Neoplasms

All Conditions

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Oropharyngeal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Durvalumab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Tremelimumab

Ipilimumab

Antineoplastic Agents, Immunological

Immunologic Factors

Immune Checkpoint Inhibitors

Beginning day 0 of course 1, participants undergo stereotactic body radiation therapy 5 days a week for 1 week and receive 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.

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.

Modified Radical Neck Dissection

Quality-of-Life Assessment

Questionnaire Administration

Stereotactic Body Radiation Therapy

Transoral Robotic Surgery

Robert Chin

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.

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.

Stereotactic Body Radiation Therapy and Durvalumab With or Without Tremelimumab Before Surgery in Treating Participants With Human Papillomavirus Positive Oropharyngeal Squamous Cell Caner

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)

Data from all cycles of treatment will be combined in the presentation of safety data. AEs will be listed individually by patient.

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.

OS will be estimated by Kaplan-Meier estimate. Summaries of the number and percentage of patients who have died, are still in survival follow-up, are lost to follow-up and have withdrawn consent will be provided along with median OS.

Kaplan-Meier estimate will be used to describe primary tumor control rate.

Distant recurrence rate will be determined by surveillance imaging, with failure defined as the appearance of new distant disease from the date of enrollment. Kaplan-Meier estimate will be used to describe distant recurrence rate.

Locoregional control rate will be determined by surveillance imaging, with failure defined as the appearance of new locoregional disease from the date of enrollment. Kaplan-Meier estimate will be used to describe locoregional control rate.

Will be determined by surveillance imaging, with failure defined as the appearance of new cervical lymphadenopathy from the date of enrollment. Kaplan-Meier estimate will be used to describe rate of contralateral neck failure.

Will be determined by surgical pathology findings.

The objective response rate will be determined by pre-surgical magnetic resonance imaging.

The safety analysis set will be used for safety analyses. The overall safety and tolerability will be assessed throughout the study period. All adverse event data will be listed individually by treatment group and patient identifier.

Will be using the University Washington's Quality of Life Questionnaire (UW-QOL) v4. Assessment at baseline, with each cycle, post-stereotactic body radiation therapy, post-surgically, and throughout adjuvant therapy on a standard schedule. The scale is 0 (worst) to 100 (best)

Will be using the Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) version 4. questionnaire. Assessment at baseline, with each cycle, post-stereotactic body radiation therapy, post-surgically, and throughout adjuvant therapy on a standard schedule. The scale is 0 to 40. The higher the score the better quality of life (QOL).

Spots Global Cancer Trial Database for p16 positive neoplastic cells present