Study of MCLA-129, a Human Bispecific EGFR and cMet Antibody, in Patients With Advanced NSCLC and Other Solid Tumors

Official title

A Phase I/II Study of MCLA-129, a Human Anti-EGFR and Anti-c-Met Bispecific Antibody, in Patients With Advanced NSCLC and Other Solid Tumors, Evaluating Safety, Pharmacokinetic Characteristics and Antitumor Activity

Overview

This is a multi-center, open-label, Phase I/II clinical study of MCLA-129 as monotherapy in patients with advanced solid tumors to evaluate the safety, pharmacokinetic characteristics and antitumor activity of MCLA-129.

Detailed description

This is a multicenter, open-label, single-agent phase I/II clinical study of MCLA-129 in patients with advanced solid tumors to evaluate the safety, pharmacokinetic profile, and antitumor activity of MCLA-129. The study consists of two parts: Part I is a phase I dose- finding study in patients with advanced solid tumors, including a dose escalation phase and a dose expansion phase; Part II is a phase II parallel cohort expansion study to further evaluate the efficacy, safety and PK profile of MCLA-129 in sub-cohorts of patients with advanced non-small cell lung cancer and other solid tumors.

Interventions

• Drug MCLA-129
  MCLA-129 will be administered by intravenous infusion on the 28-day treatment cycle.

Primary outcome measures

• Dose-Limiting Toxicity (DLT) in Part 1 [Time frame: First 28 days of treatment]
• Maximum Tolerated Dose (MTD) in Part 1 [Time frame: First 28 days of treatment]
• Overall Response Rate (ORR) in Part 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Treatment-Emergent Adverse Event (TEAE) in Part 1 and 2 [Time frame: Until 30 days after the last dosing]

Secondary outcome measures (12)

• Half-life [t1/2] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Apparent volume of distribution [VSS] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Maximum plasma concentration [Cmax] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Time to reach maximum concentration [Tmax] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Area under the concentration versus time curve from time zero to time t [AUC0-t] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Area under the concentration versus time curve [AUC0-∞] in Part 1 and 2 [Time frame: Until 30 days after the last dosing]
• Overall Response Rate (ORR) in Part 1 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Disease Control Rate (DCR) in Part 1 and 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Progression-Free Survival (PFS) in Part 1 and 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Clinical benefit rate (CBR) in Part 1 and 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Duration of Response (DOR) in Part 1 and 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]
• Time to response (TTR) in Part 1 and 2 [Time frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years]

Eligibility criteria

Inclusion criteria

• Subjects are ≥ 18 years of age, regardless of gender.
• Subjects must have histologically or cytologically confirmed metastatic or unresectable advanced NSCLC or other solid tumors (including but not limited to head and neck cancer, colorectal cancer, etc.), have disease progression after standard treatment, or are intolerant to standard treatment, or refuse standard treatment (Refusal of standard treatment does not apply to Part 2).
• For Part 1, subjects must be diagnosed with EGFR positive and/or MET positive by testing.

For patients with advanced NSCLC, EGFR positive is defined as: EGFR mutation or EGFR amplification. MET positive is defined as: MET amplification or MET exon 14 skipping mutation.

For patients with other advanced solid tumors other than NSCLC, EGFR positive is defined as: High EGFR expression or EGFR amplification. MET positive is defined as: c-Met high expression or MET amplification.

• For Part 2, patients shall meet the inclusion criteria for each cohort by biomarker testing.

Cohort A: Patients with advanced NSCLC who are previously diagnosed with EGFR mutations and treated with third-generation EGFR-TKIs for drug resistance.

Cohort B: Advanced NSCLC patients diagnosed with EGFR exon 20 insertion mutation (Exon20ins).

Cohort C: Advanced NSCLC patients with MET amplification. Cohort D: Advanced NSCLC patients with MET exon 14 skipping mutation (Exon14 skipping).

Cohort E: Patients with locally advanced or recurrent metastatic colorectal cancer (CRC) could not undergo curative treatment.

Cohort F: Other advanced solid tumors that have failed or are intolerant to standard therapy.

Cohort G: Patients with locally advanced or metastatic MET-amplified or MET-overexpressing other driver gene-negative non-small cell lung cancer, gastric/gastroesophageal junction adenocarcinoma \[including signet ring cell carcinoma, mucinous adenocarcinoma, and hepatoid adenocarcinoma\], or recurrent/metastatic \[R/M\] head and neck squamous cell carcinoma \[primary sites: oral cavity, oropharynx, hypopharynx, or larynx\], who are not candidates for curative treatment.

