Last updated on June 2019

Durvalumab and Tremelimumab With Radiotherapy for Adjuvant Treatment of Intermediate Risk SCCHN


Brief description of study

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 Study 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.

Clinical Study Identifier: NCT03529422

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Recruitment Status: Open


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