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 | 20.0 |
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 as
CA-125 (ovarian) and CA-15-3 (breast). |
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E.2.2 | Secondary objectives of the trial |
Part 1:
- 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
Part 1 - exploratory:
- Presence of biomarkers and PD responses
- Assessment of relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor biopsy material and blood.
Part 2:
- PK profile
- Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-∞, tmax
- Immunogenicity
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Evaluation of PFS and overall survival, duration of response
Part 2 – exploratory:
- Assessment of other relevant tumor biomarkers and markers of MCLA-128 activity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Inclusion Criteria Part 1+2
1. Age ≥18 yrs
2. ≥1 measurable lesion, RECIST v1.1
3. ECOG 0-1
4. life expectancy ≥12 wks
5. Toxicities of previous anti-cancer therapy resolved to ≤Gr 1, except for alopecia, lymphopenia assessed as non-clinically significant, Gr 2 sensory neurotoxicity
6. ≥4-wks between last radiotherapy and D1 (except ≤1X8 Gy for pain palliation)
7. Complete recovery from major surgery
8. Screening Labvalues
a. neutrophil count ≥1.5 x 10^9/L without colony stimulating factor support
b. Platelets ≥100 x 10^9/L
c. Hemoglobin ≥9 g/dL or ≥2.2 mmol/L (not transfusion dependent)
d. Total bilirubin <1.5 ULN (unless Gilbert’s syndrome)
e. AST(SGOT) ≤2.5 x ULN; ALT(SGPT) ≤2.5 x ULN; ≤5 x ULN for patients with advanced solid tumors with liver metastases; patients with confirmed bony metastases are permitted with isolated elevations in ALP >5 x ULN
f. Serum creatinine ≤ 1.5 x ULN or estimated GFR of >50 mL/min Cockroft-Gault
g. Coagulation function (INR and aPTT ≤1.5 ULN, unless on therapeutic anticoagulants)
h. Urine protein dipstick ≤ 2+ ; or ≤100 mg/24 hrs urine
9. Able to provide at baseline a mandatory archival tumor sample from fresh (preferred) or archival tissue
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. Patient with metastatic cancer who has disease progression after having received treatment with all available therapies known to convey clinical benefit
Specific Inclusion Criterion Part 1
15. Histologically-confirmed and documented advanced/metastatic epithelial tumors, relapsed/refractory to ≥2 prior regimens of standard treatment(s), or for which no curative therapy is available and MCLA-128 is a reasonable treatment option
Specific Inclusion Criterion Part 2:
Group A (BC)
16. Histologically-confirmed and documented advanced/metastatic breast cancer (BC), relapsed/refractory to ≥2 prior HER2 directed regimen for breast cancer
17. Confirmed HER2 amplification (HER2 2+ by IHC confirmed by FISH, or HER2 3+ by IHC) based on historical pathology report or analysis of baseline fresh/archival tumor sample
Group B (CRC)
18. Histologically-confirmed and documented advanced/metastatic colorectal cancer (CRC), relapsed/refractory to at least 2 prior regimens of standard treatments for metastatic CRC, including 1anti-EGFR treatment (if RASWT)
19. Confirmed HER2 amplification based on historical pathology report prior to commencing screening assessments
Group C (OC)
20. Histologically-confirmed and documented advanced/metastatic epithelial ovarian cancer (OC) for which no curative therapy is available
21. Prior therapy including all available standard therapies and ≥1 platinium based chemotherapy
Group D (GC or GEC)
22. Histologically-confirmed and documented advanced/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEC)
23. Prior chemotherapy including platinium and fluoropyrimidine based treatment and trastuzumab
24. Confirmed HER2 amplification (HER2+ by IHC confirmed by FISH, or HER3+ by IHC) based on historical pathology report or analysis of fresh/archival tumor sample
Groupe E (EC)
25. Histologically-confirmed and documented advanced/metastatic endometrial cancer (mEC) with no curative therapy available
26. Prior theray with all available standard and ≥1 prior chemotherapy
Group F (NSCLC)
27. Histologically or cytologically documented diagnosis of Stage IIIB not amenable to radical treatment or Stage IV NSCLC; with pathological characterization of non-squamous or squamous histological subtype and adenocarcinoma subtype classification
28. Confirmed HER2 expression (by IHC, HER2 expression 1+, 2+, 3+) on historical pathology report or analysis of baseline fresh/archival tumor sample
