Phase I/Ib Trial of Radiotherapy in Combination With Durvalumab (MEDI4736) Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma of the Head and Neck (HNSCC)
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Squamous Cell Carcinoma of the Head and Neck
- Sponsor
- University of Colorado, Denver
- Enrollment
- 21
- Locations
- 3
- Primary Endpoint
- Maximum Tolerated Dose and Dose Limiting Toxicities
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This is a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment must be diagnosed with non-metastatic, biopsy-proven stage II-IVB oral cavity, stage III-IVB larynx and hypopharynx, or stage III-IVB HPV/p16 negative intermediate-high risk oropharynx head and neck cancer, and must be eligible and amenable to surgical resection.
Detailed Description
This study will be enrolled using a 3+3 model. Patients will receive one dose of neoadjuvant durvalumab 1500 mg approximately 3-6 weeks prior to standard of care surgery. It will be given concurrently with the first dose of radiation (RT). The starting RT dose level will be given as 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to sites of gross disease (Table 1) only to minimize exposure to normal tissue. If toxicity develops and surgery is delayed by more than 8 weeks (qualifying as a DLT), the radiation dose will be dropped per protocol for the next set of patients. If this dose is tolerated, the dose will be increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients. Patients will proceed to surgical resection approximately 3-6 weeks after radiation as recommended by the ENT surgeon.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed: stage II-IVB oral cavity, stage III-IVB larynx, stage III-IVB hypopharynx, or stage III-IVB HPV and/or p16 negative intermediate-high risk oropharynx head and neck cancer (AJCC 8th edition)
- •Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>10 mm by CT, PET/CT or MRI or \>10 mm on visual inspection by clinical exam
- •Patients who are deemed resectable by ENT surgeon without pre-existing medical conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse surgery
- •Written informed consent and HIPAA authorization obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
- •Age \> 18 years at time of study entry
- •ECOG performance status ≤ 1
- •Life expectancy ≥ 24 weeks
- •Body weight \>30kg
- •Adequate normal organ and marrow function as defined below:
- •Hemoglobin ≥9.0 g/dL
Exclusion Criteria
- •Participation in another clinical study with an investigational product during the last 3 months
- •Patients with active ILD / pneumonitis or with a history of ILD/ pneumonitis requiring steroids
- •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
- •Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, anti-PD-L2, anti-CD137, or 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)
- •Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 30 days prior to the first dose of study drug for patients who have received prior TKIs \[e.g., erlotinib, gefitinib and crizotinib\] and within 6 weeks for nitrosourea or mitomycin C. (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
- •Patients with QTc interval \> 470 msec during screening
- •Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 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)
Arms & Interventions
Dose Escalation and Expansion
Part 1 of this trial will use a traditional 3+3 design will be used for this trial (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Dose escalation will occur as long as there are minimal dose limiting toxicities.The expectation is that 9 patients will be enrolled to the trial during part 1.This is based on the expectation that all dose levels are safe (i.e. patients will not experience DLTs at all dose levels). The range of patients needed will be 6-12 patients. Part 2 of this trial will be an expansion cohort. A total of 8 additional patients will be enrolled at the dose level determined to be the MTD in part 1 of the study. These 8 patients will be used to confirm that the MTD is a safe combination, as well as provide additional patients to investigate the efficacy for the treatment combination. Note: Standard of care surgery will follow 3-6 weeks after medication and radiation treatment.
Intervention: Durvalumab
Dose Escalation and Expansion
Part 1 of this trial will use a traditional 3+3 design will be used for this trial (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Dose escalation will occur as long as there are minimal dose limiting toxicities.The expectation is that 9 patients will be enrolled to the trial during part 1.This is based on the expectation that all dose levels are safe (i.e. patients will not experience DLTs at all dose levels). The range of patients needed will be 6-12 patients. Part 2 of this trial will be an expansion cohort. A total of 8 additional patients will be enrolled at the dose level determined to be the MTD in part 1 of the study. These 8 patients will be used to confirm that the MTD is a safe combination, as well as provide additional patients to investigate the efficacy for the treatment combination. Note: Standard of care surgery will follow 3-6 weeks after medication and radiation treatment.
Intervention: Stereotactic Body Radiation Therapy (SBRT)
Dose Escalation and Expansion
Part 1 of this trial will use a traditional 3+3 design will be used for this trial (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Dose escalation will occur as long as there are minimal dose limiting toxicities.The expectation is that 9 patients will be enrolled to the trial during part 1.This is based on the expectation that all dose levels are safe (i.e. patients will not experience DLTs at all dose levels). The range of patients needed will be 6-12 patients. Part 2 of this trial will be an expansion cohort. A total of 8 additional patients will be enrolled at the dose level determined to be the MTD in part 1 of the study. These 8 patients will be used to confirm that the MTD is a safe combination, as well as provide additional patients to investigate the efficacy for the treatment combination. Note: Standard of care surgery will follow 3-6 weeks after medication and radiation treatment.
Intervention: Standard of Care Therapy
Outcomes
Primary Outcomes
Maximum Tolerated Dose and Dose Limiting Toxicities
Time Frame: Study start date to study end date, or death, whichever comes first, up to 24 months
The Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT) will be discovered by using the 3+3 study design.
Secondary Outcomes
- Evaluate Biomarkers: Phenotypic Analysis(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Evaluate Biomarkers: Immune Cell Infiltration(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Clinical Response(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Pathologic Response(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Evaluate Biomarkers: Gene Expression(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Short Term Quality of Life(Study start date to study end date, or death, whichever comes first, up to 24 months)
- Toxicity Profile(Study start date to study end date, or death, whichever comes first, up to 24 months)