A Multicenter, Open-label, Phase I/II Dose Escalation and Expansion Clinical Study to Assess the Safety and Efficacy of MGD013 Monotherapy and in Combination With Brivanib Alaninate (ZL-2301) in Patients With Advanced Liver Cancer
Overview
- Phase
- Phase 1
- Intervention
- MGD013 monotherapy
- Conditions
- Advanced Hepatocellular Carcinoma (HCC)
- Sponsor
- Zai Lab (Shanghai) Co., Ltd.
- Enrollment
- 89
- Locations
- 1
- Primary Endpoint
- Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This study consists of two parts: Phase I is a dose escalation study to determine the Recommended Phase II Dose (RP2D) of MGD013 monotherapy and that of MGD013 when in combination with Brivanib Alaninate (ZL-2301) in subjects with advanced liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma). Phase II is a dose expansion study and consists of two parts: Part 1 is to assess the safety and efficacy of MGD013 monotherapy and MGD013 in combination with ZL-2301 in subjects with advanced hepatocellular carcinoma (HCC); in Part 2, a therapeutic method (MGD013 monotherapy or MGD013 in combination with ZL-2301, determined by the sponsor according to the obtained data) will be selected for dose expansion study in HCC subjects who have previously failed immune checkpoint inhibitor treatment, to further evaluate the safety and efficacy of the study treatments in the specific group of subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects who voluntarily sign the informed consent form (ICF);
- •Male or female subjects who are aged 18-75 years old;
- •Subjects with histologic, cytologic or clinical confirmed diagnosis of advanced HCC (Phase I could include intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma), and are not suitable for surgery or loco-regional therapy or have progressed following surgery and/or loco-regional therapy;
- •Subject who has at least one measurable lesion according to RECIST v1.1 criteria.
- •Phase I study: subjects who have previously received at least one line of systemic therapy, including immune checkpoint inhibitors, molecular targeted drugs or systematic chemotherapy, alone or in combination, and failed (progression confirmed by imaging) or were intolerant at the discretion of investigator; PhaseII：Advanced HCC cohort with subjects who have previously received immune checkpoint inhibitor treatment: subjects who have failed (progression confirmed by imaging) prior one line immune checkpoint inhibitor treatment, including anti-PD-1 antibody/anti-PD-L1 antibody and / or anti-CTLA-4 antibody, and/or molecular targeted therapy or systematic chemotherapy (monotherapy or in combination); Phase II: Advanced HCC cohort with subjects who have not previously received immune checkpoint inhibitor treatment: subjects who have failed (progression confirmed by imaging) or were intolerant to (at the discretion of investigator) previous molecular targeted therapy or systematic chemotherapy, without receiving immune checkpoint inhibitor treatment (including anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, and bispecific antibodies including the above targets).
- •Previous anti-tumor therapy must be completed no less than 2 weeks prior to the study treatment and all adverse events related to previous treatment must have recovered to CTCAE Grade ≤1; if subjects who have received prior immune checkpoint inhibitors have immune-related endocrinopathy, it should be controlled with hormone replacement therapy.
