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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03799445
Recruitment Status : Recruiting
First Posted : January 10, 2019
Last Update Posted : April 20, 2023
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma Oropharyngeal Basaloid Carcinoma Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Posterior Tongue Squamous Cell Carcinoma Soft Palate Squamous Cell Carcinoma Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Tonsillar Squamous Cell Carcinoma Radiation: Intensity-Modulated Radiation Therapy Biological: Ipilimumab Biological: Nivolumab Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : July 25, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment (nivolumab, ipilimumab, IMRT)
Patients 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.
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) (safety lead-in) [ Time Frame: Up to 28 days post-completion of radiation therapy ]
    Defined as any >= grade 3 adverse event (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 4) that is related to immunotherapy (IO) that does not resolve to grade 1 or less within 28 days.

  2. Complete response rate (Phase II) [ Time Frame: At 6 months ]
  3. Progression-free survival (PFS) (Phase II) [ Time Frame: From start of therapy to progression or disease or death from any cause, assessed up to 2 years ]

Secondary Outcome Measures :
  1. Number of patients who experience a >= grade 3 treatment-related adverse event (safety lead-in) [ Time Frame: Up to 28 days post-completion of radiation therapy ]
  2. Number of patients who tolerated protocol therapy (safety lead-in) [ Time Frame: Up to 12 weeks (end of cycle 2) ]
    The number of patients who tolerated protocol therapy, including completion of radiotherapy without a treatment break and who were administered immunotherapy (IO) will be assessed.

  3. Number of patients who achieve a clinical complete response (safety lead-in) [ Time Frame: Up to 28 weeks after radiation therapy ]
  4. Incidence of acute and chronic adverse events (Phase II) [ Time Frame: Up to 3 months from the end of intensity-modulated radiation therapy (IMRT) ]
    Incidence of adverse events (acute and chronic toxicities) will be assessed per CTCAE Patient Reported Outcome (PRO).

  5. Acute toxicity profiles (Phase II) [ Time Frame: At the end of radiation therapy, end of IO, and 6 months ]
    Will be assessed by CTCAE v 4.

  6. Number of patients who experience >= grade 3 treatment-related adverse event (Phase II) [ Time Frame: At the end of radiation therapy, end of IO, and 6 months ]
  7. Late toxicity profiles (Phase II) [ Time Frame: At 1 and 2 years ]
    Will be assessed per CTCAE v 4.

  8. Patient-reported swallowing outcomes (Phase II) [ Time Frame: At 1 and 2 years ]
  9. Patterns of failure (local-regional relapse versus [vs] distant) (Phase II) [ Time Frame: At 1 and 2 years ]
  10. Overall survival (Phase II) [ Time Frame: At 1 and 2 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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
  • 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

Exclusion Criteria:

  • 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)
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03799445

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Contact: Maura Gillison 713-792-6363 mgillison@mdanderson.org

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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Maura L. Gillison    713-792-6363      
Principal Investigator: Maura L. Gillison         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Maura L Gillison M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03799445    
Other Study ID Numbers: 2018-0381
NCI-2018-03260 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0381 ( Other Identifier: M D Anderson Cancer Center )
First Posted: January 10, 2019    Key Record Dates
Last Update Posted: April 20, 2023
Last Verified: April 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Oropharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action