Clinical Trials /

Durvalumab With Radiotherapy for Adjuvant Treatment of Intermediate Risk SCCHN

NCT03529422

Description:

The purpose of this study is to investigate other drugs that may be combined with radiation to treat cancer. The study focuses on determining whether a combination of two investigational immunotherapy drugs, durvalumab and tremelimumab, with radiation can both improve cure rate and at the same time have less serious side effects. Throughout this document, these investigational drugs will be referred to together as the" study drugs", or named individually (durvalumab or tremelimumab). The study drugs in this research are referred to as investigational because the U.S. Food and Drug Administration (FDA) has not yet approved them for the treatment of head and neck cancer. Durvalumab was FDA approved in 2017 for the treatment of certain types of bladder cancer, but has not been approved for use in Head and Neck cancer patients. Durvalumab and Tremelimumab are experimental drugs that use the body's immune system to fight the cancer. The combination of these study drugs is being used in other ongoing clinical trials for other types of cancers. The doctor feels that a patient may experience fewer side effects using these study drugs with radiation rather than using cisplatin. The doctor is also investigating whether using these drugs can increase the effectiveness of treatment.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Hypopharyngeal Squamous Cell Carcinoma
  • Laryngeal Squamous Cell Carcinoma
  • Oral Cavity Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Tremelimumab With Radiotherapy for Adjuvant Treatment of Intermediate Risk SCCHN
  • Official Title: A Phase I Study of Durvalumab (MEDI 4736) and Tremelimumab Together With Radiotherapy for the Adjuvant Treatment of Intermediate Risk Head and Neck Squamous Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1725
  • NCT ID: NCT03529422

Conditions

  • Larynx
  • Lip
  • Oral Cancer
  • Digestive Organs--Diseases

Interventions

DrugSynonymsArms
DurvalumabImfinziOpen-label, single-arm
TremelimumabOpen-label, single-arm

Purpose

The purpose of this study is to investigate other drugs that may be combined with radiation to treat cancer. The study focuses on determining whether a combination of two investigational immunotherapy drugs, durvalumab and tremelimumab, with radiation can both improve cure rate and at the same time have less serious side effects. Throughout this document, these investigational drugs will be referred to together as the" study drugs", or named individually (durvalumab or tremelimumab). The study drugs in this research are referred to as investigational because the U.S. Food and Drug Administration (FDA) has not yet approved them for the treatment of head and neck cancer. Durvalumab was FDA approved in 2017 for the treatment of certain types of bladder cancer, but has not been approved for use in Head and Neck cancer patients. Durvalumab and Tremelimumab are experimental drugs that use the body's immune system to fight the cancer. The combination of these study drugs is being used in other ongoing clinical trials for other types of cancers. The doctor feels that a patient may experience fewer side effects using these study drugs with radiation rather than using cisplatin. The doctor is also investigating whether using these drugs can increase the effectiveness of treatment.

Detailed Description

      Primary Objectives

        -  To determine a safe adjuvant immunotherapy regimen that includes durvalumab with or
           without tremelimumab to combine with radiotherapy in intermediate-risk HNSCC patients
           based on dose limiting toxicities.

        -  To characterize safety by evaluating Grade 3-5 acute toxicities of adjuvant durvalumab
           and tremelimumab with radiotherapy in intermediate-risk HNSCC patients.

      Secondary Objectives

        -  To characterize the Grade 3-4 chronic toxicities of adjuvant durvalumab and tremelimumab
           with radiotherapy in intermediate-risk HNSCC patients.

        -  To characterize any-grade chronic toxicities of adjuvant durvalumab and tremelimumab
           with radiotherapy in intermediate-risk HNSCC patients.

        -  To estimate median disease free survival (DFS) in patients with intermediate-risk HNSCC
           treated with adjuvant durvalumab and tremelimumab with radiotherapy.

        -  To estimate median overall survival (OS) in patients with intermediate-risk HNSCC
           treated with adjuvant durvalumab and tremelimumab with radiotherapy.

        -  To correlate PD-L1 expression with disease free survival.

      Exploratory Objectives

        -  To correlate CTLA-4 expression with disease free survival

        -  To analyze disease free survival by Human papilloma virus (HPV) status

        -  To determine how treatment with adjuvant durvalumab, tremelimumab, and radiotherapy
           changes markers of tumor infiltrating lymphocytes (TIL)

      Primary Endpoints

        -  A safe immunotherapy regimen with radiation will be determined based on pre-defined dose
           limiting toxicities following standard 3+3 regimen de-escalation rules outlined in the
           study schema in section 5.1.

        -  Grade 3-5 acute toxicity will be evaluated according to guidelines from NCI CTCAE, v5.0
           and include toxicity from the first day of treatment with immunotherapy until 30 days
           after completion of concurrent immunotherapy and radiation. Toxicity will include all
           toxicity attributed to the total study regimen (inclusive of radiation) not just to the
           immunotherapy alone.

