E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced NSCLC and other solid tumors |
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E.1.1.1 | Medical condition in easily understood language |
advanced NSCLC and other solid tumors |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 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 |
Phase 1 Dose escalation Primary Objective • To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of single-agent MCLA-129 as well as in combination with chemotherapy in patients with NSCLC, GC/GEJ adenocarcinoma, HNSCC or ESCC, with disease progression after prior therapy for advanced/metastatic disease.
Phase 2 Dose expansion Primary Objective • To evaluate the clinical activity, as assessed by ORR of MCLA-129 alone or in combination with an EGFR TKI or chemotherapy in populations of advanced/metastatic solid tumors. |
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E.2.2 | Secondary objectives of the trial |
Phase 1 Dose escalation; 2ry • Antitumor activity of single-agent MCLA-129 & in combination with chemotherapy in BOR, ORR, DCR, and DoR • PFS & OS of single-agent MCLA-129 & in combination with chemotherapy • PK of MCLA-129 including development of a population PK model • Cytokines following administration of MCLA-129 monotherapy • Immunogenicity of MCLA-129 single-agent & in combination with chemotherapy • Safety and tolerability of MCLA-129 single-agent & in combination with chemotherapy Phase 2 Dose expansion; 2ry • Antitumor activity of single-agent MCLA-129 & in combination with an EGFR TKI or chemotherapy in BOR, DCR, & DoR • PFS & OS of single-agent MCLA-129 & in combination with an EGFR TKI or chemotherapy • Safety & tolerability of MCLA-129 & at the RP2D alone or in combination with an EGFR TKI or chemotherapy • PK of MCLA-129 including development of a population PK model • Immunogenicity of single-agent MCLA-129 & in combination with an EGFR TKI or chemotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent before initiation of any study procedures. 2. Age ≥ 18 years at signature of informed consent. 3. Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced unresected disease that is incurable:
Dose Escalation Part - Patients who have failed prior standard first-line treatment. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens. Patients must have: - Non-small cell lung cancer (NSCLC) harboring activating EGFR mutations including tyrosine kinase inhibitor (TKI) sensitizing mutations (e.g., 19del and L858R), and/or approved TKI-resistance mutations (e.g., acquired TKI-resistance mutations, i.e., T790M, C797S, L792, L798I, exon 20 insertion), or any activating c-MET mutation/amplification (e.g., high-level c-MET amplification [MET/CEP7 > 5 or cfDNA ≥ 2 copies], or c-MET exon 14 skipping mutation). - Gastric/gastroesophageal junction (GC/GEJ) adenocarcinoma harboring an EGFR amplification (EGFR/CEP7 ≥2 or cfDNA ≥ 8 copies) or c-MET amplification (MET/CEP7 > 5 or cfDNA ≥ 2 copies). - Head and neck squamous cell cancer (HNSCC) or esophageal squamous cell cancer (ESCC).
Dose Expansion Part - Patients must have: • Cohort A (closed to recruitment): - NSCLC harboring an EGFR exon 20 insertion, that has progressed after platinum doublets (a limited number of first line patients can be included). Previous treatment with bispecific EGFR/c-MET antibodies is allowed as there is no approved alternative available. • Cohort B: - NSCLC harboring c-MET exon 14 skipping mutation ≥2L - Naive or pretreated to capmatinib and tepotinib • Cohort C (closed to recruitment): - Selected solid tumors (GC/GEJ/pancreas/ESCC, GBM and PRCC) harboring an EGFR or c-MET alteration - NSCLC patients with other EGFR/c-MET alterations, not otherwise included in the other cohorts - Patients must have exhausted or be intolerant to all approved therapies with rationale for clinical benefit with MCLA-129 • Cohort C1 (closed to recruitment): - HNSCC refractory to approved treatment (regardless of driver mutations) • Cohort D (closed to recruitment): - NSCLC 1L harboring EGFR sensitizing mutations (i.e. Del19, L858R) • Cohort E (closed to recruitment): - NSCLC osimertinib resistant (participant must have progressed on or after a previous osimertinib monotherapy) *NOTE: Patient identification will be based on previous treatment history with TKIs, on local tests performed in CLIA-certified laboratories or on commercial diagnostics (e.g., FoundationOne). Genetic aberrations in EGFR or c-MET will be retrospectively confirmed by central testing using a validated assay in the expansion phase. For non-first line cohorts there is no limit to the number of prior treatment regimens. • Cohort F: NSCLC 2L, osimertinib resistant, chemotherapy naïve population • Cohort G NSCLC 3L, osimertinib resistant, platinum resistant (participant must have progressed on or after a previous platinum chemotherapy) population
