Clinical Trials /

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

NCT04430452

Description:

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.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for the Treatment of Liver Cancer After Progression on Prior 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

Clinical Trial IDs

  • ORG STUDY ID: 194522
  • SECONDARY ID: NCI-2020-03671
  • NCT ID: NCT04430452

Conditions

  • 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

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm I (hypofractionated RT, durvalumab)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabArm II (hypofractionated RT, durvalumab, tremelimumab)

Purpose

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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (hypofractionated RT, durvalumab)ExperimentalPatients 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.
  • Durvalumab
Arm II (hypofractionated RT, durvalumab, tremelimumab)ExperimentalPatients 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.
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically-diagnosed HCC with progression during or after prior PD-1 checkpoint
             inhibitor immunotherapy (e.g. nivolumab and/or pembrolizumab) with last dose of PD-1
             inhibitor at least 4 weeks but within 6 months before enrollment

          -  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 or B7

          -  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

          -  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

          -  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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:up to 24 months
Safety Issue:
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.

Secondary Outcome Measures

Measure:Number of of treatment-related adverse events
Time Frame:up to 24 months
Safety Issue:
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)
Measure:Progression-free survival
Time Frame:Up to 24 months
Safety Issue:
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
Measure:Duration of overall response (DOR)
Time Frame:Up to 24 months
Safety Issue:
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
Measure:Overall survival (OS)
Time Frame:Up to 24 months
Safety Issue:
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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mary Feng, MD

Last Updated

June 10, 2020