A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma

Phase 2TerminatedNCT05908786

Hoffmann-La Roche62 enrolled

Overview

This is a Phase Ib/II, open-label, multicenter, randomized platform study to evaluate neoadjuvant immunotherapy combinations in participants with resectable HCC. The study is designed with the flexibility to open new treatment arms as new agents become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Carcinoma, Hepatocellular

Interventions

AtezolizumabDRUG

Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.

BevacizumabDRUG

Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.

TiragolumabDRUG

Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of HCC confirmed either histologically or clinically according to AASLD criteria for patients with cirrhosis. For participants without cirrhosis, histological confirmation is mandatory. * HCC that is amenable to R0 surgical resection with curative intent in the opinion of the surgeons and oncologists or hepatologists involved in the care of the participant. Patients presenting with resectable HCC within or beyond Milan criteria (without extrahepatic spread or macrovascular invasion) are eligible. * Measurable disease (at least one target lesion) according to RECIST v1.1 as determined by the investigator * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization * Child-Pugh Class A within 7 days prior to randomization * Negative HIV test at screening * No prior locoregional or systemic treatment for HCC * Adequate hematologic and end-organ function * Documented virology status of hepatitis * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm General Exclusion Criteria: * Presence of extrahepatic disease or macrovascular invasion * Known fibrolamellar HCC, sarcomatoid HCC, mixed cholangiocarcinoma and HCC, or other rare variants of HCC * History of hepatic encephalopathy if clinically significant within one year prior to initiation of study treatment * Moderate or severe ascites * Active co-infection with HBV and HCV * Known active co-infection with HBV and hepatitis D viral infection * Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding * A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment * Inadequately controlled hypertension * History of hypertensive crisis or hypertensive encephalopathy * Significant vascular disease within 6 months prior to initiation of study treatment * History of hemoptysis within 1 month prior to initiation of study treatment * Evidence of bleeding diathesis or significant coagulopathy * Current or recent (\<= 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes * History of abdominal or tracheoesophageal fistula, GI perforation or intra-abdominal abscesses within 6 months prior to initiation of study treatment * History of intestinal obstruction and/or clinical sign or symptoms of GI obstruction * Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture * Grade \>= proteinuria * Major surgical procedure, open biopsy, or significant traumatic injury, or abdominal surgery, interventions or traumatic injuries, or anticipation of need of major surgical procedure other than potentially curative liver resection * Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) * Serious infection requiring oral or IV antibiotics and/or hospitalization * Active tuberculosis

Locations (14)

University of Southern California (USC)

Los Angeles, California, United States

University of California Los Angeles (UCLA) - Cancer Care - Santa Monica

Santa Monica, California, United States

Outcomes

Primary Outcomes

Major Pathologic Response (MPR) Rate

MPR rate was defined as the percentage of participants who had achieved MPR and was estimated for each treatment cohort in the efficacy-evaluable population. MPR was defined as ≤ 10% residual viable tumor in the tumor bed at the time of surgical resection in the primary tumor, as assessed by the central pathology laboratory. Participants who did not proceed to surgery were considered as non-responders for MPR. Percentages have been rounded off.

Time frame: At the time of surgery (up to 15 weeks)

Secondary Outcomes

Pathologic Complete Response (pCR) Rate

pCR rate was defined as the percentage of participants who had achieved pCR. pCR was defined as the absence of any viable tumor cells in both the primary tumor and all sampled lymph nodes at the time of surgical resection, as assessed by central pathological review. Percentages have been rounded off.

Time frame: At the time of surgery (up to 15 weeks)

Relapse-free Survival (RFS), as Assessed by the Investigator According to European Association for the Study of the Liver (EASL) and/or Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

RFS was defined as the time from surgery to the first documented recurrence of disease (intrahepatic or extrahepatic), as assessed by the investigator according to EASL and/or RECIST v1.1, or death from any cause. Intrahepatic recurrence was defined by the appearance of one or more intrahepatic lesions with a longest diameter of \> 1 cm and a typical vascular pattern of HCC on dynamic imaging (i.e., hypervascularization in the arterial phase with washout in the portal venous or late venous phase). Extrahepatic recurrence was assessed by RECIST v1.1 as the appearance of new, measurable malignant lesions outside the liver. Data for participants who did not have documented recurrence of disease or death were censored at the day of the last tumor assessment for participants. Kaplan-Meier (K-M) method was used to estimate median RFS.

Time frame: From surgery to the first documented recurrence of disease (up to 20.5 months)

Data from ClinicalTrials.gov

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Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

Columbia University Medical Center

New York, New York, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Klinikum Klagenfurt am Wörthersee

Klagenfurt, Austria

Department of Internal Medicine III AKH and Medical University of Vienna

Vienna, Austria

Centre Georges Francois Leclerc (CGFL)

Dijon, France

Gustave Roussy

Villejuif, France

University Essen

Essen, Germany

...and 4 more locations

Event-free Survival (EFS), as Assessed by the Investigator According to EASL and RECIST v1.1

EFS was defined as the time from randomization to any of the following events, whichever occurred first: PD that precluded surgery, as assessed by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline); local, regional, or distant disease recurrence as measured by EASL and/or RECIST v1.1; or death from any cause. Data for participants who had not experienced EFS events were censored at the time of their last post-surgical tumor assessment. K-M method was used to estimate median RFS.

