Study of MCLA-129 in Combination With Ensartinib in Patients With Advanced Solid Tumors.

A Multi-cohort, Open-label Phase I/II Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of the Anti-EGFR/c-Met Bispecific Antibody MCLA-129 in Combination With Ensartinib Hydrochloride in Patients With Advanced Solid Tumors.

This is a multicenter, open-label Phase I/II clinical study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of the anti-EGFR/c-Met bispecific antibody MCLA-129 in combination with Ensartinib hydrochloride in patients with advanced solid tumors.

This is a multi-center, open-label Phase I/II clinical study of MCLA-129 in combination with ensartinib in patients with advanced solid tumors to evaluate the efficacy, safety, and pharmacokinetics of MCLA-129 in combination with ensartinib. The study is divided into two parts: Phase I is a dose-exploration study to confirm the safe tolerability and recommended Phase II combination dose (RP2CD) of MCLA-129 in combination with ensartinib, and Phase II is a parallel cohort expansion study to further evaluate the efficacy, safety, and pharmacokinetics (PK) of MCLA-129 in combination with ensartinib in patients with advanced solid tumors in cohorts.

Primary Objectives of Phase I:

To evaluate the safety and tolerability of MCLA-129 in combination with ensartinib in patients with advanced solid tumors, and to determine potential dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) To determine the recommended Phase II combination dose (RP2CD) of MCLA-129 in combination with ensartinib.

Secondary Objectives of Phase I:

To evaluate the pharmacokinetic (PK) profile of MCLA-129 in combination with ensartinib in patients with advanced solid tumors To preliminarily evaluate the efficacy of MCLA-129 in combination with ensartinib in patients with advanced solid tumors To evaluate the immunogenicity of MCLA-129

Primary Objectives of Phase II:

To evaluate the efficacy of MCLA-129 in combination with ensartinib at the RP2CD in patients with advanced solid tumors across different cohorts.

Secondary Objectives of Phase II:

To evaluate the safety of MCLA-129 in combination with ensartinib at the RP2CD in patients with advanced solid tumors.

To evaluate the immunogenicity of MCLA-129.

Inclusion Criteria:

• Subjects should be aged 18-75 years (both inclusive), regardless of gender.
• Subjects must have histologically or cytologically confirmed, locally advanced or metastatic solid tumors (including but not limited to non-small cell lung cancer, squamous cell carcinoma of the head and neck (primary site of oral cavity, oropharynx, hypopharynx, or larynx), gastric/gastroesophageal junction adenocarcinoma, etc.) that are not amenable to curative therapy.
• Subjects must have MET amplification or MET overexpression as confirmed by the tests conducted by local or central laboratory.[MET amplification for Cohort 1 and Cohort 3 is defined as: MET copy number (CN) ≥ 5 by next-generation sequencing (NGS); or MET gene copy number (GCN) ≥ 5 or MET/CEP7 ≥ 2 by fluorescence in situ hybridization (FISH). MET amplification for Cohort 2 is defined as: MET copy number (CN) ≥ 3 by next-generation sequencing (NGS); or MET gene copy number (GCN) ≥ 3 or MET/CEP7 ≥ 2 by fluorescence in situ hybridization (FISH). MET overexpression is defined as 2+ or 3+ staining of ≥50% of tumor cells in tumor tissue samples by immunohistochemistry (IHC).]
• For phase I study: subjects must meet the following conditions: with disease progression or intolerance to standard treatment after standard treatment, or evaluated by the investigator as ineligible for platinum-based chemotherapy (the standard treatment for the patient population enrolled in each cohort can refer to that for the phase II cohort study).
• For phase II study, each cohort is defined as follows:

Cohort 1: Patients with locally advanced or metastatic non-small cell lung cancer with confirmed MET amplification or MET overexpression. Prior treatment should meet the following criteria: 1) If a previous test had identified an EGFR-sensitizing mutation (exon 19 deletion or exon 21 L858R mutation), the following requirements must be met: a) Disease progression after treatment with a third-generation EGFR-TKI and platinum-based chemotherapy ± PD-1/PD-L1 inhibitor, or intolerance to such treatment, or deemed unsuitable for platinum-based chemotherapy by the investigator; or b) Disease progression after first-or second-generation EGFR-TKI treatment with T790M mutation-negative or unknown gene mutation status, followed by disease progression after treatment with platinum-based chemotherapy ± PD-1/PD-L1 inhibitor, or intolerance to such treatment, or deemed unsuitable for platinum-based chemotherapy by the investigator. 2)If a previous test had identified an EGFR non-sensitizing mutation or MET exon 14 skipping mutation, disease progression after treatment with the corresponding inhibitors and platinum-based chemotherapy ± PD-1/PD-L1 inhibitor is required, or intolerance to such treatment, or deemed unsuitable for platinum-based chemotherapy by the investigator. 3)If no other driver gene alterations were identified in previous tests, disease progression after treatment with platinum-based chemotherapy ± PD-1/PD-L1 inhibitor is required, or intolerance to such treatment, or deemed unsuitable for platinum-based chemotherapy by the investigator.