• For subjects in the dose escalation phase of Part 1, evaluable lesions must be present; other subjects must have measurable lesions that meet the definition of 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

• For colorectal cancer subjects, HER-2 positivity (IHC 2+/3+ or FISH/NGS+) confirmed by local or central laboratory genetic testing.
• Have received an investigational product or anti-tumor drug treatment within 14 days before the first dose of MCLA-129 or within 5 half-lives of the drug (whichever is longer). For cohort E1, the interval between the last dose of EGFR monoclonal antibody and the first dose of MCLA-129 was less than 6 months.
• Have undergone a major surgery and radiotherapy (local palliative radiotherapy is allowed 2 weeks or more prior to the first dose) within 4 weeks prior to the first dose of MCLA-129.
• For patients with colorectal cancerr, head and neck squamous cell carcinoma, or gastric/gastroesophageal junction adenocarcinoma: patients who have previously received systemic anti-tumor therapy beyond the third line (excluding maintenance therapy).
• For subjects with non-small cell lung cancer only: have received more than 2 prior lines of cytotoxic chemotherapy for locally advanced or metastatic diseases (excluding maintenance therapy).
• For advanced NSCLC patients with EGFR Exon20ins mutation: have received prior EGFR-TKI therapy (e.g., poziotinib, TAK-788, DZD9008, CLN-081, or furmonertinib, etc.) that is known to be effective against Exon20ins.
• Prior use of EGFR/c-Met bispecific antibody or ADC drugs (such as Amivantamab, EMB-01, GB263T, PM1080/HS-20117, TAVO412, YH013/ DM005, SHR-9839 or AZD9592 etc.).
• Prior to the first dose of MCLA-129, previous treatment-related toxicities have not resolve to Grade 1 or below (CTCAE 5.0 criteria), except for alopecia.
• Have had other malignancies within the past 3 years, except for cancers that have been totally cured or locally cured, such as basal or squamous cell carcinoma of the skin, cervical cancer in situ, or breast cancer in situ.
• Patients with primary malignant tumor of central nervous system, or metastases to meninges, spinal cord compression, or at risk of cerebral hemorrhage, or concomitantly with symptomatic brain metastases, or new therapy naive brain metastases. For cohorts E, F and G (excluding NSCLC patients): Patients with known brain metastases and/or meningeal metastases, or primary malignant tumor of central nervous system. Subjects with neurological symptoms shall have a brain CT/MRI scan to exclude brain metastases.
• With clinically significant cardiovascular and cerebrovascular diseases.
• Active hepatitis B (positive hepatitis B surface antigen (HBsAg) or core antibody (HBcAb) and serum HBV DNA ≥ 2,000 IU/mL \[equivalent to 104 copies/mL\]), positive hepatitis C virus antibody, HIV antibody and treponema pallidum antibody.
• Subjects with a history of interstitial lung disease or current clinical evidence of interstitial lung disease, including drug-induced Interstitial lung disease, radiation pneumonitis or pulmonary fibrosis. Subjects who could not be ruled out for suspected interstitial lung disease/pulmonary fibrosis through imaging examinations during screening, or those with uncontrolled/unstable non-infectious pneumonitis/pulmonary inflammation are excluded.
• Presence of a serious disease or medical condition currently, including but not limited to uncontrolled active infection, uncontrolled pleural or peritoneal effusion, unstable/uncontrolled tuberculosis, active gastrointestinal diseases, gastrointestinal obstruction or perforation risks, and clinically significant pulmonary, metabolic or psychiatric diseases.
• Females of childbearing potential, pregnant or breastfeeding women with a positive serum pregnancy test 7 days before the start of treatment, and male and female subjects who are unwilling to use effective contraceptive measures or plan to have a child throughout the treatment period and within 3 months after the end of treatment.
• Patients with known allergic reactions and hypersensitivity reactions, or be allergic to MCLA-129 or any of its excipients.
• Patients with poor compliance, inability or unwillingness to follow the study and/or follow-up procedure listed in the protocol, or patients who are not suitable to participate in this trial, as determined by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 87 centers

• Affiliated Hospital of Hebei University — Baoding
• Beijing Cancer Hospital — Beijing
• Beijing Friendship Hospital, Capital Medical University — Beijing
• Beijing Tongren Hospital — Beijing
• Cancer Institute and Hospital, Chinese Academy of Medical Sciences — Beijing
• Peking University International Hospital — Beijing
• The Fifth Medical Center of PLA Ceneral Hospital — Beijing
• The First Affiliated Hospital of Bengbu Medical College — Bengbu
• … and 79 more centers

Identifiers

NCT: NCT04930432 · BTP-21711

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