P53 Mutational Status and cf HPV DNA for the Management of HPV-associated OPSCC

LCCC 1612: P53 Mutational Status and Circulating Free HPV DNA for the Management of HPV-associated Oropharyngeal Squamous Cell Cancers

The primary objective of this study is to evaluate whether genomic based risk-stratification can be used in deciding whether to de-intensify in patients with Human Papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC) with > 10 pack years smoking history. Hypothesis: Patients with HPV-associated OPSCC, > 10 pack years smoking history, and non-mutated p53 will have similar 2 year progression-free survival (PFS) as patients with < 10 pack years smoking history.

Study Overview

• Status: Completed
• Conditions: Head and Neck Neoplasms; Carcinoma, Squamous Cell; Oropharyngeal Neoplasms
• Intervention / Treatment: Procedure: Assessment for surgical evaluation; Radiation: Intensity Modulated Radiotherapy (IMRT); Drug: Cisplatin (or alternative)

Detailed Description

The proposed study is a follow-up study to LCCC 1120 and 1413. The investigators have shown that de-intensification is efficacious in these two phase II studies. A major question is whether the investigators can de-intensify in patients with HPV-associated oropharyngeal cancer who have smoking histories. The investigators' hypothesis is that genomic profiling of patients' tumors (specifically for p53 mutations) will help in triaging patients to de-intensification versus standard of care. Patients with HPV-associated OPSCC will be enrolled regardless of smoking history and p53 mutational status will be assessed in patients with a smoking history. The investigators will use the same de-intensification chemoradiotherapy regimen already evaluated in LCCC 1120 and 1413 in patients with HPV-associated OPSCC who have a minimal smoking history and in patients with a smoking history but with wild-type p53. Patients with a smoking history who have mutated p53 will not receive de-intensified chemoradiotherapy, but instead will receive standard doses. The hypothesis is that by using genomics in the patients with a significant smoking history, the investigators will better select those who can be safely de-intensified. Circulating free HPV DNA (cf-HPV-DNA) will also be prospectively assessed from blood samples.

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Jacksonville, Florida, United States, 32206
      • University of Florida Proton Therapy Institute
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill, Department of Radiation Oncology
    • Raleigh, North Carolina, United States, 27607
      • Rex Healthcare

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. ≥ 18 years of age (no upper age limit)
2. T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx
3. Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive
4. Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to treatment
5. ECOG Performance Status 0-1
6. CBC/differential obtained within 8 weeks prior to treatment, with adequate bone marrow function defined as follows: Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl
7. Adequate renal and hepatic function within 4 weeks prior to treatment, defined as follows: Serum creatinine < 2.0 mg/dl; Total bilirubin < 2 x the institutional ULN; AST or ALT < 3 x the institutional ULN
8. Negative pregnancy test within 2 weeks prior to treatment for women of childbearing potential
9. Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment.
10. Patients must be deemed able to comply with the treatment plan and follow-up schedule.
11. Patients must provide study specific informed consent prior to study entry

Exclusion Criteria:

1. Prior history of radiation therapy to the head and neck
2. Prior history of head and neck cancer.
3. Unresectable disease (e.g. immobile node on physical exam, nodal disease that radiographically involves the carotid arteries, nerves)
4. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs)
5. Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (Note, however, coagulation parameters are not required for entry into this protocol); Pre-existing ≥ grade 2 neuropathy; Prior organ transplant; Systemic lupus; Psoriatic arthritis
6. Known HIV positive.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Radiotherapy and/or chemotherapy.; Subjects with Oropharyngeal Squamous Cell Carcinoma receiving radiotherapy and/or chemotherapy.