4. Availability of tissue sample FFPE embedded after progression at the latest therapy (preferred in escalation, mandatory in expansion). Archival tumor tissue collected in the past may also be taken into consideration, but it is not preferred. 5. Measurable disease as defined by RECIST version 1.1 by radiologic methods (patients with non-measurable but evaluable disease can be included in the dose escalation part). 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Life expectancy ≥ 12 weeks, as per Investigator judgment. 8. Adequate organ function, as per Investigator judgment • Absolute neutrophil count (ANC) ≥1.5 X 109/L • Hemoglobin ≥9 g/dL • Platelets ≥100 x 109/L • Corrected total serum calcium within normal ranges • Serum magnesium within normal ranges (or corrected with supplements) • Serum potassium within normal ranges • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN (patients with Gilbert’s syndrome are eligible if conjugated bilirubin value is within normal limits); in cases of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed • Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min calculated according to the Cockcroft and Gault formula or MDRD formula for patients aged >65 years (creatinine clearance ≥60 mL/min if the patient is receiving paclitaxel/carboplatin). If either value is not met, patient cannot be enrolled in the study. • Serum albumin >3.3 g/dL • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 x ULN unless the subject is receiving anticoagulant therapy • Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤1.5 x ULN unless the subject is receiving anticoagulant therapy |
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E.4 | Principal exclusion criteria |
1 Central nerv. system metastases that: -are untreated or symptomatic (patients with untreated, asymptomatic lesions can be included if in the inv. judgment considered clinically & radiologically stable)(exp. phase only) -require radiation or surgery(exp. phase only) -require continued steroid therapy (> 10 mg prednisone or equivalent) to control symptoms within 14 days of study entry 2 Known leptomeningeal involvement(exp. phase only) 3 Participation in another clinical study or treatment with any inv. drug within 4 weeks prior to study entry 5 Systemic anticancer therapy or immunotherapy within 4 weeks or 5 half-lives,whichever is shorter, of the first dose of study drug.For cytotoxic agents that have major delayed toxicity (e.g., mitomycin C, nitrosoureas), a washout period of 6 weeks required. Note: For agents with long half-lives, enrollm. before the fifth half-life requires Sponsor approval. Cohort E patients can continue to receive osimertinib, as last treatm. 6 Major surgery or radiotherapy within 3 weeks of the first dose. Patients who received prior radiotherapy to ≥25% of bone marrow at any time are not eligible. Pats. who received radiotherapy on lung at any time are not eligible 7 Persistent Grade >1 clinically significant toxicities, in Investigator judgment, related to prior antineoplastic therapies (except alopecia); stable sensory neuropathy ≤ Grade 2 NCI-CTCAE v5.0 and hypothyroidism ≤ Grade 2 which is stable on hormone replacement are allowed 8 History of hypersensitivity reaction or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents 9 History of clinically significant cardiovascular disease includ., but not limited to: • Prolonged QT interval > 470 msec (for women) and > 450 msec (for men), obtained from 3 electrocardiograms, or clinically significant cardiac arrythmia, conduction or morphology of resting ECG (ie., complete left bundle branch block, third degree heart block and second degree heart block), or electrophysiologic disease (i.e., placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate) or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities. Pats. with cardiac pacemakers who are clinically stable are eligible • Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years in first-degree relatives or conc. medication known to prolong QT interval and cause Torsades de Pointes • Uncontrolled (persistent) arterial hypertension: systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 100 mm Hg • Congestive heart failure defined as New York Heart Association class III-IV or hospitalization for CHF within 6 months of the first dose 10 Past medical history of interstitial lung disease (ILD) or pneumonitis, or any evidence of clinically active ILD or pneumonitis 11 Previous or concurrent malignancy, excluding non-basal cell carcinomas 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 does not affect the assessment of safety & efficacy of the study drug(exp. phase only) 13 Current serious illness or conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders 14 Active Hepatitis B infection without antiviral treatment 15 Positive test for Hepatitis C ribonucleic acid; Note: Pats. in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those who achieved a sustained virological response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months or ≥ 12 months after cessation of antiviral treatment are eligible 16 Known history of HIV (HIV 1/2 antibodies). Patients with HIV with undetectable viral load are allowed. In patients with HIV, viral RNA load and CD4+ cell count should be monitored per local standard of care (e.g., every 3 months). HIV testing is not required unless mandated by local health authority or regulations 17 Sexually active male & female patients of childbearing potential must agree to use one of the following highly effective birth control methods during entire duration of the study and for 6 months after final administration of MCLA-129: •Combined (estrogen & progestogen) hormonal contraception associated with ovulation inhibition (oral, intravaginal, transdermal) • Progestogen-only hormonal contraception associated with ovulation inhibition (oral, injectable, implantable) • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomized partner • Sexual abstinence 18 Pregnant/breast-feeding women excluded 19 Peripheral neuropathy ≥Grade 2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1 Dose escalation Primary endpoint 1. Incidence and severity of DLTs during Cycle 1.
