Phase Ib/II Trial of Stereotactic Body Radiotherapy (SBRT) in Cominbation With Immunotherapy Prior to Transoral Robotic Surgery (TORS) for Human Papillomavirus Positive (HPV+) Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC (American Joint Committee on Cancer) v8
- Sponsor
- Jonsson Comprehensive Cancer Center
- Enrollment
- 19
- Locations
- 1
- Primary Endpoint
- Progression-free survival (PFS) (Phase II)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase Ib/II trial studies the side effects and how well stereotactic body radiation therapy and durvalumab with or without tremelimumab before surgery work in treating participants with human papillomavirus positive oropharyngeal squamous cell cancer. Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy and durvalumab with or without tremelimumab before surgery may work better in treating participants with oropharyngeal squamous cell cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability associated with the following treatment regimens: Cohort 1: stereotactic body radiation therapy (SBRT) and durvalumab, followed by transoral robotic surgery (TORS) and adjuvant durvalumab and cohort 2: SBRT and durvalumab + tremelimumab, followed by TORS and adjuvant durvalumab. (Phase I safety lead-in) II. To assess the efficacy of the treatment combination deemed safe from Phase I in terms of progression free survival, in order to determine the non-inferiority of tumor control (progression-free survival \[PFS\] of 85% at 2 years) compared to conventional large field adjuvant radiotherapy +/- concurrent chemotherapy. (Phase II) III. To determine Common Terminology Criteria for Adverse Events (CTCAE) grade 3+ acute and chronic toxicities at the end of radiation, after surgery, at the end of adjuvant immunotherapy infusion, at 3 month, at 6 month, at 1 year, and at 2 years. (Phase II) SECONDARY OBJECTIVES: I. To determine the objective response rate to durvalumab +/- tremelimumab + SBRT prior to TORS. II. To determine the rate of subclinical lymph node involvement at time of TORS and neck dissection. III. To determine the rate of contra-lateral neck failure with medial oropharyngeal and base of tongue primary lesions. IV. To determine the potential salvage rate. V. To determine the locoregional control, distant control, and overall survival. VI. To determine the incidence of all toxicity associated with treatment protocol. VII. To determine the short- and long-term quality of life of patients on protocol. TRANSLATIONAL OBJECTIVES: I. To evaluate the impact of KRAS gene-variant mutation on immune response and treatment outcome. II. To evaluate the impact of PI3K gene mutation on immune response and treatment outcome. III. Saliva samples to evaluate biomarkers for immune response to human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) to be collected prior to treatment, at time of TORS, and at each yearly follow-up visit. IV. Blood samples to evaluate biomarkers of immune response to HPV associated OPSCC to be collected prior to treatment, at time of TORS, and at each yearly follow-up visit. V. Tumor tissue taken at the time of initial biopsy and at time of resection will be profiled for tumor infiltrating lymphocytes; activation markers and antigen specific T-cell receptor (TCR) utilization/diversity will be evaluated for additional checkpoint targets. VI. On long-term follow-up, tumor antigen specific T lymphocyte memory populations will be monitored for representation and robustness in in-vitro stimulation assays as potential biomarker of continued anti-tumor activity. VII. Immortalization of tumor infiltrating B-cells for identification of antigen presenting complex, antibody specificity, and potential serologic markers of continuing long-term immune response in patients. OUTLINE: Participants are assigned to 1 or 2 cohorts. COHORT I: Beginning day 0 of course 1, participants undergo stereotactic body radiation therapy 5 days a week for 1 week and receive durvalumab intravenously (IV) over 1 hour on days 0 and 27 in the absence of disease progression or unacceptable toxicity. Participants then undergo transoral robotic surgery and modified radical neck dissection between weeks 6-8. Beginning week 12, participants then receive durvalumab IV over 1 hour every 4 weeks. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. COHORT II: Beginning day 0 of course 1, participants undergo stereotactic body radiation therapy 5 days a week for 1 week and receive tremelimumab IV and durvalumab IV over 1 hour on days 0 and 27 in the absence of disease progression or unacceptable toxicity. Participants then undergo transoral robotic surgery and modified radical neck dissection between weeks 6-8. Beginning week 12, participants then receive durvalumab IV over 1 hour every 4 weeks. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up every 12 weeks for 2 years and then periodically thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluation.
- •Pathologically proven diagnosis of HPV-positive squamous cell carcinoma of the oropharynx. HPV-positivity will be defined as tumors that are p16-positive by immunohistochemistry.
- •Patients must have T0-3 disease with all gross disease amenable to R0 resection (reviewed by multidisciplinary study team) and is eligible for TORS in the opinion of the treating physician.
- •N0-N2b with all cervical disease confined to 2 cervical lymph node levels if the involved nodal levels are adjacent.
- •Karnofsky performance status \>=
- •Body weight \>= 50 kg.
- •Patients who are medically operable, without pre-existing medical conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse surgery.
- •Patients with smoking history (\< 20 pack year history) is allowed.
- •Patients must have MRI neck with and without contrast and a diagnostic positron emission tomography (PET), computed tomography (CT) or PET/CT skull base to mid-thigh with contrast within 30 days prior to SBRT.
- •Hemoglobin \>= 9.0 g/dL.
Exclusion Criteria
- •Karnofsky performance status (KPS) \<
- •Body weight \< 50 kg.
- •Histology other than squamous cell carcinoma.
- •Primary site other than oropharynx (i.e. oral cavity, salivary glands, nasal cavity, paranasal sinuses, larynx, or nasopharynx) or of unknown primary.
- •Patients with synchronous or bilateral disease.
- •Patient with N3 nodal disease, N2c nodal disease, and N2b disease with gross disease in more than 2 neck levels (levels not adjacent to each others are also not allowed).
- •Patients with recurrent head and neck cancer.
- •Patients with metastatic disease on initial staging study.
- •Patients who underwent attempted resection rather than the diagnostic biopsy of the primary site or nodal sampling of the neck disease.
- •Prior systemic therapy (chemotherapy, biologic, or immunotherapy) for the same OPSCC.
Outcomes
Primary Outcomes
Progression-free survival (PFS) (Phase II)
Time Frame: From time of enrollment to the first occurrence of disease progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 or death from any cause, assessed up to 2 years
The Kaplan-Meier product-limit estimate of the PFS function will be estimated and displayed. The median PFS time will be given with 95% confidence interval. Summaries of the number and percentage of patients experiencing a PFS event, and the type of event (RECIST v 1.1 or death) will be provided.
Incidence of grade >= adverse events (Phase II)
Time Frame: Up to 2 years
Incidence of adverse events (Phase I safety lead-in) assessed Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria
Time Frame: Up to 90 days after last dose
Data from all cycles of treatment will be combined in the presentation of safety data. AEs will be listed individually by patient.
Secondary Outcomes
- Overall survival (OS)(From the time of enrollment to date of death due to any cause, assessed up to 2 years)
- Distant recurrence rate(Up to 2 years)
- Primary tumor control determined by RECIST v. 1.1(Up to 2 years)
- Rate of subclinical lymph node involvement(At time of surgery)
- Locoregional control rate(Up to 2 years)
- Objective response rate(Up to 2 years)
- Incidence of adverse events assessed by CTCAE v4(Up to 2 years)
- Short quality of life(Up to 2 years)
- long-term quality of life(Up to 2 years)
- Rate of contralateral neck failure(Up to 2 years)