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Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8Phase 2NCT03799445

Ipilimumab, Nivolumab, and Radiation Therapy in Treating Patients With HPV Positive Advanced Oropharyngeal Squamous Cell Carcinoma

A Phase 2 study testing Intensity-Modulated Radiation Therapy, Ipilimumab and Nivolumab in people with Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 and Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, run by M.D. Anderson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

This phase II trial studies the side effects and best dose of ipilimumab, nivolumab, and radiation therapy and how well they work in treating patients with advanced human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Intensity-Modulated Radiation Therapy, Ipilimumab and Nivolumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
37 participants
Where
1 siteUnited States
Study dates
25 Jul 2019to 14 Apr 2026
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma (including the histological variants of papillary or basaloid) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls)
  • Clinical American Joint Committee on Cancer (AJCC) 7th edition stage T1N2a-N2CM0, T2N1-N2CM0, T3N0-N2CM0, equivalent to AJCC 8th edition stage 1 and 2 (T1 N2, T2 N1-N2, T3 N0-N2) excluding T1N0-N1 and T2N0 (Brian O'Sullivan et al. 2016)
  • Tumor positive for p16 immunohistochemistry (IHC) (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells) and HPV DNA in situ hybridization or HPV messenger ribonucleic acid (mRNA) RNAScope. Repeat samples may be required if adequate diagnostic tissue is unavailable for testing
  • Zubrod Performance Status of 0-1
  • Patients must have radiographically evident measurable disease at the primary site or at nodal stations per response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors [RECIST]) 1.1 documented by diagnostic quality CT or magnetic resonance imaging (MRI) of the neck with contrast within 28 days prior to registration; a FDG-PET/CT of the neck performed for the purposes of radiation planning is acceptable as a substitute if the CT is of diagnostic quality
  • Diagnostic quality cross sectional imaging of the thorax within 28 days prior to registration. A 18-FDG-PET/CT or conventional CT are acceptable
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  • FDG-PET/CT of the neck is required within 28 days prior to registration for comparison to post treatment FDG-PET/CT. Note: Repeat imaging for variability within 96 hours of this time frame should be allowed to avoid unnecessary re-imaging and its financial and potential physical consequences for patients
  • History and physical exam within 1 month prior to registration
  • Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) by radiation oncologist, medical oncologist or ear, nose, throat (ENT)/head and neck surgeons within 28 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 2 weeks prior to registration)
  • Platelets >= 100,000 cells/mm^3 (within 2 weeks prior to registration)
  • Hemoglobin >= 8.0 g/dl (within 2 weeks prior to registration); Note: The use of transfusion or other intervention to achieve Hgb >= 8.0 g/dl is acceptable
  • Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula (within 2 weeks prior to registration)
  • Bilirubin < 2 mg/dl (within 2 weeks prior to registration)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper limit of normal (within 2 weeks prior to registration)
  • Sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), albumin, amylase, lipase, thyroid stimulating hormone (TSH) within 2 weeks prior to registration
  • Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential
  • Seronegative for active hepatitis-B or hepatitis-C infection and seronegative for human immunodeficiency virus (HIV)
  • Mandatory submission of hematoxylin and eosin (H\&E) and paraffin-embedded tumor block or unstained slides

Who cannot join

  • Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive
  • Carcinoma of the neck of unknown primary site origin (even if p16 positive)
  • Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles
  • Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease
  • Simultaneous primary cancers or separate bilateral primary tumor sites
  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
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  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; patients who have received PD-1/PD-L1 or CTLA4 therapy for a previous malignancy are not eligible
  • Prior RT to the region of the study cancer that would result in overlap of radiation therapy fields
  • Severe, active co-morbidity defined as any of the following: Unstable angina and/or congestive heart failure requiring hospitalization 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 within 30 days of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; a diagnosis of immunodeficiency or use of any form of systemic immunosuppressive therapy. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor
  • Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Steroid premedications for contrast allergy allowed
  • Has evidence of active, non-infectious pneumonitis
  • Has received a live vaccine within 30 days of planned start of study therapy
  • Pregnancy or breast-feeding; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
  • History of severe hypersensitivity or contraindication to CT or PET contrast material uncontrolled with pre-medications (steroids, antihistamines)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Phase 2 Study (With Safety Lead in) of the Safety, Tolerability and Efficacy of Anti-CTLA4 (Ipilimumab) and Anti-PD-1 (Nivolumab) in Combination With Radiation Therapy to 50-66 Gy in Low-Intermediate Volume, Local-Regionally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

This phase II trial studies the side effects and best dose of ipilimumab, nivolumab, and radiation therapy and how well they work in treating patients with advanced human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving ipilimumab, nivolumab, and radiation therapy may work better in treating patients with HPV positive oropharyngeal squamous cell carcinoma.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab when administered concurrently with reduced-field radiotherapy (intensity-modulated radiation therapy [IMRT]).

II. To evaluate the clinical complete response rate to ipilimumab, nivolumab and IMRT with reduced field at six months as indicated by fluorodeoxyglucose - positron emission tomography/computed tomography (FDG-PET/CT) post completion of radiation therapy (RT).

III. To evaluate the 2-year progression-free survival (PFS) rate of subjects with low-intermediate volume, local-regionally advanced, human papilloma virus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) treated with ipilimumab, nivolumab and reduced-field IMRT.

