Clinical Trials /

Alpelisib in Treating Participants With Transorally Resectable HPV-Associated Stage I-IVA Oropharyngeal Cancer

NCT03601507

Description:

This phase II trial studies how well alpelisib works in treating participants with human papillomavirus(HPV)-associated stage I-IVA head and neck cancer that can be removed by surgery. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Alpelisib in Treating Participants With Transorally Resectable HPV-Associated Stage I-IVA Oropharyngeal Cancer
  • Official Title: Biomarker Modulation by Alpelisib (BYL719) in Transorally Resectable, HPV-Associated HNSCC: A Phase II Window Trial

Clinical Trial IDs

  • ORG STUDY ID: 1802258478
  • SECONDARY ID: NCI-2018-00507
  • SECONDARY ID: BYL719
  • SECONDARY ID: CBYL719XUS15T
  • SECONDARY ID: 1802258478
  • SECONDARY ID: P30CA023074
  • NCT ID: NCT03601507

Conditions

  • CDKN2A-p16 Positive
  • Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma
  • Stage I Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7
  • Stage II Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7
  • Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7
  • Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7

Interventions

DrugSynonymsArms
AlpelisibBYL719, Phosphoinositide 3-kinase Inhibitor BYL719Treatment (Alpelisib)

Purpose

This phase II trial studies how well alpelisib works in treating participants with human papillomavirus(HPV)-associated stage I-IVA head and neck cancer that can be removed by surgery. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the preliminary efficacy of neoadjuvant Alpelisib (BYL719) in patients with
      transorally-resectable, HPV+ head and neck squamous cell carcinoma (HNSCC), as measured by
      quantitative change in tumor size (change in T) following 14-21 days of treatment.

      II. To evaluate the relationship between genomic PIK3CA activation to change in T.

      SECONDARY OBJECTIVES:

      I. To describe the tolerability of brief neoadjuvant exposure to BYL719. II. To assess the
      effect of BYL719 on the tumoral Ki-67 proliferation index. III. To evaluate viral and
      molecular mediators of response and resistance to BYL719, including viral messenger
      ribonucleic acid (mRNA), E6 and E7 oncoproteins, and phosphorylated (p)HER3.

      OUTLINE:

      Participants receive Alpelisib orally (PO) once daily (QD) for 14-21 days in the absence of
      disease progression of unacceptable toxicity and then undergo surgery. Participants may
      receive Alpelisib for up to 28 days if surgery is delayed.

      After completion of study treatment, participants are followed up for up to 12 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (Alpelisib)ExperimentalParticipants receive Alpelisib PO QD for 14-21 days in the absence of disease progression of unacceptable toxicity and then undergo surgery. Participants may receive Alpelisib for up to 28 days if surgery is delayed.
  • Alpelisib

Eligibility Criteria

        Inclusion Criteria:

          -  Cytologic or histologic diagnosis of oropharyngeal squamous cell carcinoma

          -  Clinical stage I-IVa p16+ oropharyngeal squamous cell carcinoma, based upon the
             American Joint Committee on Cancer (AJCC) staging manual, 7th edition

          -  No evidence of distant metastatic disease

          -  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 University Advising and Career Center (UACC) and Tucson
             community sites, and may be conducted locally

          -  Appropriate and planned for primary transoral resection and/or neck dissection

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Clinically or radiologically measurable disease; the primary tumor and/or neck nodes
             may be measurable according to Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1 (tumor diameter ? 1 cm; short-axis lymph node diameter ? 1.5 cm) OR by caliper
             measurement (tumor diameter ? 1 cm)

          -  Absolute neutrophil count (ANC) ? 1,500/ul

          -  Creatinine ? 1.5 x institutional upper limit of normal (ULN)

          -  Bilirubin ? 1.5 x ULN

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ? 2.5 x ULN

          -  Ability to swallow and retain oral study medication, either as a whole tablet or a
             drinkable suspension

          -  Have signed written informed consent

        Exclusion Criteria:

          -  Subjects who fail to meet the above criteria

          -  Prior therapy for head and neck cancer is not allowed

          -  Poorly controlled diabetes mellitus

               -  Patients with type II diabetes who have either a fasting plasma glucose (FPG) of
                  ? 140 or a hemoglobin A1C (HgBA1C) of ? 6.4 will be excluded; type 1 diabetic
                  patients will also be excluded

          -  Patient has any of the following cardiac abnormalities:

               -  Symptomatic congestive heart failure

                    -  History of documented congestive heart failure (New York Heart Association
                       functional classification III-IV), documented cardiomyopathy

                    -  Left ventricular ejection fraction (LVEF) < 50% as determined by multiple
                       gated acquisition (MUGA) scan or echocardiogram (ECHO)

               -  Myocardial infarction ? 6 months prior to enrollment

               -  Unstable angina pectoris

               -  Serious uncontrolled cardiac arrhythmia

               -  Symptomatic pericarditis

               -  Fridericia's corrected QT (QTcF) > 480 msec on the screening electrocardiogram
                  (ECG) (using the QTcF formula) currently receiving treatment with medication that
                  has a known risk to prolong the QT interval or inducing Torsades de Pointes, and
                  the treatment cannot be discontinued or switched to a different medication prior
                  to starting treatment with BYL719

          -  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 BYL719 (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 study medication as a whole tablet or a drinkable suspension,
             social/psychological complications

          -  Pregnant 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 human chorionic gonadotropin (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:

                         -  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 BYL719 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

          -  Severe and/or uncontrolled medical conditions such as infection requiring systemic
             antibiotics or anti-fungals; chronic hepatitis; severely impaired lung function

          -  Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (e.g., infectious) illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Quantitative change in the sum of Response Evaluation Criteria in Solid Tumors (RECIST) - measurable index lesions on paired, pre-and post-treatment computed tomography scans (delta change in T)
Time Frame:Baseline up to 3 years
Safety Issue:
Description:Will compare quantitative change in tumor size (change in T) in patients with genomic PIK3CA pathway alteration (PIK3CA mutation, amplification, and fluorescence in situ hybridization [FISH] for PTEN loss) versus no genomic activation.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will be reported descriptively, including tabulation of toxicities according to National Cancer Institut (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Measure:Surgical complications
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Length of hospital stay
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Changes in pre- and post-treatment tumor levels of human papillomavirus (HPV) messenger ribonucleic acid (mRNA) (quantitative polymerase chain reaction [qPCR])
Time Frame:Baseline up to 3 years
Safety Issue:
Description:
Measure:Changes in pre- and post-treatment tumor levels of E6 and E7 oncoproteins
Time Frame:Baseline up to 3 years
Safety Issue:
Description:
Measure:Changes in pre- and post-treatment tumor levels of Phospho - human epidermal growth factor receptor 3 (HER3)
Time Frame:Baseline up to 3 years
Safety Issue:
Description:
Measure:Changes in pre- and post-treatment tumor levels of HER3/PI3K dimers (monogram)
Time Frame:Baseline up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Arizona

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