      Secondary Endpoints

        -  Grade chronic 3-5 toxicity will be evaluated according to guidelines from NCI CTCAE,
           v5.0 and include toxicity continuing or occurring 30 days after completion of concurrent
           immunotherapy and radiation and will be followed for up to 6 months.

        -  DFS will be estimated via the Kaplan-Meier method. DFS is defined as the time from D1 of
           treatment to time of disease recurrence or death.

        -  OS will be estimated via the Kaplan-Meier method. OS is defined as the time from D1 of
           treatment to death from any cause.

        -  Measure Programmed cell death ligand 1 (PD-LI) expression by immunohistochemistry.
           Pre-treatment PD-L1 expression will be correlated with disease free survival following
           treatment of adjuvant durvalumab and tremelimumab with radiotherapy

      Exploratory Endpoints

        -  Measure Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) expression by
           immunohistochemistry. Pre-treatment CTLA-4 expression will be correlated with disease
           free survival following treatment of adjuvant durvalumab and tremelimumab with
           radiotherapy

        -  Measure HPV status. HPV status will be correlated with disease free survival following
           treatment of adjuvant durvalumab and tremelimumab with radiotherapy

        -  Measure tumor infiltrating lymphocytes (TIL) by flow cytometry at baseline
           (post-surgical, pre-treatment tissue) and at disease progression (post-treatment
           tissue). Changes in TIL levels will be compared between these two time points.

      Treatment Dosage This Phase I trial includes a traditional 3 + 3 dose regimen de-escalation
      rules to evaluate the combination of durvalumab + tremelimumab with radiation therapy based
      on three possible combination regimens (Table 1). In regimen cohort 1, three patients will
      receive durvalumab (1500mg Q3W) with tremelimumab (75 mg IV Q3W) for four total cycles. They
      will receive radiation therapy (60Gy over 30 fractions) during cycles 2-4. During Cycle 5 and
      6, only durvalumab 1500mg Q3W will be given. Patients will be assessed for dose limiting
      toxicity (DLT) during cycles 1-4. If ≤1 patient experiences a DLT in cohort 1 on this regimen
      per the 3+3 rules outlined above, then the study will continue to enroll subjects on this
      regimen in the dose expansion cohort. If ≥2 patients experience DLTs on this regimen in
      cohort 1, it will be deemed intolerable and cohort -1 will be opened for enrolment. Three
      patients will be enrolled to receive durvalumab (1500mg Q3W) with tremelimumab (75 mg IV Q6W)
      in regimen cohort -1. Similarly, if ≤1 patient experiences a DLT at regimen level -1, then
      the study will continue to enroll patients in the dose expansion cohort. If ≥2 patients
      experience DLTs at regimen level -1, then regimen level -2 will be opened for enrolment and
      three patients will receive durvalumab (1500mg Q3W) alone with radiotherapy in this cohort.
      If ≤ 1 patient experiences a DLT at regimen level -2, then this cohort will be expanded and
      subjects treated on this combination regimen. If ≥2 patients experience DLTs at regimen level
      -2, then the study will be discontinued.

      The acceptable regimen will be defined as the immunotherapy and radiotherapy combination at
      which ≤1 out of 6 patients have experienced a dose limiting toxicity (DLT). As noted in the
      schema above, expanded enrollment of subjects on the combination regimen selected will accrue
      24 subjects.

      Duration of Follow Up All patients will be followed for up to 5 years, or until death,
      whichever occurs first after removal from study treatment for determination of study
      endpoints. Patients removed from study treatment for unacceptable adverse event (AE)s will be
      followed for resolution or stabilization of the adverse event(s). All patients (including
      those withdrawn for AEs) should be followed after removal from study treatment as stipulated
      in the protocol.
    

Trial Arms

NameTypeDescriptionInterventions
Open-label, single-armOtherDurvalumab in combination with intensity modulated radiotherapy (IMRT) treatments and tremelimumab
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent obtained to participate in the study and HIPAA authorization
             for release of personal health information. Consent for the use of any residual
             material from biopsy (archival tissue) and serial blood draws will be required for
             enrollment.

          -  Age ≥ 18 years of age on day of signing informed consent

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (See Appendix
             12.4: ECOG Performance Status)

          -  Histologically confirmed squamous cell carcinoma of the head and neck, including the
             following subtypes: oral cavity, oropharynx, hypopharynx, larynx

          -  Must have undergone gross total resection of the primary tumor with curative intent
             within the past 8 weeks with surgical pathology demonstrating ≥ 1 of the following
             criteria for "intermediate" risk of recurrence:

          -  perineural invasion

          -  lymphovascular invasion

          -  single lymph node > 3cm or at least 2 nodes without evidence of extracapsular
             extension

          -  close margins defined as < 5 mm but not frankly positive (in the case of ambiguous,
             controversial, or superseded margins, final clinical assessment regarding margin
             status will prevail

          -  pathologically confirmed T3 or T4 primary tumor

          -  No prior therapy to primary tumor prior to surgical resection (no induction therapy or
             recurrent disease).

