Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma (HIMALAYA)
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| ClinicalTrials.gov Identifier: NCT03298451 |
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Recruitment Status :
Active, not recruiting
First Posted : October 2, 2017
Results First Posted : June 18, 2023
Last Update Posted : April 25, 2024
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Sponsor:
AstraZeneca
Information provided by (Responsible Party):
AstraZeneca
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Brief Summary:
This is a randomized, open-label, multi-center, global, Phase III study to assess the efficacy and safety of durvalumab plus tremelimumab combination therapy and durvalumab monotherapy versus sorafenib in the treatment of patients with no prior systemic therapy for unresectable HCC. The patients cannot be eligible for locoregional therapy
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hepatocellular Carcinoma | Drug: Durvalumab Drug: Tremelimumab (Regimen 1) Drug: Tremelimumab (Regimen 2) Drug: Sorafenib Drug: Durvalumab (Regimen 1) Drug: Durvalumab (Regimen 2) | Phase 3 |
The study population includes patients 18 years of age or older with advanced HCC, Barcelona Clinic Liver Cancer stage B not eligible for locoregional therapy or stage C, and Child-Pugh A classification liver disease. Patients must not have received any prior systemic therapy for unresectable HCC.
Patients in all treatment arms may continue receiving their originally assigned treatment, at the Investigator's discretion, until progression
Patients in all arms with confirmed PD who, in the Investigator's opinion, continue to receive benefit from their assigned treatment and meet the criteria for treatment in the setting of PD may continue to receive their assigned treatment.
If a patient discontinues study drug(s) due to disease progression, the patient will enter survival follow-up. Patients who have discontinued treatment due to toxicity or symptomatic deterioration or who have commenced subsequent anticancer therapy, will have tumor assessments until confirmed PD and will be followed for survival
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 1324 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized, Open-label, Multi-center Phase III Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma |
| Actual Study Start Date : | October 11, 2017 |
| Actual Primary Completion Date : | August 27, 2021 |
| Estimated Study Completion Date : | August 27, 2024 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Durvalumab
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm 1
Durvalumab
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Drug: Durvalumab
Durvalumab IV (intravenous infusion).
Other Name: MEDI4736 |
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Experimental: Arm 2
Durvalumab in combination with tremelimumab (Regimen 1)
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Drug: Tremelimumab (Regimen 1)
Tremelimumab IV (intravenous infusion). Drug: Durvalumab (Regimen 1) Durvalumab IV (intravenous infusion). |
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Experimental: Arm 3
Durvalumab in combination with tremelimumab (Regimen 2)
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Drug: Tremelimumab (Regimen 2)
Tremelimumab IV (intravenous infusion). Drug: Durvalumab (Regimen 2) Durvalumab IV (intravenous infusion). |
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Active Comparator: Arm 4
Sorafenib
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Drug: Sorafenib
Sorafenib, as per standard of care |
Primary Outcome Measures :
- Overall Survival (OS) - Treme 300 mg x1 Dose + Durva 1500 mg vs Sora 400 mg [ Time Frame: From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months). ]OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This primary outcome measure presents OS analysis of Treme 300mg x1 dose + Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).
Secondary Outcome Measures :
- Overall Survival (OS) - Durva 1500 mg vs Sora 400 mg [ Time Frame: From the date of randomization until death due to any cause, assessed up to the data cut-off date (27Aug2021, to a maximum of approximately 46 months). ]OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This secondary outcome measure presents OS analysis of Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).
- Overall Survival (OS) at 18, 24, and 36 Months After Randomization [ Time Frame: At 18, 24, and 36 months post-randomization. Assessed at the final analysis DCO (27Aug2021). ]Percentage of participants who were alive at fixed time points (18, 24, and 36 months) after randomization. The estimated percentage of survival along with the 95% confidence interval were calculated using Kaplan-Meier technique on the full analysis set.
- Progression Free Survival (PFS) [ Time Frame: Tumor scans performed at baseline, every 8 weeks for the first 48 weeks following randomization, and every 12 weeks thereafter until RECIST 1.1-defined progression. Assessed up to DCO (27Aug2021, to a maximum of approximately 46 months) ]PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as the time from the date of randomization until the date of objective disease progression or death by any cause in the absence of progression, regardless of whether the patient withdrew from study treatment or received another anticancer therapy prior to progression. Progression (i.e., PD) was defined as a at least 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir.
- Time To Progression (TTP) [ Time Frame: From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]TTP was defined as the time from randomization until objective tumor progression in the absence of death. If participants died without tumor progression, they were censored at the time of death.
- Objective Response Rate (ORR) [ Time Frame: From the date of randomization until objective tumor progression, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]ORR (per RECIST 1.1 as assessed by the Investigator) was defined as the number (%) of participants with at least 1 confirmed visit response of CR or PR until progression, or the last evaluable assessment in the absence of progression. Participants who go off treatment without progression, receive a subsequent therapy, and then respond will not be included as responders in the ORR. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.
- Disease Control Rate (DCR) [ Time Frame: From the date of randomization until objective tumor progression or date of death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]Number (%) of participants with a Best Objective Response (BoR) of CR, PR, or SD. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters. Stable disease (ie., SD) was defined as neither sufficient decrease in sum of diameters to qualify for PR nor sufficient increase to qualify for progression.
