A Study Evaluating Safety, Pharmacokinetics, Pharmacodynamics, And Clinical Activity Of RO7119929 (TLR7 Agonist) In Participants With Unresectable Advanced Or Metastatic Hepatocellular Carcinoma, Biliary Tract Cancer, Or Solid Tumors With Hepatic Metastases

Roche

Status and phase: Completed; Phase 1

Conditions: Carcinoma, Hepatocellular; Biliary Tract Cancer; Liver Metastases; Secondary Liver Cancer

Treatments: Drug: Tocilizumab; Drug: RO7119929

Study type: Interventional

Funder types: Industry

Identifiers

NCT04338685

WP41377

Details and patient eligibility

About

Phase I study of RO7119929 given orally to participants with unresectable advanced or metastatic primary liver cancers and other solid tumors with predominant liver involvement. The primary objective of the study is to explore the safety and to determine the maximum tolerated dose (MTD) and/or optimal biologic dose (OBD) of RO7119929 as single agent.

Enrollment: 55 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed diagnosis of one of the following: unresectable advanced or metastatic HCC (including fibrolamellar HCC) not amenable to a curative treatment approach, unresectable advanced or metastatic intrahepatic or perihilar (Klatskin) BTC not amenable to a curative treatment approach, extrahepatic BTC or gallbladder cancer infiltrating the liver or metastasized into the liver with predominant liver disease, not amenable to a curative treatment approach, metastasized colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), Gastric cancer (GC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), cutaneous melanoma, or ocular melanoma with predominant liver disease not amenable to a curative treatment approach. Participants with other solid tumors with predominant liver disease not amenable to a curative treatment approach might be enrolled after Sponsor approval
• Measurable disease with at least one measurable locally untreated liver lesion, as defined by RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate hematologic and major organ functions
• Participants for which there is no available standard therapy likely to confer clinical benefit, or participants who are not candidates for such available therapy
• Life expectancy of ≥12 weeks, approximated with Royal Marsden Hospital score 0-1 or Gustave Roussy Immune (GRIm) score 0-1. Participants with a Royal Marsden Hospital or GRIm score of ≥2 and a life expectancy of ≥12 weeks according to the investigator's clinical judgement may be enrolled after Medical Monitor approval has been obtained.
• For participants with HCC: Child-Pugh score of A6 or better

Exclusion criteria

• History or clinical evidence of central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases, unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days prior to Screening
• Evidence of any extra-hepatic primary tumor or metastasis requiring prompt medical intervention
• Receipt of prior therapy with a TLR7/8/9 agonist and/or IFN-alpha
• Prior chemotherapy, antibody, or other registered or experimental cancer treatment within 3 weeks of study Cycle 1 Day 1. Specifically, no CPI antibody is allowed to be administered within 6 weeks of study Cycle 1 Day 1
• Receipt of investigational agent for any other indication within 3 weeks of dosing
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• Local therapy to liver (e.g. radiofrequency ablation, percutaneuous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, and transarterial embolization) within 3 weeks prior to initiation of study treatment, radioembolization within 3 months prior to initiation of study treatment, or non-recovery from side effects of such procedure
• Treatment-related toxicities from prior cancer therapy that have not resolved to </= Grade 1 CTC AE prior to study treatment with the exception of the following Grade 2 toxicities:

alopecia, peripheral neuropathy, any laboratory changes that still lie within the inclusion criteria defined above

• History of other malignancy within 2 years; exception for ductal carcinoma in situ not requiring chemotherapy, low grade cervical intraepithelial neoplasia (CIN), nonmelanoma skin cancer, low grade localized prostate cancer (Gleason score < Grade 7), or optimally treated Stage 1 uterine cancer.
• Active or history of immunologic-mediated disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome or Guillain-Barré syndrome
• Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection.
• Ascites, pleural effusion, or pericardial effusion requiring medical intervention within 12 months prior to study entry.
• History of human immunodeficiency virus (HIV) infection
• Active hepatitis B virus (HBV) infection
• Coinfection of HBV and hepatitis C virus (HCV).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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55 participants in 8 patient groups

Part A1-1 mg RO7119929

Experimental group

Description:

Participants received 1mg RO7119929 every week in 3-week cycles.

Treatment:

Drug: RO7119929

Part A1-3 mg RO7119929

Experimental group

Description:

Participants received 4 mg RO7119929 every week in 3-week cycles

Treatment:

Drug: RO7119929

Part A1 - 6 mg RO7119929

Experimental group

Description:

Participants received 6 mg RO7119929 every week in 3-week cycles

Treatment:

Drug: RO7119929

Part A1 -9 mg RO7119929

Experimental group

Description:

Participants received 9 mg RO7119929 every week in 3-week cycles

Treatment:

Drug: RO7119929

Part B1-5 mg RO7119929

Experimental group

Description:

Participants with both available and evaluable tumor biopsy samples received 5 mg RO7119929 on Cycle 1 Day 1 to month 12

Treatment:

Drug: RO7119929

Part A2- 2/5/5 mg RO7119929

Experimental group

Description:

Participants received RO7119929 QW with step-up dosing of 2/5/5 mg during Cycle 1.

Treatment:

Drug: RO7119929

Part A2- 2/5/6 mg RO7119929

Experimental group

Description:

Participants received RO7119929 QW with step-up dosing of 2/5/6 mg during Cycle 1.

Treatment:

Drug: RO7119929

Part A3-4 mg RO7119929

Experimental group

Description:

Participants received tocilizumab pre-treatment on Cycle 1 Day 1, approximately 2 hours prior to RO7119929 administration and 4 mg RO7119929 every week in 3-week cycles

Treatment:

Drug: Tocilizumab

Drug: RO7119929