Procedure: Assessment for surgical evaluation; Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.; Radiation: Intensity Modulated Radiotherapy (IMRT); 60- 70 Gy at 2 Gy/fx; Drug: Cisplatin (or alternative); The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 -7 total doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS was assessed as the time from the first day of chemoradiation therapy (CRT) until disease progression. Disease progression was defined as biopsy proven tumor cells. Positron emission tomography / computerized tomography (PET/CT) was performed at week 10-16 (optimally at week 12) after completion of therapy. Biopsies were performed for subjects with imaging or clinical exam results suspicious for tumor. Clinical follow-up occurred and chest imaging was performed during the follow-up.	Two years after completion of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Plasma Circulating Free DNA -Baseline	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.	Baseline
Number of Participants With Plasma Circulating Free DNA -3months	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.	3 months after completion of the treatment
Number of Participants With Plasma Circulating Free DNA -1 Year	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.	1 year after completion of the treatment
Number of Participants With Plasma Circulating Free DNA -2 Year	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.	2 years after completion of the treatment
Local Control Rate	The local control rate is defined as the total disappearance of the primary tumor without any local recurrence. Local recurrence was defined as biopsy-proven tumor cells in the primary tumor region. Biopsy was performed for a subject with a positive positron emission tomography / computerized tomography scan and /or clinical discretion of the surgeon 16 weeks after completion of the treatment.	2 years after completion of the treatment
Regional Control Rate	Regional control rate is defined as the total disease disappearance of the related lymph node metastases without any lymph node recurrence. Regional recurrence was defined as biopsy proven tumor cells in related lymph nodes. Biopsy was performed for a subject with a positive positron emission tomography / computerized tomography scan and /or clinical discretion of the surgeon 16 weeks after completion of the treatment.	2 years post-CRT
Local-regional Control Rate	Local-regional control rate is defined as the total disappearance of the primary tumor and related lymph node metastases without any recurrence. Local-regional recurrence was defined as biopsy-proven tumor cells in the primary tumor region and/or related lymph nodes. Biopsy was performed for a subject with a positive positron emission tomography / computerized tomography scan and /or clinical discretion of the surgeon 16 weeks after completion of the treatment.	2 years after completion of the treatment
Distant Metastasis Free Survival	Distant metastasis-free survival is defined as the time from the first day of the study treatment to the date of disease spreads while subjects are alive. Distant metastasis-free survival is defined as no disease outside of the primary tumor and related lymph node metastases. Distant metastasis was defined as biopsy-proven tumor cells outside of the primary tumor and related lymph node metastases. Biopsy was performed for a subject with a positive positron emission tomography / computerized tomography scan and /or clinical discretion of the surgeon 16 weeks after completion of the treatment.	Two years after completion of the treatment
Overall Survival Rate	The overall survival rate is defined as the time from the first day of the study treatment to the date of death for any cause. Subjects who have not had an event will be censored at the date of the last assessment documenting the subject was alive.	Up to 2 years after completion of treatment

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Investigators: Principal Investigator: Wendell Gray Yarbrough, MD, University of North Carolina at Chapel Hill, Department of Radiation Oncology

Publications and helpful links

General Publications

• Chera BS, Kumar S, Shen C, Amdur R, Dagan R, Green R, Goldman E, Weiss J, Grilley-Olson J, Patel S, Zanation A, Hackman T, Blumberg J, Patel S, Thorp B, Weissler M, Yarbrough W, Sheets N, Mendenhall W, Tan XM, Gupta GP. Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer. J Clin Oncol. 2020 Apr 1;38(10):1050-1058. doi: 10.1200/JCO.19.02444. Epub 2020 Feb 4. Erratum In: J Clin Oncol. 2020 Oct 20;38(30):3579. J Clin Oncol. 2023 Sep 20;41(27):4449.

Helpful Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): December 14, 2022
• Study Completion (Actual): December 14, 2022

Study Registration Dates

• First Submitted: January 30, 2017
• First Submitted That Met QC Criteria: March 6, 2017
• First Posted (Actual): March 10, 2017

Study Record Updates

• Last Update Posted (Actual): May 2, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Chemotherapy; Squamous Cell Carcinoma; Radiation Therapy; p16; Human Papillomavirus; Oropharynx; Oropharyngeal Squamous Cell Carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Neoplasms, Squamous Cell; Neoplasms; Head and Neck Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Oropharyngeal Neoplasms; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: LCCC1612

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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