A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma

MedImmune

Status and phase: Active, not recruiting; Phase 2

Conditions: Hepatocellular Carcinoma

Treatments: Biological: Bevacizumab; Biological: Durvalumab; Biological: Tremelimumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02519348

2015-001663-39 (EudraCT Number)

2024-517085-41-00 (Registry Identifier)

D4190C00022

Details and patient eligibility

About

This is a multicenter, open-label, stratified, randomized study to evaluate the safety, tolerability, antitumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of durvalumab or tremelimumab monotherapy, or durvalumab in combination with tremelimumab or bevacizumab in advanced hepatocellular carcinoma.

Full description

The study will comprise of 6 parts. Participants in Part 1A (safety run-in cohort), Part 1B (efficacy-gating cohort), Part 2A, and Part 4 will receive weight-based dosing regimens; and participants in Part 2B and Part 3 will receive fixed dosing regimens. Part 1A Stage 2 of the study may start after the first 3 participants in Stage 1 have been observed on study for at least 4 weeks. In addition, a separate cohort of participants will be enrolled in mainland China (China cohort) once global recruitment in Part 2A will be closed.

• In Part 1 (both 1A and 1B), participants will receive tremelimumab 1 mg/kg intravenous (IV) every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W.

• In Part 2A, participants will be randomized in a 1:1:1 ratio to receive:

  • Durvalumab 20 mg/kg Q4W
  • Tremelimumab 10 mg/kg Q4W × 7 doses followed by every 12 weeks (Q12W)
  • Tremelimumab 1 mg/kg Q4W × 4 doses + durvalumab 20 mg/kg Q4W, followed by durvalumab 20 mg/kg Q4W

• In China cohort, Part 2A study design will be followed.

• In Part 2B, participants will receive tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W.

• In Part 3, participants will be randomized in a 2:2:1:2 ratio to receive:

  • Durvalumab 1500 mg Q4W
  • Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W
  • Tremelimumab 750 mg Q4W for 7 doses followed by Q12W
  • Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg Q4W, followed by durvalumab 1500 mg Q4W.

Following protocol amendment 5, enrollment into 'Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg' arm will close. Participants will be randomized at a ratio of 2:1:2 in 'Durvalumab 1500 mg Q4W', 'Tremelimumab 750 mg Q4W for 7 doses followed by Q12W', and 'Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W' arms, respectively.

• In Part 4, participants will receive durvalumab 1120 mg (15 mg/kg) + bevacizumab 15 mg/kg every 3 weeks (Q3W).

Participants will receive the treatment until confirm progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

All participants will be followed for survival until the end of study visit (last participant discontinues the study treatment).

Enrollment: 433 patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Male or female participants
2. 18 years and older (Japan-20 years and older)
3. Confirmed hepatocellular carcinoma (HCC) based on histopathological findings from tumor tissues. Advanced HCC with diagnosis confirmed pathologically or with noninvasive methods.
4. Immunotherapy-naïve
5. Have either progressed on, are intolerant to, or refused treatment with sorafenib or another approved TKI. For arm 5 only: Have not received any prior systemic therapy for HCC.

Exclusion criteria

1. Prior exposure to immune-mediated therapy
2. Hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy
3. Gastrointestinal bleeding (eg, esophageal varices or ulcer bleeding) within 12 months
4. Ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.
5. Main portal vein thrombosis (Vp4) as documented on imaging
6. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment
7. Active or prior documented autoimmune or inflammatory disease with some exceptions
8. Current or prior use of immunosuppressive medication within 14 days with some exceptions

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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433 participants in 9 patient groups

Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg

Experimental group

Description:

Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) will receive tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Tremelimumab

Biological: Durvalumab

Parts 2 and 3: Durvalumab 1500 mg

Experimental group

Description:

Participants will receive durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Durvalumab

Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg

Experimental group

Description:

Participants will receive tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Tremelimumab

Biological: Durvalumab

Parts 2 and 3: Tremelimumab 750 mg

Experimental group

Description:

Participants will receive tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Tremelimumab

Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg

Experimental group

Description:

Participants will receive tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. Participant recruitment to this arm was closed following protocol amendment 5.

Treatment:

Biological: Tremelimumab

Biological: Durvalumab

Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg

Experimental group

Description:

Participants will receive durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first

Treatment:

Biological: Durvalumab

Biological: Bevacizumab

China Cohort: Durvalumab 20 mg/kg

Experimental group

Description:

Participants will receive durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Durvalumab

China Cohort: Tremelimumab 10 mg/kg

Experimental group

Description:

Participants will receive tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Tremelimumab

China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg

Experimental group

Description:

Participants will receive tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Treatment:

Biological: Tremelimumab

Biological: Durvalumab