Cohort 2: Patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (primary site in the oral cavity, oropharynx, hypopharynx, or larynx) with confirmed MET amplification or MET overexpression. Patients must have experienced disease progression or intolerance after previous treatment of platinum-based chemotherapy ± PD-1/PD-L1 inhibitor/EGFR monoclonal antibody therapy.

Cohort 3: Locally advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma (including signet ring cell carcinoma, mucinous adenocarcinoma, hepatoid adenocarcinoma) with detected MET amplification or MET overexpression. Prior treatment should meet the following criteria:1)Disease progression or intolerance after treatment with a chemotherapy regimen consisting of platinum agents (cisplatin or oxaliplatin),paclitaxel/docetaxel, and fluoropyrimidines (5-FU,capecitabine or S-1),with or without PD-1/PD-L1 inhibitor;2)For patients with HER-2 positivity, disease progression after treatment with anti-HER-2 agents is required, or intolerance to such treatment, or deemed unsuitable for anti-HER-2 treatment by the investigator;3)For patients with Claudin 18.2 expression, disease progression after treatment with anti-Claudin 18.2 agents is required, or intolerance to such treatment.

• Subjects in the phase I dose-exploration study must have evaluable lesions; other subjects (including dose-backfill stage in phase I and phase II) must have measurable lesions as per RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Expected survival ≥ 3 months.
• Have adequate organ function (no blood transfusion or use of blood component or G-CSF support within 14 days before testing)
• Willing and able to follow the trial and follow-up procedures.
• Able to understand the nature of the trial and voluntarily sign the written informed consent form.

Exclusion Criteria:

• Subjects with non-small cell lung cancer who have been tested positive for ALK in the genetic tests conducted by the local or central laboratory.
• Subjects have received any investigational drug or antitumor agent (for drugs with a long half-life, the time interval since the last dose should be no more than 4 weeks; for chemotherapy with delayed toxicity, such as nitrosoureas or mitomycin C, within the previous 6 weeks) within 14 days prior to the first dose of the study drug or within 5 half-lives of the drug (whichever is longer). Subjects have used any traditional Chinese medicine or Chinese herbal preparations with antitumor indications or definitive antitumor effects within 14 days prior to the first dose of the study drug.
• Subjects who have undergone any major surgery or radiotherapy within 4 weeks prior to the first dose of the study drug (palliative local radiotherapy is allowed if it was administered at least 2 weeks prior to the first dose of the study drug).
• For subjects with non-small cell lung cancer, prior receipt of more than two lines of systemic chemotherapy is required; for subjects with squamous cell carcinoma of the head and neck and gastric cancer/gastroesophageal junction adenocarcinoma, prior receipt of more than three lines of systemic anti-tumor treatment (excluding maintenance therapy) is required. For subjects who have received neoadjuvant/adjuvant therapy (chemotherapy or radio chemotherapy), if recurrence or metastasis occurs during treatment or within 6 months after discontinuation of treatment, it should be considered as first-line treatment.
• Prior use of EGFR/c-Met bispecific antibody or ADC drugs.
• Subjects who require concomitant use of strong CYP3A inhibitors or inducers within 14 days before the first administration of the investigational drug or during the study period.
• Toxicities related to prior treatment have not resolved to Grade 1 or below (CTCAE 5.0 criteria) prior to the first dose of the study drug, except for alopecia.
• Subjects who have had other malignancies within the past 3 years, except for malignancies that have been clearly cured or are locally curable, such as basal or squamous cell skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast.
• Cohort 1: Patients with primary central nervous system malignancy, or presence of meningeal metastases, or presence of spinal cord compression, or risk of cerebral hemorrhage, or symptomatic brain metastases, or unstable brain metastases requiring treatment with steroids and/or dehydration to reduce cranial pressure 2 weeks prior to enrollment.

