Clinical Trials /

Durvalumab, Tremelimumab and Hypofractionated Radiation Therapy in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

NCT03522584

Description:

This phase I/II trial studies the side effects of durvalumab, tremelimumab and hypofractionated radiation therapy in treating patients with head and neck squamous cell carcinoma that has come back (recurrent) or that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving durvalumab, tremelimumab, and hypofractionated radiation therapy may work better in treating patients with recurrent or metastatic head and neck squamous cell carcinoma.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab, Tremelimumab and Hypofractionated Radiation Therapy in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
  • Official Title: Durvalumab (MEDI4736), Tremelimumab and Palliative Hypofractionated Radiation Therapy in Patients With Recurrent/Metastatic Squamous Cell Carcinomas of the Head and Neck Previously Treated With Immune Checkpoint Inhibitors

Clinical Trial IDs

  • ORG STUDY ID: 9881
  • SECONDARY ID: NCI-2018-00540
  • SECONDARY ID: 9881
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG1717067
  • NCT ID: NCT03522584

Conditions

  • Metastatic Head and Neck Squamous Cell Carcinoma
  • Recurrent Head and Neck Squamous Cell Carcinoma

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, MEDI4736Treatment (tremelimumab, durvalumab, HIGRT, SBRT)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabTreatment (tremelimumab, durvalumab, HIGRT, SBRT)

Purpose

This phase I/II trial studies the side effects of durvalumab, tremelimumab and hypofractionated radiation therapy in treating patients with head and neck squamous cell carcinoma that has come back (recurrent) or that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving durvalumab, tremelimumab, and hypofractionated radiation therapy may work better in treating patients with recurrent or metastatic head and neck squamous cell carcinoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To demonstrate safety and tolerability of durvalumab and tremelimumab and palliative
      radiation therapy in patients with recurrent metastatic squamous cell carcinomas of the head
      and neck previously exposed to an anti PD-1 or PDL-1 monoclonal antibody.

      SECONDARY OBJECTIVES:

      I. Measure objective response rates based on Response Evaluation Criteria in Solid Tumors
      (RECIST) 1.1. criteria in patients receiving the durvalumab, tremelimumab and palliative
      radiation therapy (RT) combination.

      II. Determine overall and progression free survival in patients enrolled in the study.

      OUTLINE:

      Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on
      day 1, week 1. Treatment repeats every 4 weeks for up to 4 cycles or every 6 weeks for up to
      3 cycles in the absence of disease progression or unacceptable toxicity. Patients then
      receive durvalumab IV over 60 minutes on day 1, week 1. Treatment repeats every 4 weeks for
      up to 9 cycles or every 6 weeks for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity. Patients also undergo hypofractionated radiation therapy using either
      hypofractionated, image-guided radiotherapy (HIGRT) or stereotactic body radiation therapy
      (SBRT) over 3 fractions every other day (QOD) during week 3.

      After completion of study treatment, patients are followed up at 30 days, 2, 3, 4, 6, 8, and
      10 months, and then every 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tremelimumab, durvalumab, HIGRT, SBRT)ExperimentalPatients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1, week 1. Treatment repeats every 4 weeks for up to 4 cycles or every 6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes on day 1, week 1. Treatment repeats every 4 weeks for up to 9 cycles or every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo hypofractionated radiation therapy using either HIGRT or SBRT over 3 fractions QOD during week 3.
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven recurrent/metastatic squamous cell carcinoma arising from a
             previous head and neck primary site, and located within the head and neck region, lung
             mediastinum, lymph nodes, soft tissue metastases or bone, and who are not candidates
             for curative intent therapy

          -  An actual body weight > 40kg

          -  Demonstrated disease progression during, or after discontinuation, of the most recent
             line of systemic therapy

          -  Have received any number lines of prior systemic therapy (including systemic therapy
             in the curative intent setting, and including a platinum containing regimen)

          -  Have received an anti-PD1 or anti PDL1 monoclonal antibody

          -  Have a target lesion/s deemed suitable by the treating physicians for hypofractionated
             radiation therapy (HIGRT or SBRT) with the intent of palliation or prevention of
             symptoms; this lesion must be: a) 1-3 non overlapping sites in the head and neck
             region OR b) metastatic lesions outside the head and neck (H&N) region in the lung
             mediastinum, soft tissue metastases, lymph nodes or bone (a minimum of 1 and a maximum
             5 lesions will be irradiated), provided there is no significant overlap between the
             lesions; patients should have RECIST 1.1 criteria measurable disease in addition to
             the lesion/s treated with radiation; if the site/s of radiation were previously
             radiated to high dose RT (> 50 Gy), there should be > 6 month time interval between
             the last dose of radiation and the start of radiation

          -  Have the ability to tolerate required radiotherapy-related procedures (e.g.: lie flat
             and hold position for treatment) as determined by the treating physician