- Duration of Objective Response (DoR) [ Time Frame: From the date of first documented response until the first date of documented progression or death, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]Time from the date of first documented confirmed response (complete or partial response) until the first date of documented progression or death in the absence of disease progression. Complete response (ie., CR) was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to <10 mm. Partial response (ie., PR) was defined as at least a 30% decrease in the sum of the diameter of TL, taking as reference the baseline sum of diameters.
- Overall Survival (OS) by PD-L1 [ Time Frame: From the date of randomization until death due to any cause, assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]Overall survival by baseline PD-L1 expression levels (positive vs. negative). PD-L1 expression level is based on the Tumor and Immune Cell Positivity (TIP) score method as: PD-L1 Positive (TIP ≥ 1%) or PD-L1 Negative (TIP < 1%).
- EORTC QLQ-C30 Time to Global Health Status/QoL Deterioration [ Time Frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months. ]European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30), which consists of 30 questions combined to produce a global health status/QoL scale. Higher scores indicate better health. A clinically meaningful deterioration is defined as a decrease in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
- EORTC QLQ-HCC18 Time to Symptom (Abdominal Pain) Deterioration [ Time Frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months. ]EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
- EORTC QLQ-HCC18 Time to Symptom (Shoulder Pain) Deterioration [ Time Frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months. ]EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
- EORTC QLQ-HCC18 Time to Symptom (Abdominal Swelling) Deterioration [ Time Frame: At baseline and every 8 weeks for the first 48 weeks and then every 12 weeks thereafter until death or the final analysis DCO (27Aug2021), assessed up to approximately 46 months. ]EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18) is an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30, which includes 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. A high score for a symptom scale/item represents a high level of symptomatology/problem. A clinically meaningful deterioration is defined as an increase in the score from baseline of ≥10. Time to deterioration is defined as the time from the date of randomization until the date of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death by any cause in the absence of a clinically meaningful deterioration, regardless of whether the patient discontinues study drug(s) or receives another anticancer therapy.
- Presence of ADA for Durvalumab [ Time Frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of durvalumab. Assessed until the final analysis DCO (27Aug2021, to a maximum of approximately 46 months). ]Number of participants with Anti-Drug Antibody (ADA) response to Durvalumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Durvalumab for each indicated category.
- Presence of ADA for Tremelimumab [ Time Frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of tremelimumab. Assessed up to approximately 46 months after the first randomization. ]Number of participants with Anti-Drug Antibody (ADA) response to Tremelimumab. ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA. Results are reported as number of participants with ADA responses to Tremelimumab for each indicated category.
- Summary of Durvalumab Concentration Over Time [ Time Frame: To evaluate the PK of Durvalumab, samples were collected pre-dose at week 4 and week 12 and post-dose at week 12. Assessed at the final analysis DCO (27Aug2021). ]Blood sample were collected at pre-specified timepoints and Durvalumab concentrations in serum (ug/mL) were reported over time.
- Summary of Tremelimumab Concentration Over Time [ Time Frame: To evaluate the PK of Tremelimumab, samples were collected at week 0 (post-dose), week 4, and week 12. Assessed at the final analysis DCO (27Aug2021). ]Blood sample were collected at pre-specified timepoints and Tremelimumab concentrations in serum (ug/mL) were reported over time.
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| Ages Eligible for Study: | 18 Years to 100 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion criteria
- HCC based on histopathological confirmation
- No prior systemic therapy for HCC
- Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C
- Child-Pugh Score class A
- ECOG performance status of 0 or 1 at enrollment
Exclusion criteria
- Hepatic encephalopathy within past 12 months or requirement for medication to prevent or control encephalopathy
- Clinically meaningful ascites
- Main portal vein tumor thrombosis
- Active or prior documented GI bleeding (eg, esophageal varices or ulcer bleeding) within 12 months
- HBV and HVC co-infection, or HBV and Hep D co-infection
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03298451
Locations
Show 160 study locations
Sponsors and Collaborators
AstraZeneca
Study Documents (Full-Text)
Documents provided by AstraZeneca:
Documents provided by AstraZeneca:
Study Protocol [PDF] September 22, 2021
Statistical Analysis Plan [PDF] July 31, 2021
Additional Information:
| Responsible Party: | AstraZeneca |
| ClinicalTrials.gov Identifier: | NCT03298451 |
| Other Study ID Numbers: |
D419CC00002 2016-005126-11 ( EudraCT Number ) |
| First Posted: | October 2, 2017 Key Record Dates |
| Results First Posted: | June 18, 2023 |
| Last Update Posted: | April 25, 2024 |
| Last Verified: | April 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by AstraZeneca:
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Hepatocellular Carcinoma Non-Resectable |
Additional relevant MeSH terms:
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Carcinoma Carcinoma, Hepatocellular Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Adenocarcinoma Liver Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Liver Diseases |
Sorafenib Durvalumab Tremelimumab Antibodies, Monoclonal Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Immunologic Factors Physiological Effects of Drugs |