 weeks prior to the initiation of study treatment
2.QTc ≥480 msec using Fredericia’s QT correction formula (based on an average of triplicate recordings)
3.Prior allogeneic stem cell or solid organ transplantation
4.Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks (or 5 half-lives) whichever is shorter prior to initiation of study treatment
5.Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-α agents) administered at >10 mg/day prednisone or equivalent within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions:
a. Participants who received low dose (≤10 mg/day prednisone or equivalent), systemic immunosuppressant medications or a one-time pulse dose of systemic immunosuppressant medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained.
b. Participants who received mineralocorticoids (eg, fludrocortisone), inhaled or intranasal corticosteroids for chronic obstructive pulmonary disease or asthma, or low dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study after Medical Monitor approval has been obtained.
6.Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the last dose of study treatment
7.Current treatment with anti-viral therapy for HBV
8.Structurally unstable bone lesions suggesting impending fracture
9.Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
a. Participants with a history of treated CNS metastases are eligible, if all of the following criteria are met:
i. The participant has no history of intracranial hemorrhage or spinal cord hemorrhage.
ii. Metastases are limited to the cerebellum or the supratentorial region (ie, no metastases to the midbrain, pons, medulla, or spinal cord).
iii. There is no evidence of interim progression between completion of CNS directed therapy and the screening brain scan.
iv. The participant has not received stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole brain radiotherapy within 14 days prior to initiation of study treatment.
v. The participant has no ongoing requirement for corticosteroids as therapy for CNS disease. Anti-convulsant therapy at a stable dose is permitted.
b. Asymptomatic participants with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan
10.History of leptomeningeal disease
11.History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
b. Participants with ground-glass opacities of unknown significance may be eligible following a discussion with the Medical Monitor. Participants must be asymptomatic and without evidence of hypoxia on ambulation.
12.History of malignancy other than colorectal cancer within 2 years prior to screening, except for malignancies with a negligible risk of metastasis or death (eg, 5-year OS rate >90%), such as non-melanoma skin carcinoma or ductal carcinoma in situ
13.Active tuberculosis
14.Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment
a. Participants receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
15.Severe infection within 4 weeks (28 days) prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
16.Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable angina or new onset angina within 3 months prior to initiation of study treatment, myocardial infarction within 6 months prior to initiation of study treatment, or unstable arrhythmia
Due to limited space please refer to section 7.3 of the protocol for all other exclusion criteria
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Cohort A (2nd line [2L])
• Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by the Investigator
Cohort B (3rd line [3L]) (Co-primary)
• PFS according to RECIST v1.1 as assessed by the Investigator
• Overall survival (OS)
Cohort C (>3 lines [>3L])
• Objective response rate (ORR) according to RECIST v1.1, as assessed by the Investigator
Safety:
All Cohorts (including Safety Run-in Cohort)
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
Cohort A (2nd line [2L]): PFS
Defined as the time from treatment assignment until first documentation of progressive disease or death, whichever occurs first.
Cohort B (3rd line [3L]) (Co-primary): PFS and OS
PFS (defined above) and OS, defined as the time from treatment assignment until death due to any cause.
Cohort C (>3 lines [>3L]): ORR
Defined as the proportion of participants with a best overall response of CR or PR according to RECIST v1.1
Safety:
Throughout the trial |
|
| E.5.2 | Secondary end point(s) |
Cohort A (2L)
• ORR according to RECIST v1.1, as assessed by the Investigator, duration of response (DoR; defined as the time from first documentation of disease response [complete response (CR) or partial response (PR)] until first documentation of confirmed progressive disease), disease control rate (DCR; defined as CR, PR, or stable disease [SD] for >12 weeks), and OS
Cohort B (3L)
• ORR, DoR, and DCR (CR, PR, or SD for >12 weeks) according to RECIST v1.1, as assessed by the Investigator.
Cohort C (>3L)
• DoR and DCR (CR, PR, or SD for >12 weeks) according to RECIST v1.1, as assessed by the Investigator
All Cohorts (including Safety Run-in Cohort)
• Serum/plasma concentration and PK parameters for components of etruma-based combination therapy
All Cohorts (including Safety Run-in Cohort)
• Number and percentage of participants who develop antidrug antibodies (ADAs) to the biologic component(s) of combination therapy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort A (2L):
ORR Defined as the proportion of participants with a best overall response of CR or PR according to RECIST v1.1.
DoR defined as the time from first documentation of disease response (CR or PR) until first documentation of confirmed progressive disease.
DCR defined as the proportion of participants with a best overall response of CR, PR, or SD. The duration of time required for a participant with SD to be considered in disease control is >12 weeks.
OS Defined as the time from treatment assignment until death due to any cause.
• Cohort B (3L): ORR, DoR, and DCR (as defined above)
• Cohort C (>3L): DoR and DCR (as defined above)
All cohorts
Throughout the trial |
|
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Study Evaluating the Efficacy and Safety of AB928-Based Treatment Combinations |
|
| 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 | 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 | 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 | 6 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Korea, Republic of |
| Singapore |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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