          -  Demonstrate adequate organ function as defined in the table below; all screening labs
             to be obtained within 14 days prior to initiating study treatment

          -  Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 24 days prior to registration. NOTE: Females are considered of child bearing
             potential unless they are surgically sterile (have undergone a hysterectomy, bilateral
             tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at
             least 12 consecutive months. Documentation of postmenopausal status must be provided.

          -  WOCBP must be willing to abstain from heterosexual activity or to use at least 1
             highly effective method of contraception from the time of informed consent until 180
             days after durvalumab and tremelimumab combination therapy is stopped; or 90 days
             after durvalumab monotherapy treatment is discontinued (whichever is longer).

          -  Male patients with female partners must have had a prior vasectomy or agree to use an
             adequate method of contraception (i.e., double barrier method: condom plus spermicidal
             agent) starting with the first dose of study therapy through 6 months (180 days) after
             the last dose of durvalumab and tremelimumab combination therapy; or 90 days after
             durvalumab monotherapy is discontinued (whichever is longer).

          -  Subjects are willing and able to comply with study procedures based on the judgment of
             the investigator or protocol designee.

        Exclusion Criteria:

        Subjects meeting any of the following exclusion criteria will not be able to participate in
        this study:

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

          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study.

          -  Has evidence of metastatic disease at time of diagnosis

          -  Is receiving concurrent chemotherapy, investigational drug, biologic, or hormonal
             therapy for cancer treatment. Concurrent use of hormonal therapy for
             non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

          -  Treatment with any investigational drug within 28 days or 5 half-lives of Day 1 of
             treatment on this study.

          -  Known allergy or hypersensitivity to 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.

          -  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., CT scan premedication)

          -  Has received systemic steroid therapy or any other form of immunosuppressive therapy
             within 7 days prior to the first dose of trial treatment.

          -  Active infection requiring systemic therapy including tuberculosis (TB) (clinical
             evaluation that includes clinical history, physical examination and radiographic
             findings, and TB testing in line with local practice), hepatitis B (known positive HBV
             surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
             (positive HIV 1/2 antibodies).

          -  Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
             core antibody [anti-HBc] and absence of HBsAg) are eligible.

          -  Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
             reaction is negative for HCV RNA.

          -  Has a known contraindication to radiation therapy, including inherited syndromes
             associated with hypersensitivity to ionizing radiation such as Ataxia-Telangiectasia
             and Nijmegen Breakage Syndrome

          -  Has a history of liver disease (including but not limited to cirrhosis)

          -  Subjects with baseline weight ≤ 40kg (88 lbs). Female patients who are pregnant or
             breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is
             being treated on study) or male or female patients of reproductive potential who are
             not willing to employ effective birth control from screening to 90 days after the last
             dose of durvalumab monotherapy or 180 days after the last dose of durvalumab +
             tremelimumab combination therapy.

          -  History of another primary malignancy except for.

          -  Malignancy treated with curative intent and with no known active disease ≥5 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.

          -  Has an active autoimmune disease (or inflammatory disorders) requiring systemic
             treatment within the past 3 months or a documented history of clinically severe
             autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive
             agents. Subjects with 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:

          -  Subjects with vitiligo or alopecia or resolved childhood asthma/atopy

          -  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 or Sjorgen's syndrome will
             not be excluded from the study

          -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
             replacement

          -  Any chronic skin condition that does not require systemic therapy

          -  Subjects without active disease in the last 5 years may be included but only after
             consultation with the study physician

          -  Subjects with celiac disease controlled by diet alone

          -  Has a history of non-infectious pneumonitis that required steroids or evidence of
             interstitial lung disease or current active, non-infectious pneumonitis.

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
             acceptable.

          -  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.

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             drug. Note: Patients, if enrolled, should not receive live vaccine whilst receiving
             study treatment and up to 30 days after the last dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safe immunotherapy regimen with radiation
Time Frame:12 weeks
Safety Issue:
Description:A safe adjuvant immunotherapy regimen that includes durvalumab with or without tremelimumab to combine with radiotherapy in intermediate-risk HNSCC patients based on dose limiting toxicities

Secondary Outcome Measures

Measure:Chronic toxicity
Time Frame:12 weeks
Safety Issue:
Description:Grade 3-4 chronic toxicities of adjuvant durvalumab and tremelimumab with radiotherapy
Measure:All chronic toxicities
Time Frame:12 weeks
Safety Issue:
Description:All chronic toxicities of adjuvant durvalumab and tremelimumab with radiotherapy
Measure:Disease free survival
Time Frame:5 years
Safety Issue:
Description:Median disease free survival (DFS) in patients with intermediate-risk HNSCC treated with adjuvant durvalumab and tremelimumab with radiotherapy
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:Median overall survival in patients with intermediate-risk HNSCC treated with adjuvant durvalumab and tremelimumab with radiotherapy
Measure:PD-LI expression
Time Frame:12 weeks
Safety Issue:
Description:PD-LI expression with disease free survival

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • Head and Neck
  • Larynx
  • Lip
  • Oral Cancer

Last Updated