- •Phase I: Child-Pugh Class A; Phase II: Child-Pugh Class A or B with a score of ≤ 7;
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
- •Subjects with life expectancy ≥12 weeks;
- •Subjects with chronic HBV infection must have HBV-DNA \<500 IU/ml, and have received at least 14 days of anti-HBV treatment (e.g. entecavir, tenofovir) prior to the initiation of study treatment and are willing to receive antiviral treatment throughout the study; Subjects with RNA-positive HCV must have received standard antiviral treatment and the elevation of their liver enzymes must not exceed the level of CTCAE Grade 1;
Exclusion Criteria
- •Subjects who have known fibrolamellar carcinoma of liver for phase I and subjects who have fibrolamellar carcinoma, mixed HCC- cholangiocarcinoma or cholangiocarcinoma for phase II;
- •Subjects with brain metastasis or leptomeningeal metastasis confirmed by brain MRI during screening period;
- •Subjects with a diagnosis of other malignant tumors within 5 years prior to first administration, except for skin basal cell carcinoma, skin squamous cell carcinoma and/or in situ cancer following radical resection;
- •Subjects who had liver or other sites loco-regional treatment (including transcatheter arterial chemoembolization (TACE), transcatheter arterial embolization (TAE), hepatic artery infusion (HAI), local radiotherapy, radioembolization, radiofrequency ablation, cryoablation or percutaneous ethanol injection) , or who had major surgery of liver or other sites within 4 weeks prior to first administration, or had minor surgical procedures (e.g. simple excision, tooth extraction) within one week prior to first administration, or had received palliative radiotherapy for bone metastasis within 2 weeks and radiotherapy-related toxicity ≥ CTCAE Grade
- •Subjects who have moderate or severe ascites (detected by B-ultrasound or CT), or require therapeutic abdominal paracentesis or drainage;
- •Subjects with a history of hepatic encephalopathy;
- •Subjects with a history of unhealed wounds or ulcers or bone fractures within 3 months prior to study enrollment;
- •Subjects who plan to have or had allogenic organ or bone marrow transplantation;
- •Subjects who are at increased risk of bleeding or have history of thrombosis:
- •(1) Clinically significant bleeding within 3 months prior to screening or clear bleeding tendency; (2) Gastrointestinal hemorrhage within 6 months prior to screening or clear tendency of gastrointestinal hemorrhage; (3) Arterial/venous thromboembolic events within 6 months prior to screening, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, etc.; (4) Require anticoagulation therapy with an agent such as warfarin or heparin; (5) Require chronic anti-platelet therapy (such as aspirin≥100 mg/day, clopidogrel, etc.);
Arms & Interventions
MGD013
MGD013 monotherapy dose escalation and expansion
Intervention: MGD013 monotherapy
MGD013+Brivanib Alaninate
MGD013+Brivanib Alaninate dose escalation and expansion
Intervention: MGD013 in combination with Brivanib Alaninate
Outcomes
Primary Outcomes
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
Time Frame: The first two cycles (Cycle 1 and Cycle 2) of the study treatment(s). A cycle lasted for two weeks (14 days) in the study.
DLT was defined as the adverse events (AEs) listed in the protocol occurring within 4 weeks (the first 2 cycles, 28 days) after the investigational drugs which were at least possibly related to the study drugs. AE severity was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
Phase 1 and Phase 2: Safety
Time Frame: AEs would be collected throughout the clinical trial, from the signing of the informed consent form (ICF) to the end of the trial (until 30 days after the last dose of investigational drugs). Up to approximately 24 months.
All adverse events (AEs) occurring on or after the first study treatment were listed and summarized. Treatment-Emergent Adverse Event (TEAE) was defined as an AE that had an onset date or a worsening in severity from baseline on or after the first dose of study treatment (any component of combination treatment whichever is first) up to 30 days following study treatment (any component of combination treatment whichever was last) discontinuation. All adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
Phase 2: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) According to RECIST 1.1
Time Frame: Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.
ORR was defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), before progression based on RECIST v1.1. Participants who had no measurable disease at baseline and/or no post-baseline tumor assessment due to any reason will be considered nonresponders. An estimate of ORR was calculated for each treatment arm, and its 95% CI was calculated using the Clopper-Pearson method.
Secondary Outcomes
- Phase 2: Duration of Response (DoR) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 2: Overall Survival (OS)(From the date of the first dose of study treatment to the date of death from any cause. Up to approximately 24 months.)
- Phase 1: Objective Response Rate (ORR) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 2: Disease Control Rate (DCR) by BICR / Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at basline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 2: Progression-Free Survival (PFS) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 2: Objective Response Rate (ORR) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 2: Time to Response (TTR) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at baseline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)
- Phase 1: Disease Control Rate (DCR) by Investigator Assessment According to RECIST 1.1(Radiologic examinations were conducted at basline within 28 days prior to the start of study medication and every 8 weeks (±7 days) dated from the first day of the first cycle until disease progression. Up to approximately 24 months.)