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

Phase 2

Completed

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

• Registration Number: NCT03077243
• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

Brief Summary

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.

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 Timeline

• Study Start: 2016-12
• Study First Submitted: 2017-01-30
• Study First Submitted QC: 2017-03-06
• Study First Posted: 2017-03-10
• Primary Completion: 2022-12-14
• Study Completion: 2022-12-14
• Results First Submitted: 2023-11-06
• Status Verified: 2024-04
• Results First Submitted QC: 2024-04-05
• Last Update Submitted: 2024-04-05
• Results First Posted: 2024-05-02
• Last Update Posted: 2024-05-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 195

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Radiotherapy and/or chemotherapy.	Cisplatin (or alternative)	Subjects with Oropharyngeal Squamous Cell Carcinoma receiving radiotherapy and/or chemotherapy.
Radiotherapy and/or chemotherapy.	Assessment for surgical evaluation	Subjects with Oropharyngeal Squamous Cell Carcinoma receiving radiotherapy and/or chemotherapy.
Radiotherapy and/or chemotherapy.	Intensity Modulated Radiotherapy (IMRT)	Subjects with Oropharyngeal Squamous Cell Carcinoma receiving radiotherapy and/or chemotherapy.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Two years after completion of the treatment	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.

Secondary Outcome Measures

Name	Time	Method
Local Control Rate	2 years after completion of the treatment	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.
Number of Participants With Plasma Circulating Free DNA -3months	3 months after completion of the treatment	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.
Number of Participants With Plasma Circulating Free DNA -1 Year	1 year after completion of the treatment	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.
Regional Control Rate	2 years post-CRT	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.
Number of Participants With Plasma Circulating Free DNA -Baseline	Baseline	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.
Number of Participants With Plasma Circulating Free DNA -2 Year	2 years after completion of the treatment	The number of subjects who have or do not have plasma circulating free Human papillomavirus Deoxyribonucleic acid (HPV- DNA) was tabulated.
Distant Metastasis Free Survival	Two years after completion of the treatment	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.
Overall Survival Rate	Up to 2 years after completion of treatment	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.
Local-regional Control Rate	2 years after completion of the treatment	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.

Trial Locations

Locations (4)

University of Florida Proton Therapy Institute; 🇺🇸 Jacksonville, Florida, United States

Rex Healthcare; 🇺🇸 Raleigh, North Carolina, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of North Carolina at Chapel Hill, Department of Radiation Oncology; 🇺🇸 Chapel Hill, North Carolina, United States