Alpelisib, Cetuximab, and Cisplatin in Treating Patients with HPV-Associated Oropharyngeal Cancer That Can Be Removed by Surgery

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, TreatmentNot yet active18 and overUPCI 14-057
NCI-2016-00439, NCT02298595

Trial Description


This phase I/II trial studies the side effects and best way to give alpelisib, cetuximab, and cisplatin and to see how well these drugs work in treating patients with human papillomavirus (HPV)-associated oropharyngeal cancer that can be removed by surgery. Drugs used in chemotherapy, such as alpelisib and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving alpelisib, cisplatin, and cetuximab together may kill more tumor cells.

Further Study Information


I. To determine the recommended phase II dose (RP2D) of the combination of BYL719(alpelisib), cetuximab, and cisplatin as induction chemotherapy in patients with stage III-IVa, HPV-associated, oropharyngeal squamous cell carcinoma (OPSCC) when used as a component of curative-intent therapy. (Phase I)

II. To evaluate the efficacy of induction chemotherapy with the combination of BYL719, cetuximab, and cisplatin in patients with stage III-IVa, HPV-associated OPSCC when treated at RP2D, as measured by clinic-radiologic complete response. (Phase II)


I. To estimate preliminary PI3K pathway biomarker prevalence in a prospectively defined clinical trial cohort with HPV-associated OPSCC. (Phase I)

II. To estimate preliminary clinical efficacy of induction chemotherapy with the combination of alpelisib, cetuximab, and cisplatin. (Phase I)

III. To study any dose-response of alpelisib on either efficacy or toxicity. (Phase I)

IV. To estimate the prevalence of biomarkers of PI3K pathway activation in a prospectively defined clinical trial cohort with HPV-associated OPSCC. (Phase II)

V. To evaluate the efficacy of the combination, as measured by pathologic complete response. (Phase II)

VI. To obtain a preliminary estimate of the relationship between biomarkers of PI3K pathway activation and efficacy of induction chemotherapy with the combination of alpelisib, cetuximab and cisplatin. (Phase II)

VII. To evaluate the impact of PI3K inhibition on viral biology. (Phase II)

VIII. To assess the safety and feasibility of the combination of alpelisib, cetuximab and cisplatin as induction chemotherapy in patients with HPV-associated OPSCC. (Phase II)

IX. To evaluate the efficacy of the comprehensive treatment strategy of induction chemotherapy followed by transoral robotic surgery (TORS) followed by risk-stratified adjuvant radiation, as measured by 2-year recurrence-free survival (RFS). (Phase II)

X. To estimate the rate of R0 endoscopic head and neck surgery (eHNS) transoral resections following induction chemotherapy with the combination of alpelisib, cetuximab and cisplatin. (Phase II)

XI. To study the concordance of clinical and pathologic complete response rates. (Phase II)

XII. To describe acute and late toxicity of the comprehensive treatment strategy. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of alpelisib followed by a phase II study.


Patients receive alpelisib orally (PO) once daily on days 2, 8, and 15 during course 1 and day 1 during courses 2-3. Patients receive cetuximab intravenously (IV) over 1-2 hours, or per institutional standard, on days 1, 8, and 15. Patients receive cisplatin IV over 1-2 hours on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.


Within 2-4 weeks of the completion of induction chemotherapy, patients undergo transoral resection of the oropharyngeal tumor and selective lymph node dissection.


No later than 6 weeks from surgery, patients undergo intensity modulated radiation therapy.

After completion of study treatment, patients are followed up for every 3 months for 2 years, then every 6 months for 3 years, for a total of 5 years.

Eligibility Criteria

Inclusion Criteria:

Newly diagnosed, cytologically or histologically confirmed squamous cell carcinoma (and common variants, including poorly differentiated carcinoma; undifferentiated carcinoma; basaloid carcinoma) of the oropharynx; patients must have resectable oropharyngeal and nodal disease, including the following stages according to the American Joint Commission on Cancer Staging 7th edition:




T4aN0-3; note: eligible T4a tumors may include deep/extrinsic tongue muscle invasion and must be judged resectable by transoral laser microsurgery (TLM) or transoral robotic surgery (TORS), according to the surgeon-investigator; patients with T4a tumors with clear radiologic mandibular, hard palate or medial pterygoid invasion are not eligible

