A Randomized Phase II/III Trial of De-Intensified Radiation Therapy for Patients With Early-Stage, P16-Positive, Non-Smoking Associated Oropharyngeal Cancer

Plain English Summary

De-intensified Radiation Therapy With Chemotherapy (Cisplatin) or Immunotherapy (Nivolumab) in Treating Patients With Early-Stage, HPV-Positive, Non-Smoking Associated Oropharyngeal Cancer is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma. Tests a lower dose of radiation therapy with nivolumab or cisplatin for early-stage, HPV-positive, non-smoking oropharyngeal cancer. For patients with early-stage, HPV-positive oropharyngeal cancer who have not smoked in the past 10 years and have no distant metastases. Participation involves a biopsy, blood draw, and radiation therapy with or without chemotherapy, followed by regular check-ups. Alternatives include standard radiation therapy with cisplatin or other treatments recommended by your doctor. The trial aims to enroll 384 participants.

Official Summary

This phase II/III trial studies how well a reduced dose of radiation therapy works with nivolumab compared to cisplatin in treating patients with human papillomavirus (HPV)-positive oropharyngeal cancer that is early in its growth and may not have spread to other parts of the body (early-stage), and is not associated with smoking. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see if a reduced dose of radiation therapy and nivolumab works as well as standard dose radiation therapy and cisplatin in treating patients with oropharyngeal cancer.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if you have early-stage, HPV-positive oropharyngeal cancer, have not smoked in the past 10 years, and have no distant metastases. Not eligible if you have a neuroendocrine phenotype or if your p16 result is not positive. Age must be 18 or older. Must have a strong immune system (Zubrod performance status of 0-1). This trial is studying Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures include progression-free survival and quality of life, which are important for patients to understand their chances of staying cancer-free and maintaining their quality of The specific primary outcome measures are: Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) (From randomization to first progression or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.); Progression-free Survival (Phase III) (Percentage of Participants Alive Without Progression) (From randomization to first progression or last follow-up. Maximum follow-up was 4.6 years.); MD Anderson Dysphagia Inventory (MDADI) Global Quality of Life (QOL) Score (Baseline to two years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a treatment gap by testing a reduced dose of radiation therapy with immunotherapy for early-stage, HPV-positive oropharyngeal cancer. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma, where improved treatment options are needed.

Investor Insight

The market for head and neck cancer treatments is growing, with this trial potentially offering a less aggressive treatment option, which could be a significant competitive advantage. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential benefits and risks of participating in the trial. Day-to-day participation involves regular check-ups, blood draws, and radiation therapy sessions. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 384 participants

Interventions

• PROCEDURE: Biopsy Procedure — Undergo tissue biopsy
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• DRUG: Cisplatin — Given IV
• PROCEDURE: Computed Tomography — Undergo CT
• OTHER: Fludeoxyglucose F-18 — Receive FDG

Primary Outcomes

• Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression) (From randomization to first progression or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
• Progression-free Survival (Phase III) (Percentage of Participants Alive Without Progression) (From randomization to first progression or last follow-up. Maximum follow-up was 4.6 years.)
• MD Anderson Dysphagia Inventory (MDADI) Global Quality of Life (QOL) Score (Baseline to two years)

Secondary Outcomes

• Locoregional Failure (Percentage of Participants With Locoregional Failure) (From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
• Distant Failure (Percentage of Participants With Distant Failure) (From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
• Overall Survival (Percentage of Participants Alive) (From randomization to death from any cause or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
• Number of Participants by Highest Grade Adverse Event Reported (From randomization to last known follow-up. Maximum follow-up at the time of analysis was 4.6 years.)
• Hearing (Baseline up to 24 months from end of radiation therapy (RT))

Full Eligibility Criteria

Inclusion Criteria:

* Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma but not neuroendocrine phenotype) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage)
* Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =\< 4 nodes are permitted and considered as non-therapeutic nodal excisions
* P16-positive based on local site immunohistochemical tissue staining (defined as greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification

  * Note: Institutions must screen patients, whose tumors must be p16-positive by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. The p16-positive results must be reported on the pathology report being submitted
  * Note: If p16 result is equivocal, positive HPV deoxyribonucleic acid (DNA) test of tumor specimen is acceptable and fulfills the eligibility criteria
* Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer \[AJCC\], 8th edition \[ed.\]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based on the following diagnostic workup:

  * General history and physical examination within 56 days prior to registration;
  * Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;
  * One of the following imaging studies is required within 56 days prior to registration:

    * FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR
    * Chest CT (with or without contrast)
  * One of the following imaging studies is required within 28 days prior to registration:

    * A diagnostic CT scan of neck (with contrast and of diagnostic quality) OR
    * An magnetic resonance imaging (MRI) of the neck (with contrast and of diagnostic quality)
    * Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools
* Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years. The following formula is used to calculate the pack-years during the periods of smoking in the patient's life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history

  * Number of pack-years = \[Frequency of smoking (number of cigarettes per day) x duration of cigarette smoking (years)\] / 20
  * Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined. While there are reportedly increased risks of head and neck cancer associated with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette products is unusual and does not appear to convey added risk with synchronous cigarette smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is no clear scientific evidence regarding the role of chewing tobacco-containing products in this disease, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators are discouraged from enrolling patients with a history of very sustained use (such as several years or more) of non-cigarette tobacco products alone
* Zubrod performance status of 0-1 within 14 days prior to registration
* Age \>= 18
* Absolute neutrophil count \>= 1,500/mcL (within 14 days prior t

Trial Locations

• University of Alabama at Birmingham Cancer Center, Birmingham, Alabama, United States
• Banner MD Anderson Cancer Center, Gilbert, Arizona, United States
• Banner University Medical Center - Tucson, Tucson, Arizona, United States
• University of Arizona Cancer Center-North Campus, Tucson, Arizona, United States
• Kaiser Permanente-Deer Valley Medical Center, Antioch, California, United States
• PCR Oncology, Arroyo Grande, California, United States
• Sutter Auburn Faith Hospital, Auburn, California, United States
• Sutter Cancer Centers Radiation Oncology Services-Auburn, Auburn, California, United States
• AIS Cancer Center at San Joaquin Community Hospital, Bakersfield, California, United States
• Tower Cancer Research Foundation, Beverly Hills, California, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• HPV-positive oropharyngeal cancer, Basaloid Squamous Cell Carcinoma, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Squamous Cell Carcinoma

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