Cohorts 2 and 3: Patients with known brain and/or meningeal metastases, or primary central nervous system malignancies are excluded. Subjects with neurological symptoms shall have a brain CT/MRI scan to exclude brain metastases.

• Subjects with clinically significant abnormal cardiovascular or cerebrovascular diseases, including but not limited to: Subjects with arterial thromboembolism, deep vein thrombosis, or pulmonary embolism within 3 months prior to the first dose of the study drug. Clinically insignificant non-obstructive catheter-related clots are not deemed as constituting an exclusion criterion. Subjects with a history of other venous thrombosis must be clinically stable for at least 4 weeks prior to the first dose of the study drug.

Subjects with any of the following medical history within 6 months prior to the first dose of the study drug: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, transient myocardial ischemia, coronary or peripheral artery bypass grafting (including coronary intervention), or any acute coronary syndrome.

With abnormal ECG corrected QT interval (QTcF) of ECG at rest in the screening period, with the test been repeated twice at an interval 5 minutes above, and with the average QTcF of three ECG examinations: ≥ 450 msec for male, and ≥ 470 msec for female. Various clinically significant abnormalities in rhythm, conduction, resting ECG morphology within 3 months prior to the first dose of investigational drug, such as complete left bundle branch block, third degree block, second degree block, PR interval >250 msec, bigeminy, trigeminy, pre-excitation syndrome, ST-segment elevation, atrial fibrillation, ventricular fibrillation, etc.

Poorly controlled hypertension judged by investigators (systolic blood pressure > 180 mmHg, or diastolic blood pressure > 100 mmHg).

New York Heart Association (NYHA) Class III-IV congestive heart failure (see Appendix 2) or hospitalization for congestive heart failure within 6 months prior to the first dose of investigational drug; left ventricular ejection fraction (LVEF) <50%.

Pericarditis/clinically significant pericardial effusion. Subjects with cardiomyopathy, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and myocarditis.

Subjects with other clinically significant cardiovascular or cerebrovascular diseases.

• Subjects with active hepatitis B (HBsAg positive and serum HBV DNA quantitative results ≥ the lower limit of detection (as per criteria of local laboratory)); positive for anti-hepatitis C virus antibody, anti-HIV antibody, or anti-treponema pallidum antibody (subjects with a history of HCV who have completed antiviral treatment and have laboratory test results showing HCV-RNA below the lower limit of quantification are eligible for enrollment; and subjects with negative syphilis titer tests are eligible for enrollment).
• Subjects with a history of interstitial lung disease or current clinical evidence of interstitial lung disease/pneumonia, including but not limited to drug-induced interstitial lung disease/pneumonia, radiation pneumonitis, or pulmonary fibrosis. Patients who cannot exclude suspected interstitial pneumonia/pulmonary fibrosis or uncontrolled stable non-infectious pneumonia/pulmonary inflammation by imaging examination during screening are not eligible for enrollment.
• Subjects with current severe illness or medical conditions, including but not limited to uncontrolled or poorly controlled active infections, uncontrolled pleural or peritoneal effusion, unstable tuberculosis, or other clinically significant pulmonary, metabolic, or psychiatric disorders.
• Subjects with gastric cancer/gastroesophageal junction adenocarcinoma with signs of active bleeding, active gastrointestinal (GI) diseases, or risk of gastrointestinal (GI) perforation, or other diseases that can significantly interfere with the absorption, distribution, metabolism, or excretion of the investigational drug.
• Subjects with hepatic encephalopathy, hepatorenal syndrome, or ≥ Child-Pugh class B cirrhosis.
• Women of childbearing potential with a positive serum pregnancy test within 7 days prior to the initiation of treatment, pregnant or breastfeeding women, and male or female subjects unwilling to use effective contraception or plan for pregnancy during the entire treatment period and for 3 months after treatment completion (see Appendix 3 for guidelines on contraception).
• Subjects with a history of allergy or suspected allergic symptoms to the study drug MCLA-129 or ensartinib or tartrazine (a dye used in ensartinib 100 mg capsules) or any other component or excipient
• Subjects judged by the investigator to have poor compliance, inability or unwillingness to adhere to the study and/or follow-up procedures listed in the protocol, or otherwise unsuitable for participation in this study.