The Sinai Robotic Surgery Trial in HPV-related Oropharyngeal Squamous Cell Carcinoma (SIRS 2.0 Trial)

The purpose of this study is to determine whether treatment of HPV-related oropharyngeal squamous cell carcinoma in patients with undetectable postoperative HPV circulating tumor DNA (cfHPVDNA), either with transoral robotic surgery (TORS) alone or combined with reduced doses of radiation and chemotherapy can result in cancer control and survival comparable to those previously reported with standard therapy.

The hope is that with this newer approach, the long-term complications from chemotherapy and radiation can be reduced.

Study Overview

• Status: Recruiting
• Conditions: HPV-positive Oropharyngeal Squamous Cell Carcinoma
• Intervention / Treatment: Procedure: Robotic surgery; Radiation: De-intensified XRT; Drug: Cisplatin

Detailed Description

There has been significant increase in the incidence of oropharynx cancer in North America and Europe. It is now understood that there are two dominant carcinogenic pathways for oropharyngeal squamous cell carcinoma. Environmentally related which is caused mainly by smoking and alcohol, and HPV-related oropharyngeal squamous cell carcinoma (HPVOPSCC). HPVOPSCC now accounts for over 80% of OPC seen in the USA and an increasing fraction of these malignancies in Europe. It has been shown that HPVOPSCC confers an excellent prognosis for intermediate staged disease and this has called into question the rational for aggressive concurrent chemoradiotherapy. High-dose radiotherapy (RT) and chemoradiotherapy (CRT) have substantial impact on local tissues and organ function and result in a significant rate of late mortality and morbidity. Studies are now being designed to reduce the impact of RT and CRT for patients.

Recently, a new test has been developed that measures HPV circulating tumor DNA (cfHPVDNA) in the blood. The test has emerged as a promising biomarker for HPVOPSCC, correlating with both treatment response as well as surveillance for cancer recurrence. Data suggests that a negative test in the surveillance period following treatment is highly sensitive and specific for recurrent disease.

In this trial, the study will be stratifying p16 positive patients with PCR detectable high-risk (HR) HPV DNA or RNA following TORS into risk groups based on final pathology to determine appropriate treatment intensity. Patients with low-risk pathologic disease and undetectable postoperative cfHPVDNA will receive no adjuvant therapy. Patients with high-risk pathologic disease and undetectable postoperative cfHPVDNA will receive de-intensified adjuvant radiation and chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 199
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tanvir Queraishi; Phone Number: (908) 340-7842; Email: tanvir.queraishi@mountsinai.org

Study Locations

• United States
  • New Jersey
    • Paramus, New Jersey, United States, 07652
      • Recruiting
      • Valley - Mount Sinai Comprehensive Cancer Care
  • New York
    • New York, New York, United States, 10019
      • Recruiting
      • Mount Sinai Health System
      • Contact: Alecia Charles; Phone Number: (212) 241-7107; Email: Alecia.Charles@mountsinai.org
      • Principal Investigator: Raymond Chai, MD
      • Contact: Joshua Barlow; Email: joshua.barlow@icahn.mssm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• OPSCC with positive p16 immunohistochemistry and HR-HPV DNA or RNA PCR
• Detectable baseline cfHPVDNA (greater than or equal to 10 fragments/mL)
• Undetectable baseline cfHPVDNA (less than 5 fragments/mL)
• Early and intermediate stage (T1N0-2B, T2N0-2B) disease without evidence of distant metastases or gross extranodal extension
• Age > 18 years
• No previous surgery, radiation therapy, or chemotherapy for head and neck cancer
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Less than or equal to 20 pack year tobacco history with no active tobacco use
• Adequate bone marrow, hepatic and renal functions
• Undetectable cfHPVDNA after surgery. Undetectable cfHPVDNA is defined as <5 fragments/mL

Exclusion Criteria:

• Advanced nodal stage (AJCC 7th edition N2C, N3) or surgically unresectable disease or disease that cannot be fully resected, unequivocal radiographic extranodal extension, supraclavicular or matted metastatic disease, >3 radiographic pathologic cervical nodes
• Previous or current malignancies at other sites, except for adequately treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, prostate cancer treated with surgery/radiotherapy, ductal carcinoma in situ of the breast treated with surgery/radiotherapy, or other cancer curatively treated and with no current evidence of disease for at least 3 years.
• Non-high-risk HPV subtype on initial biopsy or final pathology
• Presence of 5 or more positive nodes, irrespective of size, on final pathology
• p16 negative or HPV negative OPSCC as determined by IHC and PCR or ISH, respectively.
• Undetectable or < 5 copies/mL baseline cfHPVDNA prior to surgery
• Detectable repeat cfHPVDNA 1-5 weeks postoperatively via the NavDX assay, defined as > 5 fragments/mL
• Autoimmune disease treated with chemotherapy agents or anti TNF agents within the last 2 years.
• Other serious illnesses or medical conditions
• Participation in an investigational therapeutic drug trial within 30 days of study entry
• Detectable repeat cfHPVDNA postoperatively, defined as >5 fragments/mL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Robotic surgery only; Complete resection to negative frozen section margins (pT1-2); < 4 nodes, ≤ 2 mm extranodal extension (ENE), no supraclavicular nodes	Procedure: Robotic surgery; Transoral robotic surgical resection of the tumor with negative intraoperative frozen section margins.
Experimental: Robotic surgery with de-intensified adjuvant therapy; The presence of any of the following: 4 positive nodes, gross ENE, final positive margins, or bilateral neck disease; High-risk PNI/LVI (defined as PNI and LVI in combination or either factor in the presence of 3 or more positive nodes)	Procedure: Robotic surgery; Transoral robotic surgical resection of the tumor with negative intraoperative frozen section margins.; Radiation: De-intensified XRT; Daily reduced-dose radiation treatment equal to 4600 cGy with either intensity-modulated radiotherapy (IMRT) or proton beam therapy; Drug: Cisplatin; Dose: 40mg/M2/week Route: IV over approximately 30 minutes, mixed in 250ml normal saline Schedule: Weekly on Monday or Tuesday any time, or Wednesday prior to radiation for 5 weeks (total dose 200 mg/M2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local and/or regional disease recurrence (LRR)	Local and/or regional disease recurrence (LRR) at 2 years	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS at 2 years as defined as the proportion of patients without events (recurrence or death) at 2 years	2 years
Disease free survival (DFS)	PFS at 2 years as defined as the proportion of patients without events (recurrence or death) at 2 years	2 years
Overall Survival (OS)	OS at 2 years is defined as the proportion of patients alive at 2 years	2 years
M.D. Anderson Dysphagia Inventory	20 items instrument: a global assessment (a single question), it comprises three subscales: the emotional subscale (8 items), the functional subscale (5 items), and the physical subscale (6 items). The global assessment refers to the individual's swallowing difficulty as it affects one's overall daily routine. The emotional, functional, and physical subscales refer to the individual's affective response to the swallowing disorder, the impact of the disorder on daily activities, and the self-perception of the swallowing difficulties, respectively. Using a five-point scale (1-5), the minimum total score is 20 and the maximum 100. Higher score indicates the least interference with daily life.	2 years
Xerostomia Questionnaire (XQ)	Scale range from 1-10 (1 being dry as a desert and 10 is normal). Higher score indicates better health outcomes	2 years
European Organization of Research and Treatment Of Cancer (EORTC QLQ-C30)	EORTC QLQ-C30 is a 30-question tool used to assess the overall QoL in cancer participants. It consisted of 15 domains: 1 GHS/QoL scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). Most items are scored 1 ("not at all") to 4 ("very much") except for the items contributing to the GHS/QoL, which are scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that all transformed scores lie between 0 to 100. For the GHS/QoL and 5 functional scales a high score indicates better global health status/functioning and a negative change from baseline indicated less improvement. Scale ranges from 0-100. For the symptom scales, a high score indicates a higher level of symptoms, and a negative change from baseline indicated an improvement in symptoms.	2 years
European Organization of Research and Treatment of Head and Neck cancer questionnaire (EORTC QLQ-H&N35)	EORTC QLQ-H&N35 is a 35-question site-specific tool and is used in conjunction with EORTC QLQ-C30 measurement tool. Scale range from 0-100. Higher score indicates poorer health outcomes.	2 years
M.D. Anderson Symptom Inventory - Head & Neck (MDASI-HN)	MDASI-HN is a 28 symptom items questionnaire: 13 general cancer-related symptoms, such as pain, fatigue and nausea; 9 HNC-related symptoms, such as problems with mucus in the mouth and difficulty in swallowing or chewing; 6 items to evaluate the effects of symptoms on daily life, including mood and enjoyment of life. Each item is rated on a 11-point scale from 0 (not at all) to 10 (as bad as you can imagine), while the items that assess the interference of symptoms on daily activities are rated from 0 (does not interfere) to 10 (interfered completely). Subscales and full scale range from 0-10. Higher score indicates poorer health outcome.	2 years

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Raymond Chai, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2022
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: June 10, 2022
• First Submitted That Met QC Criteria: June 10, 2022
• First Posted (Actual): June 15, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Human papillomavirus; ctDNA; HPV; p16; Oropharyngeal squamous cell carcinoma; OPSCC; circulating tumor DNA; Transoral robotic surgery; TORS; cfHPVDNA
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: STUDY 22-00279

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No