29. Prior treatment included all available standard therapies with ≥1 prior regimen of platinum-based chemotherapy in locally advanced/metastatic setting/recurrent NSCLC with documented disease progression by investigator assessment
30. Patients with ALK fusion oncogene with documented disease progression or intolerance with a first-line ALK Tyrosine Kinase Inhibitor approved for treatment of ALK fusion oncogene NSCLC
31. Patients with known mutation in the EGFR gene must have documented disease progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant NSCLC |
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E.4 | Principal exclusion criteria |
General Exclusion Criteria for Part 1 and Part 2
1. Pregnant or lactating;
2. Presence of an active 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 may be enrolled;
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, Hepatitis B or Hepatitis C; patients who have previously been treated for Hepatitis C and have undetectable viral loads are eligible;
5. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) all known CNS lesions have been treated with radiotherapy and/or surgery and b) patient remained without evidence of CNS disease progression ≥ 4 weeks after treatment and c) patients must be off corticosteroid therapy for ≥ 3 weeks;
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 intent more than 2 years prior to study entry;
8. Prior anti-tumor therapy including:
a. Approved anti-HER2 therapies and/or anti-EGFR approved therapies within 28 days prior to the first scheduled day of dosing with MCLA-128;
b. Investigational therapy administered within 28 days prior to the first scheduled day of dosing with MCLA-128. Dosing with MCLA-128 within 28 days of receiving investigational therapy is acceptable once a time interval equal to at least five half-lives of the investigational agent has passed or in case of prior checkpoint inhibitory treatment;
c. Treatment with chemotherapy agents within 28 days prior to the first scheduled day of dosing with MCLA-128;
9. 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;
10. 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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), end of every two cycles: (Cyc 2 D21, Cyc 4 D21, Cyc 6 D21, Cyc 8 D21…) until end of treatment, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21; EOT; 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 1 - exploratory:
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128.
- Assessment of relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor biopsy material and blood. The following candidate biomarkers will be assessed:
o HER2, HER3, pHER2, pHER3 and heregulin;
o KRAS, NRAS, PIK3CA, BRAF mutation status (metastatic colorectal cancer (mCRC) patients only);
o circulating tumor deoxyribonucleic acid (DNA) and mutations in genes associated with HER2/HER3 signaling;
o phosphorylated molecules in the MAPK and AKT signaling pathway.
Part 2:
- 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
Part 2 - exploratory:
- Assessment of other relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor sample/biopsy material and blood.
- The following candidate biomarkers will be assessed if sufficient sample is available:
Tumor sample:
o pHER2, pHER3, HER2:HER3 dimerization;
o Heregulin and (depending on availability) mutations in genes associated with HER2 and HER3
o Phosphorylated molecules in the MAPK and AKT signaling pathway.
o Heregulin-gene fusions (in case of a validated assay
Blood:
o CD16 (Fcgamma receptor polymorphism)
o Circulating tumor DNA and mutation analysis in genes associated with HER2/HER3 signaling;
o Circulating Tumor Cells for HER2 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK assessed at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1
- Immunogenicity assessed at Cyc 1 D1; Cyc 2-4 D1; EOT; FSV
- Biomarker/PD: Biopsy assessed at Screening (up to 28 days prior to Cyc 1 D1), end of Cyc 2-4, EOT; Blood assessed at Cyc 1 D1 (pre-dose), end of Cyc 2-4, end of every fourth cycle starting cycle 5 and EOT
- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), end of every two cycles: (Cyc 2 D21, Cyc 4 D21, Cyc 6 D21, Cyc 8 D21…) until end of treatment, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21, EOT, 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 | 10 |
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 |
France |
Italy |
Netherlands |
Portugal |
Spain |
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 | 2 |
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 | 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 | 0 |