Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for the Treatment of Liver Cancer After Progression on Prior PD-1 Inhibition
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|ClinicalTrials.gov Identifier: NCT04430452|
Recruitment Status : Recruiting
First Posted : June 12, 2020
Last Update Posted : November 9, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Advanced Hepatocellular Carcinoma Stage III Hepatocellular Carcinoma AJCC v8 Stage IIIA Hepatocellular Carcinoma AJCC v8 Stage IIIB Hepatocellular Carcinoma AJCC v8 Stage IV Hepatocellular Carcinoma AJCC v8 Stage IVA Hepatocellular Carcinoma AJCC v8 Stage IVB Hepatocellular Carcinoma AJCC v8||Biological: Durvalumab Radiation: Hypofractionated Radiation Therapy Biological: Tremelimumab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Trial of Palliative Hypofractionated Radiotherapy Followed by Durvalumab (MEDI4736) With/Without Tremelimumab for Advanced Hepatocellular Carcinoma After Progression on Prior PD-1 Inhibition|
|Actual Study Start Date :||February 4, 2022|
|Estimated Primary Completion Date :||February 28, 2027|
|Estimated Study Completion Date :||February 28, 2027|
Experimental: Arm I (hypofractionated RT, durvalumab)
Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Radiation: Hypofractionated Radiation Therapy
Undergo hypofractionated RT
Experimental: Arm II (hypofractionated RT, durvalumab, tremelimumab)
Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who complete the first dose of tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or other clinical response without progression for at least 6 cycles or 6 months on treatment, whichever is shorter, and subsequently have evidence of progressive disease during the durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next scheduled cycle of treatment with durvalumab per physician discretion.
Radiation: Hypofractionated Radiation Therapy
Undergo hypofractionated RT
- Objective response rate (ORR) [ Time Frame: up to 24 months ]Defined per Response Evaluation Criteria in Solid Tumors 1.1, excluding radiation therapy-treated lesions. assessed from initiation of study treatment until discontinuation of treatment. Proportion of response and corresponding exact confidence intervals will be reported for objective response rate in each Arm. Patients with unevaluable or unknown response status will be considered non-responders.
- Number of of treatment-related adverse events [ Time Frame: up to 24 months ]Summary tables for AEs will include only AEs that started or worsened during the on-treatment period, the treatment-emergent AEs graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)
- Progression-free survival [ Time Frame: Up to 24 months ]Progression will be calculated in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause. For cases without progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within a short period of time following the date last known progression-free, in which case the death will be counted as a failure. The 'short period of time' will generally be no more than 3 months. For patients discontinued from study for other reasons than progression or death, progression-free survival will be censored at the date last known to be progression-free
- Duration of overall response (DOR) [ Time Frame: Up to 24 months ]The period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started
- Overall survival (OS) [ Time Frame: Up to 24 months ]Survival will be measured from the date of entry on study and from first dose of protocol therapy to the date of death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint inhibitor immunotherapy (e.g., nivolumab and/or pembrolizumab or atezolizumab; prior durvalumab excluded.
a. For patients without prior histologic or cytologic diagnosis, radiographic diagnosis is allowed provided patients meet American Association for the Study of Liver Diseases (AASLD) criteria for radiographic diagnosis.
- At least 1 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-measurable tumor present which has not received RT or other local therapy prior to enrollment.
- Clinical indication for RT to any site (e.g. painful primary or metastatic tumor, local complication risk such as impending biliary or vascular obstruction).
- Child Pugh score of A, B7, or B8 provided other liver function criteria are met.
- Eastern Cooperative Oncology Group (ECOG) 0 or 1
- Appropriate antiviral therapy for hepatitis B virus (HBV) according to institutional standard of care with HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) < 2000 IU/mL.
Adequate organ function as defined below:
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count >= 1,500/microliter (mcL)
- Platelet count >= 75,000/mcL
- Serum bilirubin =< 1.5 x institutional upper limit of normal. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
- Aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case it can be =< 5 x upper limit of normal (ULN)
- International normalized ratio (INR) < 1.5
- Creatinine clearance > 40 mL/min by Cockcroft Gault formula.
- No contraindication to immune checkpoint inhibitor immunotherapy.
- No contraindication to RT.
- Age >=18 years at time of study entry.
- Life expectancy of >= 12 weeks.
- Body weight > 30 kg (66.1 pounds).
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
- Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
- Women of childbearing potential and men must agree to use adequate contraception from the time of screening through the duration of study participation and for at least 6 months after receiving combination of durvalumab plus tremelimumab and 3 months after last dose of durvalumab.
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the United States (US) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
- Prior radiotherapy to tumor sites requiring RT which could compromise safety of additional treatments.
- Prior radiotherapy to more than 30% of bone marrow or to a wide field within 4 weeks of the first study treatment.
- Prior treatment with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or PD-L1 inhibitor.
- History of allogenic organ transplantation.
On prior PD-1 inhibitor immunotherapy:
- Must not have experienced immune-related adverse events with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 grade >= 3 on any prior immunotherapy or toxicity that led to permanent discontinuation of prior immunotherapy.
- All AEs while receiving prior immunotherapy must have resolved to grade =< 1 or resolved to baseline prior to screening for this study, with the exception of patients with endocrine AE of grade =< 2, who are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic
- Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of a grade >= 3 AE if previously re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
- Major surgery, liver-directed therapy, or any other anticancer therapy (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) less than 4 weeks prior to enrollment
Any other unresolved toxicity NCI CTCAE grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
- Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician
- Concurrent enrollment in another interventional clinical study, except only in the follow-up period of that study.
- Participation in another interventional clinical study with an investigational product during the past 4 weeks except only in the follow-up period of that study.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients with celiac disease controlled by diet alone
- Patients without active disease in the last 5 years may be included but only after consultation with the study physician
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease >= 2 years before the first dose of investigational product (IP) and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis.
- History of active primary immunodeficiency.
- Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice).
- Known human immunodeficiency virus (HIV) infection.
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab/tremelimumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening through the duration of study participation and for at least 6 months after receiving combination of durvalumab plus tremelimumab and 3 months after last dose of durvalumab.
- Known allergy or hypersensitivity to IP, any of the study drugs, or any of the study drug excipients.
- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
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): NCT04430452
|Contact: Hewitt Chang||(415) 514-1571||Hewitt.Chang@ucsf.edu|
|United States, California|
|University of California, San Francisco||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Hewitt Chang 415-514-1571 Hewitt.Chang@ucsf.edu|
|Contact 877-827-3222 firstname.lastname@example.org|
|Principal Investigator: Mary Feng, MD|
|Principal Investigator:||Mary Feng, MD||University of California, San Francisco|
|Responsible Party:||Mary Feng, MD, Principal Investigator, University of California, San Francisco|
|Other Study ID Numbers:||
NCI-2020-03671 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
|First Posted:||June 12, 2020 Key Record Dates|
|Last Update Posted:||November 9, 2022|
|Last Verified:||November 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
|Product Manufactured in and Exported from the U.S.:||No|
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Antineoplastic Agents, Immunological
Physiological Effects of Drugs
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action