Time frame: From randomization to PD that precluded surgery or disease recurrence or death from any cause, whichever occurred first (up to 20.5 months)

Overall Survival (OS)

OS was defined as the time from randomization to death from any cause. Data for participants who had not died were censored at the last date they were known to be alive. K-M method was used to estimate median OS.

Time frame: From randomization to death from any cause (up to 20.5 months)

OS Rate at 6 Months, 12 Months, and 18 Months

OS rate at 6, 12, and 18 months was defined as the percentage of participants who had not experienced death from any cause at 6 months, 12 months, and 18 months after randomization, respectively. OS was defined as the time from randomization to death from any cause. K-M method was used to estimate OS rate. Percentages have been rounded off. Due to the low number of events the results need to be interpreted with caution.

Time frame: At Months 6, 12, and 18

Objective Response Rate (ORR), as Assessed by the Investigator According to RECIST v1.1

ORR was defined as the percentage of participants with a radiographic objective response (OR), characterized by a complete response (CR) or a partial response (PR) prior to surgery, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off.

Time frame: Prior to surgery (at approximately Week 11)

ORR, as Assessed by the Investigator According to Hepatocellular Carcinoma-Specific Modified Response Evaluation Criteria in Solid Tumors (HCC mRECIST)

ORR was defined as the percentage of participants with a radiographic OR, characterized by a CR or a PR prior to surgery, as determined by the investigator according to HCC mRECIST. CR was defined as the disappearance of any intratumoral arterial enhancement in all target and non-target lesions. PR was defined as an increase of at least 30% in the sum of the longest diameters of viable (contrast enhancement in the arterial phase) target lesions, taking as reference the baseline SOD of target lesions. Percentages have been rounded off.

Time frame: Prior to surgery (at approximately Week 11)

Percentage of Participants Downstaged to Within Milan Criteria (for Participants Beyond Criteria at Randomization)

Percentage of participants downstaged to within Milan Criteria was defined as the number of participants who were beyond Milan criteria at enrollment and staged as within Milan criteria (single tumor ≤ 5 or 2 to 3 nodules all ≤ 3 centimeters \[cm\]) during the study. Milan criteria=single tumor \> 5 cm or 2 to 3 nodules \> 3 cm, or ≥ 4 nodules. Percentages have been rounded off.

Time frame: At the time of surgery (up to 15 weeks)

Negative Surgical Margins (R0) Resection Rate

R0 resection rate was defined as the percentage of resected participants who achieved complete resection (R0 resection), confirmed by pathology. R0 resection was defined as a microscopically margin-negative resection, in which no tumor (gross or microscopic) remains in the primary tumor bed. Percentages have been rounded off.

Time frame: At the time of surgery (up to 15 weeks)

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Immune-related AEs

An AE was defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any AE that meets any of the following criteria: Is fatal; Is life threatening; Requires or prolongs inpatient hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study treatment; Is a significant medical event in the investigator's judgment. Participants with immune-mediated Hepatitis (Diagnosis and Lab Abnormalities) have been reported as immune-related AEs.

Time frame: From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (up to 7.7 moths)

Percentage of Participants With Delayed or Cancelled Surgery Due to Treatment-related Adverse Events (TRAEs)

Delayed Surgery was defined as delay in surgery by \> 28 days from the surgical restaging or pre-surgery visit. Percentages have been rounded off.

Time frame: Assessed at pre-surgery (scheduled at Week 11)

Length of Surgical Delays

Delayed Surgery was defined as a delay in surgery by \> 28 days from the surgical restaging or pre-surgery visit.

Time frame: Assessed at pre-surgery (scheduled at Week 11) up to 20 weeks

Duration of Surgery

Time frame: At the time of surgery (up to 15 weeks)

Duration of Hospital Stay Post-surgery

Time frame: From time of surgery (15 weeks) up to 6 weeks (± 2 weeks) post-surgery (up to 23 weeks)

Number of Participants With Specific Surgical Approach

The surgical approach was categorized as: Hemihepatectomy; Sectionectomy; Segmentectomy; Other.

Time frame: At the time of surgery (up to 15 weeks)

Intraoperative Blood Loss

Time frame: At the time of surgery (up to 15 weeks)

Number of Participants Needing Intraoperative Blood Transfusion

Time frame: At the time of surgery (up to 15 weeks)

Post-operative Surgical Complication Rates Assessed According to the Clavien-dindo Surgical Classification

Clavien-dindo Surgical Classification graded surgical complications as: Grade I- Any complication that does not need pharmacological treatment or surgical, endoscopic, \& radiological interventions; Grade II- Complications requiring pharmacological treatment with drugs other than such allowed for Grade I complications or complications requiring blood transfusions \& total parenteral nutrition; Grade III- Complications requiring surgical, endoscopic, or radiological intervention with (Grade IIIb) or without (Grade IIIa) general anesthesia; Grade IV- Life-threatening complications requiring intensive care unit (ICU) management, which may be single organ (Grade IVa) or multiorgan (Grade IVb) dysfunction; Grade V- Complications causing death. The percentage of participants with any post-surgical complications specifically related to the HCC resection was reported. Percentages have been rounded off.

Time frame: From time of surgery (15 weeks) up to neo-adjuvant treatment completion/discontinuation (6 weeks [± 2 weeks]) (up to 23 weeks)

Number of Participants With Post-operative Mortality

Time frame: From surgery (15 weeks) up to 90 days post-surgery (up to 27.8 weeks)