SECONDARY OBJECTIVES:

  1. To evaluate overall response rate to six weeks of induction immunotherapy (IO).

II. To evaluate the frequency of pharyngeal dysphasia as measured by Dynamic Imaging (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST]) grade on modified barium swallow (MBS) and patient-reported symptoms (MD Anderson Dysphagia Inventory [MDADI]) at 6 month, 1 and 2 years after radiotherapy ([IMRT].

III. To measure acute and chronic toxicities per Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (CTCAE PRO).

IV. To measure acute toxicity profiles at the end of radiation therapy and IO and at 6 months.

  1. To measure late toxicity profiles at 1 and 2 years. VI. To determine local and regional control at 6 and 12 months. VII. To determine patterns of failure (local-regional relapse vs. distant) at 1 and 2 years.

VIII. To determine overall survival (OS) at 1 and 2 years.

CORRELATIVE OBJECTIVES:

  1. To evaluate associations between total mutational load, interferon (INF) gamma score, T cell clonality at diagnosis with clinical response to induction, combination CTLA-4 PD-1 checkpoint blockade.

II. To evaluate changes in the tumor immune microenvironment (CD8 + INF gamma score, T cell clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO).

III. To evaluate dynamic changes in and clearance of oral HPV and cell-free deoxyribonucleic acid (cfDNA) viral load during therapy and to investigate associations with PFS and OS.

EXPLORATORY OBJECTIVES:

  1. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles before and after induction IO.

II. To evaluate changes in the T cell receptor repertoire in tumor-infiltrating lymphocyte (TIL) and the peripheral blood in tumor biopsy specimens pre and post induction IO.

III. To determine the negative and positive predictive values (NPV and PPV) of FDG-PET/CT 12-14 weeks after end of RT for 1 year and 2 year PFS and OS.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Being tested
Intensity-Modulated Radiation Therapy, Ipilimumab, Nivolumab, Quality-of-Life Assessment, Questionnaire Administration
Medical subject headings
Oropharyngeal Neoplasms, Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Intensity-Modulated Radiation TherapyRadiation

    Also called IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy

    Undergo IMRT

  • IpilimumabBiological

    Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4

    Given IV

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

  • Quality-of-Life AssessmentOther

    Also called Quality of Life Assessment

    Ancillary studies

  • Questionnaire AdministrationOther

    Ancillary studies

Study groups in NCT03799445
Study groupRoleWhat they receive
Treatment (nivolumab, ipilimumab, IMRT)ExperimentalPatients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity.
Receives: Radiation: Intensity-Modulated Radiation Therapy; Biological: Ipilimumab; Biological: Nivolumab; Other: Quality-of-Life Assessment; Other: Questionnaire Administration

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Radiographic (RECIST) Response

    Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v.1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD; Progressive Disease (PD), >= 20% increase in the sum of the longest diameter with an absolute increase of at least 5 mm or the appearance of new lesions

    Measured: 6 months post completion of radiation therapy (approximately 9 months post start of treatment)

  2. Pathologic Response -- Percent Viable Tumor Change

    Pathologic response refers to the evaluation of how much a tumor has shrunk after treatment by the pathologist on trial examining tissue samples under a microscope. Tissue samples from baseline and at follow up were evaluated for tumor response. Percent viable tumor change is calculated using viable tumor data collected at the biopsy to the biopsy at the end of Cycle 1 of treatment.

    Measured: From first registration on trial (baseline biopsy) to post Cycle 1 of IO (6 weeks after start of treatment)

Secondary outcomes (3)

  1. Toxicity (Number of Adverse Events)

    Adverse events (AEs) are categorized as follows: Treatment-Emergent Adverse Events (TEAEs), which refer to any AEs that arise or worsen in severity after the initiation of treatment with the study product; and Treatment-Related Adverse Events (TRAEs), defined as TEAEs that are considered possibly, probably, or definitely related to the treatment. Adverse Events were graded 1 to 5 via CTAE 4.0 guidelines. All AEs, whether serious or non-serious, will be captured from the time of the first administration of the investigational agent until 30 days following the last dose of study drug or until the initiation of alternative anticancer therapy

    Measured: time of first drug administration to 30 days after last drug administration

  2. Survival Analysis -- Progression Free Survival

    Analyses of overall survival (OS) and progression-free survival (PFS) were performed. PFS was defined as from treatment initiation to progression or death, whichever occurred first, or last follow-up. The distribution was estimated by Kaplan-Meier method.

    Measured: 12 month post treatment follow up (15 months post treatment start), 18 month post treatment follow up (21 months post treatment start), 24 month post treatment follow up (27 months post treatment start)

  3. Survival Analysis -- Overall Survival (Percentage of Participants Alive at 12 Months, 18 Months, and 24 Months)

    Analyses of overall survival (OS) and progression-free survival (PFS) were performed. OS was defined as from treatment initiation to death or last follow-up time. The distribution was estimated by Kaplan-Meier method. No death was observed.

    Measured: 12 month post treatment follow up (15 months post treatment start), 18 month post treatment follow up (21 months post treatment start), 24 month post treatment follow up (27 months post treatment start)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Jan 2019
  2. Study start25 Jul 2019
  3. Primary completion25 Jul 2025
  4. Study completion14 Apr 2026

Why it stopped: \<75% participation

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03799445
Sponsor's protocol ID
2018-0381
Other IDs
NCI-2018-03260, 2018-0381
Status last verified
Apr 2026
First submitted
13 Dec 2018
Last updated
30 Apr 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

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