Phase 1/2 dose escalation and expansion study evaluating MCLA-129, a human anti-EGFR and anti-c-MET bispecific antibody, in patients with advanced NSCLC and other solid tumors

EGFR and c-MET are frequently mutated or overexpressed in epithelial tumors,
driving ligand-independent receptor activation. This is associated with tumor
invasion, metastasis, resistance to chemotherapy and poor prognosis. Mutations
in EGFR have been identified in several tumor types, notably in non-small cell
lung cancer (NSCLC). These tumors are currently treated with EGFR tyrosine
kinase inhibitors (EGFR TKIs), however ultimately develop resistance.
Dysregulation of c-MET has also been identified as a key driver of tumor
invasion, angiogenesis, and metastasis. c-MET overexpression has been reported
in NSCLC (15-70%) and gastroesophageal adenocarcinoma (4-10%), however single
agent anti-c-MET antibodies show low anti-cancer activity. Acquired high-level
c-MET amplifications offer an escape mechanism of resistance for tumors under
selective pressure of EGFR targeted therapy. High-level c-MET amplification has
been identified in 5-20% of NSCLC patients with sensitizing EGFR mutations
treated with EGFR TKIs.
MCLA-129 is a common light chain human full length IgG1 bispecific antibody
that specifically targets the receptor tyrosine kinases EGFR and c-MET with
enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. MCLA-129 was
developed to overcome EGFR TKI resistance mechanisms associated with c-MET
signaling. NSCLC patients with cancers harboring EGFR and c-MET alterations and
with disease progression following available first and/or later generation EGFR
TKIs lack effective therapies. MCLA-129 will be evaluated in advanced NSCLC
patients with a tumor harboring EGFR mutations or amplifications and/or c-MET
mutations or amplifications, as well as in patients with other solid tumors
harboring EGFR amplifications and/or c-MET amplifications, including
gastric/gastroesophageal junction (GC/GEJ), head and neck squamous cell cancer
(HNSCC) adenocarcinoma, and esophageal squamous cell cancer (ESCC).

This study has been transitioned to CTIS with ID 2024-514461-19-00 check the CTIS register for the current data.

Phase 1 - Primary Objective
• To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose
(RP2D) of single-agent MCLA-129 in patients with NSCLC, GC/GEJ adenocarcinoma,
HNSCC or ESCC, with disease progression after prior therapy for
advanced/metastatic disease.

Phase 1 - Secondary Objectives
• To evaluate preliminary antitumor activity in terms of best overall response
(BOR), overall response rate (ORR), disease control rate (DCR), and duration of
response (DoR).
• To evaluate progression-free survival (PFS) and overall survival (OS).
• To characterize the pharmacokinetics (PK) of MCLA-129 including development
of a population PK model.
• To assess changes in cytokines following administration of MCLA-129.
• To assess the immunogenicity of MCLA-129.

Phase 2 - Primary Objective
• To evaluate the ORR in molecularly defined populations of advanced/metastatic
solid tumors including NSCLC, GC/GEJ adenocarcinoma, and other selected solid
tumors selected according to their molecular profile.

Phase 2 - Secondary Objectives
• To evaluate preliminary antitumor activity in terms of BOR, DCR, and DoR.
• To evaluate PFS and OS.
• To characterize the safety and tolerability of MCLA-129 at the RP2D.
• To characterize the PK of MCLA-129 including development of a population PK
model.
• To assess the immunogenicity of MCLA-129.

A phase 1/2 open-label multicenter study will be performed with an initial dose
escalation part to determine the MTD and/or the RP2D of MCLA-129 as monotherapy
in patients with NSCLC (harboring an activating EGFR mutation or activating
c-MET mutation/amplification), GC/GEJ adenocarcinoma (harboring an EGFR or
c-MET amplification), or HNSCC or ESCC (all-comers), and who have progressed
after receiving prior therapy for advanced/metastatic disease.
Once the RP2D is determined, a cohort expansion part evaluating MCLA-129
monotherapy will be initiated to evaluate the ORR at the RP2D in molecularly
defined selected populations of advanced/metastatic solid tumors, including
NSCLC (defined in terms of the EGFR/c-MET molecular profile), GC/GEJ
adenocarcinoma, and other solid tumors (with EGFR amplification or high-level
c-MET).
Additional efficacy parameters will be evaluated, and safety, pharmacokinetics
(PK), cytokines, and immunogenicity of MCLA-129 as monotherapy will be
characterized, and retrospective biomarker analyses including evaluation of
EGFR and c-MET target expression will be performed.
The Sponsor and Investigators will review data throughout the study and the
Sponsor in conjunction with the Investigators will decide on dose-limiting
toxicities (DLTs), addition of extra patients, dose escalation, opening of
expansion cohorts, and ad hoc safety decisions including the modification of
dosing increments and dosing frequency.