          -  Be willing and able to provide written informed consent for the trial and comply with
             the study visit requirements

          -  Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that will be
             treated with stereotactic radiation therapy)

          -  Have provided tissue from an archival tissue sample or newly obtained core or
             excisional biopsy of a tumor lesion

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Hemoglobin >= 9.0 g/dL (should be performed within 10 days of treatment initiation)

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3) (should be
             performed within 10 days of treatment initiation)

          -  Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3) (should be performed within 10
             days of treatment initiation)

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (should be
             performed within 10 days of treatment initiation); this will not apply to subjects
             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/serum glutamic-oxaloacetic transaminase (AST/SGOT)/alanine
             aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT) =< 2.5 x
             institutional upper limit of normal unless liver metastases are present, in which case
             it must be =< 5 x ULN (should be performed within 10 days of treatment initiation)

          -  Serum creatinine clearance (CL) > 60 mL/min by the Cockcroft-Gault formula (Cockcroft
             and Gault 1976) or by 24-hour urine collection for determination of creatinine
             clearance (should be performed within 10 days of treatment initiation)

          -  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).

          -  Female subjects of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication; if
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

          -  Female subjects of childbearing potential should be willing to use 1 method of highly
             effective birth control or be surgically sterile, or abstain from heterosexual
             activity for the course of the study through 180 days after the last dose of study
             medication; subjects of childbearing potential are those who have not been surgically
             sterilized or have not been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 180 days after the last dose of study therapy

          -  Patient is >= 5 years free of another primary malignancy, except: a) if the other
             malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other
             primary malignancy is not considered clinically significant and is requiring no active
             intervention

        Exclusion Criteria:

          -  Has a body weight ≤ 40kg at the time of enrollment

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of treatment

          -  Has a target lesion/s for radiotherapy that is > 5 cm (> 50 cc) in greatest dimension

          -  Has a target lesion/s in a region that previously received high dose radiation therapy
             (RT) (> 50 Gy) demonstrating any of the following:

               -  carotid artery encasement (> 180 degrees)

               -  unprotected carotid artery (i.e. skin is directly over the carotid without
                  intervening soft tissue, especially after prior neck dissection without a
                  vascularized free flap) (a&b due to risk of carotid blow out)

               -  skin infiltration by tumor (due to risk of fistula)

               -  located in the larynx/hypopharynx primaries (due airway threat) treated with high
                  dose radiation therapy (>50 Gy) within 6 months or less of trial enrollment

          -  Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving a prior
             immunotherapy agent, or any unresolved irAE > grade 1

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or 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)

          -  Has received a prior monoclonal antibody within 4 weeks prior to study day 1 or who
             has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier

          -  Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at
             baseline) from adverse events due to a previously administered agent

               -  Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy

          -  Has known brain metastases or spinal cord compression unless the patient is stable
             (asymptomatic; no evidence of new or emerging brain metastases; and stable and off
             steroids for at least 14 days prior to start of study treatment); following
             radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks
             following the intervention and before initiating study treatment with imaging to
             confirm stability

          -  Has an active autoimmune disease requiring systemic treatment within the past 2 years
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents; subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule; subjects that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study; subjects with hypothyroidism stable on hormone replacement
             will not be excluded from the study

          -  Has evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
             history of ILD or pneumonitis requiring oral or intravenous glucocorticoids

          -  Has an active infection requiring systemic therapy

          -  Requires therapeutic anticoagulation or has known active bleeding diathesis

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 180 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-Cytotoxic T-lymphocyte-associated antigen-4
             (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically
             targeting T-cell co-stimulation or checkpoint pathways)

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has evidence of acute or chronic hepatitis B or hepatitis C

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment

          -  Has a mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3
             electrocardiograms (ECGs) using Fridericia's Correction

          -  Has a history of primary immunodeficiency or an allogeneic organ transplant

          -  Has a history of hypersensitivity to durvalumab or tremelimumab excipient

          -  Known history of previous clinical diagnosis of tuberculosis

          -  Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
             heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac
             arrhythmia, active peptic ulcer disease or gastritis, seizures
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse effects graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:Adverse events will be recorded and graded based on CTCAE v. 4, and their relationship to the experimental agents reported.

Secondary Outcome Measures

Measure:Response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Clinical responses to the combination of durvalumab, tremelimumab and hypofractionated radiation will be based on RECIST 1.1 criteria
Measure:Progression-free survival
Time Frame:From the date of study enrollment for up to 2 years
Safety Issue:
Description:Survival estimates will be calculated using the Kaplan-Meier method
Measure:Overall survival
Time Frame:From the date of study enrollment for up to 2 years
Safety Issue:
Description:Survival estimates will be calculated using the Kaplan-Meier method

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

December 30, 2019