Clinical trial NCT02519348: A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma
Official title: A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab Administered as Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Subjects With Advanced Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
Immunotherapy
Antibodies, Monoclonal
Tremelimumab
MEDI4736
Durvalumab
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2015-08-10
Enrollment: 433
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: From Day 1 to Day 28 after first dose of study drug
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Number of Participants With Clinically Important Changes in Hematology and Clinical Chemistry Parameters
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
Secondary outcomes:
measure: Overall Objective Response Rate (ORR) Based on Investigator Assessments and Blinded Independent Central Review (BICR)
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Disease Control Rate (DCR) Based on Investigator Assessments and BICR
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Time to Response (TTR) Based on Investigator Assessments and BICR
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Duration of Response (DoR) Based on Investigator Assessments and BICR
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Time to Progression (TTP) Based on Investigator Assessments and BICR
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Progression Free Survival (PFS) Based on Investigator Assessments and BICR
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
measure: Overall Survival (OS)
timeFrame: From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: San Francisco
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Stony Brook
country: United States
facility: Research Site
state: New York
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Hangzhou
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Sha Tin
country: Hong Kong
facility: Research Site
city: Benevento
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Osakasayama-shi
country: Japan
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Jung-gu
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Bukit Merah
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: Pamplona
country: Spain
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan City
country: Taiwan
facility: Research Site
Study officials:
affiliation: MedImmune LLC
name: MedImmune, LLC MedImmune, LLC
role: STUDY_DIRECTOR
References:
citation: Kelley RK, Sangro B, Harris W, Ikeda M, Okusaka T, Kang YK, Qin S, Tai DW, Lim HY, Yau T, Yong WP, Cheng AL, Gasbarrini A, Damian S, Bruix J, Borad M, Bendell J, Kim TY, Standifer N, He P, Makowsky M, Negro A, Kudo M, Abou-Alfa GK. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. J Clin Oncol. 2021 Sep 20;39(27):2991-3001. doi: 10.1200/JCO.20.03555. Epub 2021 Jul 22.