DOSE ESCALATION
In the dose escalation phase 1 part, MCLA-129 will be administered with
increasing doses to patients with NSCLC harboring an activating EGFR mutation
(TKI sensitizing mutations and/or approved TKI-resistance mutations) or an
activating c-MET mutation (exon 14 skipping)/amplification (MET/CEP7 > 5 or
cfDNA >= 2 copies), patients with GC/GEJ adenocarcinoma with an activating EGFR
amplification (EGFR/CEP7 >= 2 or cfDNA >= 8 copies) or c-MET amplification
(MET/CEP7 > 5 or cfDNA >= 2 copies), or patients with HNSCC or ESCC
(all-comers), who in all cases, have progressed after receiving prior therapy
for advanced/metastatic disease.
Allometric scaling of a preclinical PK model was used to predict MCLA-129
exposure in humans. The MCLA-129 starting dose is 100 mg (flat dose,
intravenously) once every 2 weeks (q2w), with 4-week cycles (28 days). Five
dose levels are planned to be investigated as follows: 100, 300, 600, 1000, and
1500 mg.
Cohorts of patients will be treated with MCLA-129 until the MTD is reached or a
lower recommended dose(s) is established. The dose escalation will be guided by
an adaptive Bayesian logistic regression model (BLRM), according to the
*escalation with overdose control* principle. During the course of the dose
escalation, additional cohorts of up to 6 patients may be enrolled at any
planned or intermediate dose level below the next dose level or the MTD, to
better characterize safety, PK, and/or pharmacodynamic activity.
Enrollment will commence at dose level 1 (MCLA-129, 100 mg q2w) with the option
to escalate or de-escalate at higher doses based on defined criteria. DLTs
occurring up to and including Day 28 will guide dose escalation/de-escalation
and determination of the RP2D or MTD. If the lowest dose level is not deemed
safe, then enrollment will be halted.
The MTD is defined as the highest dose not expected to cause DLT in >= 33% of
patients in the first 28 days of MCLA-129 treatment during the dose escalation
portion of the study. Based on the BLRM, the MTD has the highest posterior
probability of being in the target DLT rate (16% to < 33%), where the posterior
probability of excessive toxicity (>= 33%) is less than 25%.
The RP2D is defined as the dose at or below the MTD, taking into account
available data for PK, pharmacodynamic activity, and preliminary antitumor
activity.

Dose-limiting toxicity
Any of the following clinical adverse events (AEs) and/or laboratory
abnormalities, excluding those clearly related to disease progression or
intercurrent illness, occurring during the first cycle (28 days), will be
considered a DLT:
• Hematologic toxicities of:
- Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 x109 cells/L) for
>=7 days
- Grade 3-4 febrile neutropenia
- Grade 3 thrombocytopenia associated with bleeding episodes
- Grade 4 thrombocytopenia
- Other grade 4 hematologic toxicity
• Any grade 4 infusion-related reactions (IRR) and grade 3 infusion IRRs that
are either prolonged (i.e., not rapidly responsive to symptomatic medication
and/or brief interruption of infusion) or recurrent (recurrence of symptoms
following initial improvement).
• Steven-Johnson syndrome (SJS) regardless of grade or duration.
• Any liver function abnormalities that meet the definition of Hy*s law.
• Grade 4 increase in amylase or lipase regardless of duration.
• Other grade 3-4 non-hematologic AEs and laboratory toxicities, with the
exception of:
- Grade 3 skin toxicity that recovers to grade <=2 within 2 weeks with
optimal treatment
- Grade 3 diarrhea, nausea and/or vomiting that recovers to grade <=1 or
baseline within 3 days with optimal treatment
- Grade 3 electrolyte abnormalities that resolve with optimal treatment
within 48 hours, and other abnormal laboratory values without associated
clinically significant signs and symptoms that recover to grade <=1 or baseline
with appropriate management or supplementation within 72 hours of onset of
treatment.
• Any AE that results in a dose delay or interruption that prevents the next 2
study drug administrations.

DOSE EXPANSION
Once the RP2D has been determined, the planned expansion cohorts in the phase 2
part can be initiated. The safety of the RP2D will be confirmed during dose
expansion in the first 12 patients treated for at least 2 cycles in any of the
planned expansion cohorts. Antitumor activity of MCLA-129 monotherapy will be
evaluated in terms of ORR, and an evaluation of other efficacy parameters,
safety, tolerability, PK, immunogenicity, and biomarkers will be performed.

The following cohorts of locally advanced unresectable/metastatic solid tumors
including NSCLC (defined in terms of the EGFR/c-MET molecular profile), GC/GEJ
adenocarcinoma, and other solid tumors (with EGFR amplification or high-level
c-MET) may be opened:
• Cohort A: NSCLC harboring an EGFR exon 20 insertion
• Cohort B: NSCLC harboring an acquired EGFR C797S TKI resistance mutation
• Cohort C: NSCLC harboring a c-MET amplification (c-MET/CEP7 > 5 copies or
cfDNA >= 2 copies)
• Cohort D: GC/GEJ adenocarcinoma or other selected solid tumors harboring an
EGFR amplification (EGFR/CEP7 >=2 or cfDNA >= 8 copies) or a c-MET amplification
(c-MET/CEP7 > 5 copies or cfDNA >= 2 copies)

Initial enrollment per cohort will be limited to 20 patients. If at least 3
patients per cohort have a confirmed response, the cohort may be expanded to a
total of up to 40 patients to further characterize clinical activity.

MCLA-129 will be administered as an IV infusion, once every 2 weeks (q2w) with
4-week cycles.

MCLA-129 may treat the subject's cancer, but that is not certain. The cancer
may come back or get worse at any time during this study.

Taking part in the study can have these cons: :
- Side effects or adverse effects of Study Drug and Study visits and
procedures, as described in Section 6 and Appendix D in the informed consent
form.
- Taking part in the study will cost extra time.
- You may need to be hospitalised. Or longer than usual.
- You have to comply with the study agreements.