E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
E.1.2 | Classification code | 10049280 |
E.1.2 | Term | Solid tumour |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Part 1: - Determination of MTD/MRD and tolerability - Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2: Primary Safety End Point: - To characterize the safety and tolerability of MCLA-128 - Frequency and nature of AEs
Primary Efficacy End Point: - To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers - Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST 1.1 as per local investigator’s assessment. The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored, and serum biomarkers such as CA-125 (ovarian, endometrial) and CA-19-9 (gastric). - Magnitude of anti-tumor activity of MCLA-128 in patients with NRG1 fusion (Cohorts F, G, H) |
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E.2.2 | Secondary objectives of the trial |
Part1: - safety and tolerability of MCLA-128 - PK profile of MCLA-128 - Immunogenicity of MCLA-128 - Evaluation of anti-tumor response and CBR. - Frequency and nature of AEs/SAEs - Assessment of PK variables - Incidence and serum titers of anti-drug antibodies against MCLA-128 - Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining ORR, DOR, PFS and survival
Part2: Key secondary: - Durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions (Cohorts F, G, H)
Secondary: - PK profile - Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-∞, tmax - Immunogenicity - Population PK analysis - Incidence and serum titers of anti-drug antibodies against MCLA-128 - Evaluation of PFS and overall survival, duration of response
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Age ≥18 yrs 2.≥1 measurable lesion, RECIST v1.1 or evaluable disease for a limited number of patients in group H 3.ECOG 0-1 4.life expectancy ≥12 wks 5. Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1 except for alopecia, Grade 2 sensory neurotoxicity, or any other toxicity that in the opinion of the investigator does not affect the assessment of adverse events related to the study drug 6.Treatment with anti-cancer or investigational product within set intervals before first dose of IMP: a.>14d or >5 half-lives prior to study entry, whichever is shorter. b.>14d for radiotherapy. Note: A less than 1-week wash-out period is permitted only for palliative radiation to non-CNS disease with Sponsor approval. 7.Recovery from prior surgery/other procedure/ complication to ≤ Grade 2 or to baseline condition that in opinion of the investigator does not affect the assessment of adverse events related to the study drug; 8.Screening Lab values: a.Absolute neutrophil count ≥1.5 x 109/L without colony stimulating factor support; b.Platelets ≥100 x 109/L; c.Hemoglobin ≥8 g/dL or ≥2.2 mmol/L; d.ALT, AST ≤3 x ULN and total bilirubin ≤1.5 x ULN (for exceptions please refer to protocol) e.Estimated glomerular filtration rate (GFR) of >30 mL/min based on the Cockroft-Gault formula; 9.Able to provide at baseline a mandatory tumor biopsy sample, preferably a block. If safe/feasible, a fresh FFPE biopsy sample is preferred; archival tissue is acceptable (preferably not more than 2 years old* 10.Negative pregnancy test at Screening and ≤7 days of D1 11.Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control during entire study and 6 months after final administration of MCLA-128 12.Give written informed consent 13.Capable of understanding protocol requirements, is willing and able to comply with study procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required. 14.Patients must have received prior standard therapy appropriate for their tumor type and stage of disease. 15. Locally-advanced unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified through molecular assays such as PCR, next generation sequencing-based assays [DNA or RNA], or FISH as routinely performed at CLIA or other similarly-certified laboratories**
*For patients who received afatinib or other HER-targeting agents, a biopsy collected after the last line of treatment is strongly preferred to assess for mechanisms of acquired resistance.
** Patients harboring fusions that are predicted to be non-functional, i.e. lack of EGF-domain, will not be included in the study. For equivocal cases, including those with NRG1 as the upstream partner, the sponsor will manually review genomic results and may request collateral testing, approve, or deny the case. |
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating; 2. Presence of an active uncontrolled infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever or a clinically insignificant minor infection may be enrolled (i.e. mild upper respiratory infection); 3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies; 4. Known HIV, active Hepatitis B or Hepatitis C; patients who have previously been treated for Hepatitis C and have undetectable viral loads are eligible; 5. Known symptomatic or unstable brain metastases. Patients with asymptomatic brain metastases are eligible to participate if the metastases have been radiographically and clinically stable for at least one month. If on steroids for this indication, the patient must be on a stable dose for at least one month. 6. Patients with leptomeningeal metastases 7. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative or palliative intent and in the opinion of the investigator, with sponsor agreement, the previous or concurrent malignancy condition doesn’t affect the assessment of safety and efficacy of the study drug; 8. Presence of NYHA Class III or IV congestive heart failure or LVEF <50% or history of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication; 9. Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: - Determination of MTD/MRD and tolerability - Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2: Primary Safety End Point: - To characterize the safety and tolerability of MCLA-128 - Frequency and nature of AEs
Primary Efficacy End Point: - To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers - Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST 1.1 as per local investigator’s assessment.The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored and serum biomarkers as CA-125 (ovarian) and CA-15-3 (breast) - To assess magnitude of anti-tumor activity of MCLA-128 in patients with NRG1 fusion (Cohorts F, G, H) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessment • 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker: Scr., end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU • 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. Serum marker: Screening, end of every cycle (pre-dose day 1), EOT, FSV, LTFU • biweekly (groups F, G & H): Scr., every 8 weeks until EoT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
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E.5.2 | Secondary end point(s) |
Part 1: - To characterize the safety and tolerability of MCLA-128 - PK profile of MCLA-128 - Immunogenicity of MCLA-128. - Evaluation of anti-tumor response and CBR. - Frequency and nature of AEs/serious adverse events (SAEs). - Assessment of PK variables, including total exposure, maximum concentration (Cmax) clearance, volume of distribution (V), volume of distribution at steady state (Vss), half-life (t1/2), AUC0-t (area under the concentration versus time curve from time zero to time t), AUC0-∞ (area under the concentration versus time curve), tmax (time to reach maximum concentration). - Incidence and serum titers of anti-drug antibodies against MCLA-128. - Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and survival; CBR is defined as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks).
Part 2: Key Secondary: - Durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions (Cohorts F, G, H)
Secondary: - PK profile of MCLA-128 - Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-∞, tmax. - Immunogenicity of MCLA-128 - Incidence and serum titers of anti-drug antibodies against MCLA-128. - Evaluation of PFS and overall survival, duration of response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK •3week: Cyc1 D1, 4 (or 3), 8, 15, Cyc 2-4 D1 •4week: Cyc1 D1, 8, 15, 22, Cyc2-3 D15, Cyc4 D1, 15, Cyc>5 (every 2 • biweekly (groups F, G & H): Cyc1-3 D1,D15, Cyc4 and every 2 cycles thereafter D1
Immunogenicity: Cyc1-4 D1, then D1 of every 4 Cyc, EOT, FSV
Tumor assessment • 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker: Screening, end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU • 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. • biweekly (groups F, G & H): Scr., every 8 weeks until EoT, FSV, LTFU
Serum marker: Scr., end of every cycle (predose day 1), EOT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 2 is parallel design, Part 1 is not |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Singapore |
Spain |
Taiwan |
United Kingdom |
United States |
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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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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 | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |