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

Sponsor: MedImmune LLC

Sponsor score: 0

ClinicalTrials ID:NCT02519348

This multicenter, open-label study evaluates the safety and efficacy of durvalumab, tremelimumab, and bevacizumab in advanced hepatocellular carcinoma. Participants, aged 18+ (20+ in Japan), must have confirmed HCC and be immunotherapy-naïve. Treatments include various dosing regimens of the biological agents administered via IV infusion. Eligibility requires prior progression on or intolerance to sorafenib or other TKIs.

Patient Parameters

Program Overview

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.

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).

Eligibility Criteria

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

Locations

FACILITYZIPCITYSTATE
Research Site85054PhoenixArizona
Research Site94158San FranciscoCalifornia
Research Site06510New HavenConnecticut
Research Site32224JacksonvilleFlorida
Research Site33612TampaFlorida
Research Site46202IndianapolisIndiana
Research Site02114BostonMassachusetts
Research Site10065New YorkNew York
Research Site11794Stony BrookNew York
Research Site27705DurhamNorth Carolina

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