Nivolumab, Nab-paclitaxel, and Carboplatin Induction Chemotherapy Followed by Response-Based Locoregional Therapy in Treating Patients with Locally Advanced HPV-Positive Oropharyngeal Squamous Cell Carcinoma
This phase II trial studies how well nivolumab, nab-paclitaxel, and carboplatin induction chemotherapy followed by response-based locoregional therapy works in treating patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma that has spread from where it started to nearby tissue or lymph nodes. 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. Drugs used in chemotherapy, such as nab-paclitaxel and carboplatin, 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. Locoregional therapy, such as surgery, radiation therapy, or chemoradiotherapy, may help decrease the side effects associated with treatment. Giving nivolumab, nab-paclitaxel, and carboplatin induction chemotherapy followed by response-based locoregional therapy may work better in treating patients with HPV-positive oropharyngeal squamous cell carcinoma.
Inclusion Criteria
- Subjects must have pathologically confirmed HPV-positive head and neck squamous cell carcinoma of the oropharynx; confirmed HPV-positive disease of other subsites are uncommon but also eligible
- HPV testing must be compliant with the following criteria: * p16 immunohistochemistry (IHC) positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al) * p16 IHC positivity is to be validated using an HPV polymerase chain reaction (PCR) during the induction phase; this is essential as HPV genotype influences treatment arm allocation, with non-HPV16 HPV strains being considered high risk
- Availability of >= 10 unstained 5 micron slides (to be provided to Human Tissue Resource Center [HTRC] at the University of Chicago); subjects who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study
- Subjects with American Joint Committee on Cancer (AJCC) (7th edition, 2010) N2-N3 nodal disease or T3-T4 primary tumor; those with AJCC (8th edition 2018) TXNX are also allowed
- Measurable disease (either primary site and/or nodal disease) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- No previous radiation or chemotherapy for a head and neck cancer
- No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual disease is acceptable)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 80%)
- Leukocytes >= 3000/mm^3
- Platelets >= 100,000/mm^3
- Absolute neutrophil count >= 1,500
- Hemoglobin > 9.0 gm/dL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
- Alkaline phosphatase =< 2.5 x ULN
- Albumin > 2.9 gm/dL
- Total bilirubin =< 1.5 mg/dl
- Creatinine clearance > 45 mL/min (or serum creatinine [SCr] =< 1.5 mg/dL), normal within 2 weeks prior to start of treatment; the standard Cockcroft and Gault formula or the measured glomerular filtration rate must be used to calculate creatinine clearance (CrCl) for enrollment or dosing
- Subjects must sign a study-specific informed consent form prior to study entry; subjects should have the ability to understand and the willingness to sign a written informed consent document
- Age, sex, and reproductive status: * Women of childbearing potential (WOCBP=premenopausal woman capable of becoming pregnant) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug * Women must not be breastfeeding * WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 30 days (duration of ovulatory cycle) for up to 5 months post-treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for up to 7 months post treatment completion * Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements; however, they must still undergo pregnancy testing as described in this section * Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy; investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception; highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly * At a minimum subjects must agree to the use of one method of highly effective contraception; in addition, male subjects are expected to use a condom
Exclusion Criteria
- Unequivocal demonstration of distant metastases (M1 disease)
- Unidentifiable primary site
- Intercurrent medical illnesses which would impair subject tolerance to therapy or limit survival; including but not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance; once clinically stable, as defined by the principal investigator (PI), they are eligible
- Pregnant and nursing women are excluded because of the potential teratogenic effects and potential unknown effects on nursing newborns (please see above paragraph under inclusion criteria regarding WOCBP)
- Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors; residual measurable tumor is required for enrollment on study as outlined above
- Subjects receiving other investigational agents
- Peripheral neuropathy > grade 1
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess of physiologic dose or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active tuberculosis (Bacillus tuberculosis infection)
- Has hypersensitivity to nivolumab or any other drug used in this protocol
- Has had a prior systemic anti-cancer treatment within the last 8 weeks
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence live expectancy in the subsequent 3 years without active treatment (e.g. low grade prostate cancer in absence of therapy)
- Has active autoimmune disease that has required systemic treatment in the past year (i.e. with use of steroids or immunosuppressive drugs); replacement therapy e.g. levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or pituitary insufficiency, etc. are not considered a form of systemic treatment
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has a history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); however, if eradicated subject is eligible
- Has received a live vaccine within 28 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed within 28 days prior to initiation of treatment
Additional locations may be listed on ClinicalTrials.gov for NCT03107182.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To measure the deep response rate (DRR) to induction chemotherapy with carboplatin/nab-paclitaxel/nivolumab and determine its activity compared to the DRR using carboplatin/nab-paclitaxel in the Optima I trial.
SECONDARY OBJECTIVES:
I. To determine the tolerability of the nivolumab/carboplatin/nab-paclitaxel induction chemotherapy regimen and its impact on subsequent receipt of definitive chemoradiotherapy.
II. To determine 2-year progression-free survival (PFS) for the entire cohort and all arms and compare them to the entire cohort and corresponding arms in Optima I.
III. To determine 2-year overall survival (OS) for the entire cohort and all arms and compare them to the entire cohort and corresponding arms in Optima I.
IV. To determine 2-year rates of locoregional and distant control for the entire cohort and all arms and compare them to the entire cohort and corresponding arms in Optima I.
V. To determine rates of acute and late toxicity and compare them to rates of G-tube dependency on the Optima I and response-adapted volume de-escalation (RAVD) trials.
VI. To determine quality of life scores in subjects and compare them to quality of life scores on the RAVD trial.
VII. To determine the comparative efficacy and toxicity profiles of transoral robotic surgery (TORS) versus radiation therapy (RT) for management of low risk disease.
LABORATORY OBJECTIVES:
I. To evaluate quantitative HPV titers pre-treatment, post-induction, and post-definitive locoregional therapy at defined intervals on blood and saliva samples.
II. To evaluate changes in the immune micro-environment at a) baseline and b) during combined anti-PD-1/chemotherapy induction (paired biopsies).
EXPLORATORY OBJECTIVES:
I. To evaluate the efficacy and utility of a visual aid used during the consent process by anonymous and optional subject and provider questionnaires.
II. To determine whether magnetic resonance imaging (MRI) (namely diffusion weighted imaging, and radiomics) can predict response to induction (chemotherapy + immunotherapy).
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1, nab-paclitaxel IV over 30 minutes on days 1, 8, and 15, and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
LOCOREGIONAL THERAPY: Patients with low risk (LR) and >= 50% tumor shrinkage undergo radiation therapy (RT) and surgery. Patients with high risk (HR) and >= 50% tumor shrinkage or LR and < 50% but >= 30% tumor shrinkage undergo low dose chemoradiotherapy (CRT). Patients with LR and < 30% tumor shrinkage, HR and < 50% shrinkage, or any with stable disease (SD)/partial disease (PD) undergo standard CRT.
ADJUVANT CHEMOTHERAPY: Patients then receive nivolumab IV over 60 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at every 3 months in year 1, every 6 months in years 2 and 3, and annually in years 4 and 5.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorEverett E. Vokes
- Primary IDIRB17-0104
- Secondary IDsNCI-2017-01735
- ClinicalTrials.gov IDNCT03107182