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Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for Liver Cancer After Progression on PD-1 Inhibition

Primary Purpose

Advanced Hepatocellular Carcinoma, Stage III Hepatocellular Carcinoma AJCC v8, Stage IIIA Hepatocellular Carcinoma AJCC v8

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Durvalumab
Hypofractionated Radiation Therapy
Tremelimumab
Sponsored by
Mary Feng, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. 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.

  2. 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.
  3. Clinical indication for RT to any site (e.g. painful primary or metastatic tumor, local complication risk such as impending biliary or vascular obstruction).
  4. Child Pugh score of A, B7, or B8 provided other liver function criteria are met.
  5. Eastern Cooperative Oncology Group (ECOG) 0 or 1
  6. 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.
  7. 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.
  8. No contraindication to immune checkpoint inhibitor immunotherapy.
  9. No contraindication to RT.
  10. Age >=18 years at time of study entry.
  11. Life expectancy of >= 12 weeks.
  12. Body weight > 30 kg (66.1 pounds).
  13. 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)
  14. 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.
  15. 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.
  16. 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.

Exclusion Criteria:

  1. Prior radiotherapy to tumor sites requiring RT which could compromise safety of additional treatments.
  2. Prior radiotherapy to more than 30% of bone marrow or to a wide field within 4 weeks of the first study treatment.
  3. Prior treatment with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or PD-L1 inhibitor.
  4. History of allogenic organ transplantation.
  5. 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
  6. 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
  7. 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
  8. Concurrent enrollment in another interventional clinical study, except only in the follow-up period of that study.
  9. 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.
  10. 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
  11. 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
  12. 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
  13. History of leptomeningeal carcinomatosis.
  14. History of active primary immunodeficiency.
  15. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice).
  16. Known human immunodeficiency virus (HIV) infection.
  17. 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)
  18. 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.
  19. 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.
  20. Known allergy or hypersensitivity to IP, any of the study drugs, or any of the study drug excipients.
  21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
  23. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.

Sites / Locations

  • University of California, San FranciscoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (hypofractionated RT, durvalumab)

Arm II (hypofractionated RT, durvalumab, tremelimumab)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Objective response rate (ORR)
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.

Secondary Outcome Measures

Number of of treatment-related adverse events
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
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)
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)
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

Full Information

First Posted
June 10, 2020
Last Updated
July 31, 2023
Sponsor
Mary Feng, MD
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT04430452
Brief Title
Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for Liver Cancer After Progression on PD-1 Inhibition
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 4, 2022 (Actual)
Primary Completion Date
February 28, 2027 (Anticipated)
Study Completion Date
February 28, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mary Feng, MD
Collaborators
AstraZeneca

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well standard of care hypofractionated radiation therapy followed by durvalumab with or without tremelimumab works in treating patients with hepatocellular cancer (liver cancer) that has spread to other places in the body (advanced) and that is growing, spreading, or getting worse (progressing) after treatment with PD-1 inhibitor immunotherapy. In some patients, cancer cells and immune cells start to express signals that stop the body's immune system from killing the cancer. New drugs being developed, such as durvalumab and tremelimumab, are designed to target and block these signals and may help increase the immune response to prevent or slow down cancer growth. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may help the immune system work even better. Giving durvalumab with or without tremelimumab after radiation therapy may work better than radiation therapy alone in treating patients with liver cancer.
Detailed Description
PRIMARY OBJECTIVE: I. Determine objective response rate (ORR) of durvalumab (D) and D + tremelimumab (T) after radiation therapy (RT) in advanced hepatocellular carcinoma (HCC) patients with progression on prior PD-1 immune checkpoint inhibitor. SECONDARY OBJECTIVES: I. To determine the safety of D and D + T in advanced HCC patients with progression on prior PD-1 immune checkpoint inhibitor. II. Determine the efficacy of D and D + T in advanced HCC patients with progression on prior PD-1 immune checkpoint inhibitor. EXPLORATORY OBJECTIVES: I. Profile peripheral blood mononuclear cell (PBMC) immune cells and plasma samples before RT, after RT, and during D or D + T immunotherapy. II. Explore relationship between plasma biomarkers and PBMC immune profiles, the proportion of participants with adverse events (AEs), (safety endpoint), and clinical outcomes (ORR), progression-free survival (PFS), duration of response (DOR), overall survival (OS). III. Profile immune cells in archival pre-treatment tumor tissue for all patients and on-/post-treatment tumor samples and/or non-tumor liver tissue samples when available, and explore for relationship with safety/tolerability and clinical outcomes. IV. Determine incidence of tumor PD-L1 expression by immunohistochemistry (IHC) in pre-treatment archival tumor samples in all patients, and in on-/post-treatment tumor samples if repeat tumor sampling is obtained for clinical indications. V. Explore relationship between tumor PD-L1 status and clinical outcomes. VI. Explore relationship between viral hepatitis status, viral load, safety/tolerability, and clinical outcomes. VII. Measure tumor marker alpha-fetoprotein (AFP) response to immunotherapy plus RT and explore for relationship with clinical outcomes. VIII. Explore relationship between site of RT (liver, bone, other soft tissue), number of RT sites (1 or > 1), safety/tolerability, clinical outcomes, and changes in immune cell profiles on treatment. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients undergo standard of care hypofractionated RT over 5 fractions once daily (QD) for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab intravenously (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. This arm will close after the 6th participant is enrolled. ARM II: 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. After completion of study treatment, patients are followed up every 2 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm I (hypofractionated RT, durvalumab)
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm II (hypofractionated RT, durvalumab, tremelimumab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Hypofractionated Radiation Therapy
Other Intervention Name(s)
Hypofractionated Radiotherapy, hypofractionation
Intervention Description
Undergo hypofractionated RT
Intervention Type
Biological
Intervention Name(s)
Tremelimumab
Other Intervention Name(s)
Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, Ticilimumab
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Objective response rate (ORR)
Description
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.
Time Frame
up to 24 months
Secondary Outcome Measure Information:
Title
Number of of treatment-related adverse events
Description
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)
Time Frame
up to 24 months
Title
Progression-free survival
Description
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
Time Frame
Up to 24 months
Title
Duration of overall response (DOR)
Description
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
Time Frame
Up to 24 months
Title
Overall survival (OS)
Description
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
Time Frame
Up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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: Any 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. Any AEs while receiving prior immunotherapy not resolved to grade =< 1 or resolved to baseline, 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 Required the use of additional immunosuppression other than corticosteroids for the management of an AE, experienced recurrence of a grade >= 3 AE if previously re-challenged, and 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hewitt Chang
Phone
(415) 514-1571
Email
Hewitt.Chang@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary Feng, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hewitt Chang
Phone
415-514-1571
Email
Hewitt.Chang@ucsf.edu
Phone
877-827-3222
Email
cancertrials@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Mary Feng, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for Liver Cancer After Progression on PD-1 Inhibition

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