Carcinoma must be HPV-associated, which is defined as positive for p16 protein by immunohistochemistry (IHC); p16 positivity is defined as >= 70% of tumor cells demonstrating diffuse cytoplasmic and nuclear staining for p16 by immunohistochemistry in a Clinical Laboratory Improvement Amendments (CLIA) certified pathology lab. p16 testing is standard at participating institutions and may be conducted locally

No evidence of distant metastatic disease

Patients must have a clinically measurable primary oropharyngeal tumor, defined as measuring >= 1 cm by spiral computed tomography (CT), per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and/or by clinical examination

No prior systemic chemotherapy, systemic biologic/molecular targeted therapy or radiation treatment for head and neck cancer

Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed without evidence of recurrence

Patients must be untreated with radiation above the clavicles

Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at least 2 years except for excised and cured: carcinoma-in-situ of breast or cervix; non-melanomatous skin cancer; T1-2, N0, M0 resected differentiated thyroid carcinoma; superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection

Patient has signed the Informed Consent Form (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements

Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) =< 1 that the investigator believes is stable at the time of screening

Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L

Platelets >= 100 x 10^9/L

Hemoglobin >= 9.0 g/dL

International normalized ratio (INR) =< 1.5

Serum creatinine =< 1.5 x upper limit of normal (ULN)

Creatinine Clearance >= 60 mg/mL as calculated by the modified Cockraft-Gault formula

Total serum bilirubin =< 1.5 x ULN

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

Fasting plasma glucose (FPG) =< 140mg/dL or =< 7.8 mmol/L

Patient is able to swallow and retain oral medication

Exclusion Criteria:

Patient has a known hypersensitivity to any of the excipients of BYL719 (alpelisib)

Patient has distant metastatic disease, including central nervous system (CNS) tumor involvement

Patient with poorly controlled diabetes mellitus or documented steroid-induced diabetes mellitus (defined as FPG > 140 mg/dL or Hemoglobin A1C (HbA1C) > 7.8)

Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry

Prior systemic chemotherapy, molecularly targeted therapy, or radiation therapy for the current OPSCC diagnosis

History of radiation to the head and neck (above the clavicles)

Patient who has undergone major surgery =< 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure; note: core needle biopsy, diagnostic tonsillectomy or excisional lymph node biopsy do not constitute major surgery

Patient has clinically significant cardiac disease or impaired cardiac function, such as:

Congestive heart failure (CHF) requiring treatment (New York Heart Association [NYHA] Grade >= 2), left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)

History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV)-blockage; patients with asymptomatic and rate-controlled atrial fibrillation are not excluded

Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3 months prior to screening

QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening electrocardiogram (ECG)

Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment

Patient who has participated in a prior investigational study within 30 days prior to enrollment

Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed

Patient is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A; the patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the start of treatment; switching to a different medication prior to randomization is allowed

Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral alpelisib (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

Patient with known positive serology for human immunodeficiency virus (HIV)

Patient with any other condition that would, in the Investigator’s judgment, preclude patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow oral medication, social/psychological complications

Pregnant or or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)

Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment:

Sexually active males should use a condom during intercourse while taking BYL719 and for 16 weeks after the final dose of BYL719, and should not father a child in this period, but may be recommended to seek advice on conservation of sperm; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid; moreover, sexually active males should not father a child for 6 months after completion of radiation per standard clinical practice

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through at least 12 weeks after the final dose of BYL719; moreover, per standard clinical practice, women should not become pregnant for 12 months after completion of radiation; highly effective contraception is defined as either:

  • Total abstinence: when this is in line with the preferred and usual lifestyle of the subject; [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception]
  • Female sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); [for female study subjects, the vasectomized male partner should be the sole partner for that patient]
  • Use a combination of the following (both a+b):

*** Placement of an intrauterine device (IUD) or intrauterine system (IUS)

*** Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

*** Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed as alpelisib may decrease the effectiveness of hormonal contraceptives

NOTE: Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago

Chronic treatment with corticosteroids or other immunosuppressive agents

Grade >= 2 peripheral neuropathy

Grade >= 2 sensorineural hearing loss

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

University of Pittsburgh Cancer Institute (UPCI)

  • National Cancer Institute
Julie E. Bauman, Principal Investigator

Link to the current record.
NLM Identifier NCT02298595

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the record via the link above for more information about participating sites.