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.
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 164
- Locations
- 1
- Primary Endpoint
- Dose-Limiting Toxicity (DLT) in Phase I
Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
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.
Arms & Interventions
Patients with locally advanced NSCLC.
Patients with locally advanced NSCLC with previously detected EGFR-sensitizing mutations (exon 19 deletion or exon 21 L858R mutation) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: MCLA-129 (Drug)
Patients with locally advanced NSCLC.
Patients with locally advanced NSCLC with previously detected EGFR-sensitizing mutations (exon 19 deletion or exon 21 L858R mutation) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: Ensartinib (Drug)
Patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck.
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) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: MCLA-129 (Drug)
Patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck.
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) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: Ensartinib (Drug)
Patients with locally advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma
Patients with locally advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma (including signet ring cell carcinoma, mucinous adenocarcinoma, hepatoid adenocarcinoma) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: MCLA-129 (Drug)
Patients with locally advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma
Patients with locally advanced or metastatic gastric cancer/gastroesophageal junction adenocarcinoma (including signet ring cell carcinoma, mucinous adenocarcinoma, hepatoid adenocarcinoma) who have progressed after prior standard treatment and with MET amplification or overexpression.
Drug: MCLA-129 and Ensartinib MCLA-129 will be administered intravenously at two different frequencies: 1500 mg every two weeks and 2000 mg every three weeks, in combination with Ensartinib.
Ensartinib will be administered orally at 200 mg every day; if dose-limiting toxicity (DLT) is observed and deemed intolerable, a lower dose of 150 mg will be explored in combination with MCLA-129.
Other Names:
- MCLA-129 and Ensartinib Hydrochloride
- MCLA-129 and Ensacove
Intervention: Ensartinib (Drug)
Outcomes
Primary Outcomes
Dose-Limiting Toxicity (DLT) in Phase I
Time Frame: Until 28 days after the first dosing in MCLA-129 1500mg Q2W group or 21 days after the first dosing in MCLA-129 2000mg Q3W group
To evaluate the safety of MCLA-129 in combination with Ensartinib hydrochloride in patients with advanced solid tumors in terms of dose-limiting toxicity (DLT)
Maximum Tolerated Dose (MTD) in Phase I
Time Frame: From date of first treatment until the end of Phase I, approximately 6 months
To evaluate the safety of MCLA-129 in combination with Ensartinib hydrochloride in patients with advanced solid tumors in terms of maximum tolerated dose (MTD)
Treatment-Emergent Adverse Events (TEAE) in Phase I
Time Frame: From date of first treatment until 30 days after the last dose or the start of other anti-tumor treatment (whichever occurs first)
To evaluate the safety of MCLA-129 in combination with Ensartinib hydrochloride in patients with advanced solid tumors in terms of treatment-emergent adverse event (TEAE)
Overall Response Rate (ORR) in Phase II
Time Frame: From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years
To evaluate the efficacy of MCLA-129 in combination with Ensartinib hydrochloride at RP2D in patients with advanced solid tumors in each cohort in Phase II in terms of overall response rate (ORR)
Secondary Outcomes
- Clinical benefit rate (CBR) in Phase I and II(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 Phase I and II(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 Phase I and II(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 Phase I and II(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 Phase I and II(From date of first treatment every 6 weeks until disease progression, death or withdrawal, whichever came first, approximately 2 years)
- Overall Survival (OS) in Phase II(From date of first treatment every 6 weeks until death or withdrawal, whichever came first, approximately 2 years)
- Treatment-Emergent Adverse Event (TEAE) in Phase II(Until 30 days after the last dosing)
- Area under the concentration versus time curve [AUC0-∞] in Phase I(Until 30 days after the last dosing)
- Anti-Drug Antibody (ADA) in Phase I and II(Until 30 days after the last dosing)