Phase 2 Dose expansion Primary endpoint 2. ORR per RECIST v.1.1 based on Investigator assessment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 2. Along the study phase 2
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E.5.2 | Secondary end point(s) |
Phase 1 Dose escalation Secondary endpoints 1. Safety: Incidence, severity and relationship of AEs and SAEs; incidence, severity and changes in laboratory values; measures and changes in ECG and vital signs. 2. Tolerability: Discontinuations due to AEs, dose modifications due to AEs. 3. Efficacy: BOR, DCR, DoR, PFS and OS, per RECIST v1.1 based on Investigator assessment and OS. 4. Pharmacokinetics: MCLA-129 concentration CEOI, Cmax, C0h and PK parameters including AUC, CL, Vss, tmax and t1/2 and to develop a population PK model. 5. Immunogenicity: Incidence and serum titers of antidrug antibodies against MCLA-129. 6. Cytokines: Change from baseline in systemic cytokines.
Exploratory endpoints 7. Biomarkers: Change from baseline in biomarkers, and correlative analyses of biomarkers with antitumor response.
Phase 2 Dose expansion Secondary endpoints 8. Efficacy: BOR, DCR, DoR, PFS and OS, per RECIST v1.1 based on Investigator assessment and OS. 9. Safety: Incidence, severity and relationship of AEs and SAEs; incidence, severity and changes in laboratory values; measures and changes in ECG and vital signs. 10. Tolerability: Discontinuations due to AEs, dose modifications due to AEs. 11. Pharmacokinetics: MCLA-129 concentration CEOI, Cmax, C0h, and PK parameters including AUC, CL, Vss, tmax and t1/2 and to develop a population PK model. 12. Immunogenicity: Incidence and serum titers of antidrug antibodies against MCLA-129.
Exploratory: 13. Biomarkers: Change from baseline in biomarkers, and correlative analyses of biomarkers with antitumor response.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2.Along phase1 3.Every 8 wks after start treatment until progression 4.Cycle 1:Day1,4,8,15,22. Cycle 2:Day1&15. Cycle 3:Day1, then every 4 cycles after Day1 5.Day1 Cycles1,2,3 then every 4 cycles & EoT visit 6.Cycle1 only, on Day1 pre-dose, 2,4&22 h post-end of infusion (EOI) and Day15, pre-dose, 2&4 h post-EOI 7.Cycle1:Pre-dose Day1,EOI,22 h post- EOI; Any time on Days4 or 5 & 8; pre-dose and EOI, Day15; Day22 Cycle2:pre-dose & EOI on Days1&15 8.Every 8 wks after start treatment until progression 9,10.Along phase2 11.Cycles1,2,3 then every 4 cycles 12.Day1 Cycles 1,2,3 then every 4 cycles 13.ctDNA:Pre-dose Day 1 Cycle 1. Plasma & Serum PD: Cycle 1: Pre-dose Day 1,EOI,22 h post-EOI; any time on Days 4 or 5,&8; pre-dose & EOI Day 15; Day 22. Cycle 2: pre-dose & EOI on Day 1 & 15 |
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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 | 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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 |
Singapore |
Japan |
Korea, Republic of |
Mexico |
Thailand |
United States |
Belgium |
France |
Germany |
Italy |
Netherlands |
Portugal |
Spain |
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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 study will be closed after the last patient on study has been followed-up for 12 months or initiates a new anticancer treatment, whichever occurs first. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |