Clinical Trials /

Cetuximab, Cisplatin and BYL719 for HPV-Associated Oropharyngeal Squamous Cell Carcinoma

NCT02298595

Description:

This study evaluates the combination of BYL719, cisplatin and cetuximab as induction chemotherapy prior to minimally-invasive transoral surgery (TORS or TLM) and selective lymph node dissection (SLND), followed by risk-adapted intensity-modulated radiation therapy (IMRT) in patients with transorally resectable, Stage III-IVa, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cetuximab, Cisplatin and BYL719 for HPV-Associated Oropharyngeal Squamous Cell Carcinoma
  • Official Title: A Phase I/II Study of BYL719, Cetuximab, and Cisplatin in Transorally Resectable, HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 14-057
  • SECONDARY ID: CBYL719XUS08T
  • NCT ID: NCT02298595

Conditions

  • Carcinoma, Squamous
  • Squamous Cell Carcinoma
  • Oropharyngeal Neoplasms
  • Oropharyngeal Cancer

Interventions

DrugSynonymsArms
cisplatinPlatinol, Cisplatinum1: Low risk
Cetuximab1: Low risk
BYL7191: Low risk

Purpose

This study evaluates the combination of BYL719, cisplatin and cetuximab as induction chemotherapy prior to minimally-invasive transoral surgery (TORS or TLM) and selective lymph node dissection (SLND), followed by risk-adapted intensity-modulated radiation therapy (IMRT) in patients with transorally resectable, Stage III-IVa, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

Detailed Description

      HPV status and tobacco use are the major independent prognostic factors for patients with
      OPSCC. Patients with HPV-associated OPSCC have a favorable prognosis when treated with
      chemotherapy, radiation, and/or surgery. This has resulted in national trials investigating
      de-intensification strategies for good-risk patients with HPV-associated OPSCC, where current
      multimodality paradigms may represent overtreatment.

      The PI3K/Akt/mTOR signaling network, a mitogenic pathway regulating cellular metabolism,
      proliferation and survival, plays a major role in HPV biology. Starting with early infection,
      activation of PI3K suppresses autophagy and induces functional protein translational
      machinery. Activation of the pathway is a nearly universal aspect of mammalian viral
      infection, and is of particular importance for dsDNA viruses such as HPV. The oncoproteins
      E5, E6 and E7 also have direct roles in pathway activation. Moreover, HPV-associated OPSCC
      demonstrates a strikingly high prevalence of genomic activation of the PI3K pathway,
      including activating PIK3CA mutations (27-31%), PIK3CA amplification (20%), and loss of PTEN
      (30%), the negative regulator of PI3K. Overall genomic events hypothesized to result in PI3K
      pathway activation are present in approximately 45-60% of HPV-transformed OPSCC.

      BYL719 is an oral, small molecule, alpha-specific inhibitor of PI3-Kinase. Because
      HPV-associated OPSCC demonstrates a high rate of both genomic and non-genomic PI3K pathway
      activation, we hypothesize that adding BYL719 to platinum-taxane induction chemotherapy in
      HPV-associated OPSCC will increase clinico-radiologic complete response relative to
      historical control. In this phase I/II trial, eligible patients wiht HPV-associated OPSCC
      will be treated with 3 cycles of induction BYL719, cisplatin and paclitaxel. Induction will
      be followed by minimally-invasive, transoral surgery (TORS or TLM) then risk-adapted IMRT.
    

Trial Arms

NameTypeDescriptionInterventions
1: Low riskExperimental3 cycles (3 weeks) of induction chemotherapy (cisplatin+paclitaxel+BYL719) followed by transoral resection (TORS or TLM) and then observation.
  • cisplatin
  • Cetuximab
  • BYL719
2: Intermediate riskExperimental3 cycles (3 weeks) of induction chemotherapy (cisplatin+paclitaxel+BYL719) followed by transoral resection (TORS or TLM) and then Intensity Modulated Radiation Therapy (IMRT).
  • cisplatin
  • Cetuximab
  • BYL719
3: High riskExperimental3 cycles (3 weeks) of induction chemotherapy (cisplatin+paclitaxel+BYL719) followed by transoral resection (TORS or TLM) and then Intensity Modulated Radiation Therapy (IMRT) + cisplatin.
  • cisplatin
  • Cetuximab
  • BYL719

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:

               -  T1N1-3

               -  T2N1-3

               -  T3N0-3

               -  T4aN0-3. Note: Eligible T4a tumors may include deep/extrinsic tongue muscle
                  invasion and must be judged resectable by TLM or 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 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 CT, per 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.

          -  Age ≥ 18 years

          -  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

          -  Patient has adequate bone marrow and organ function as defined by the following
             laboratory values:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

               -  Platelets ≥ 100 x 109/L

               -  Hemoglobin ≥ 9.0 g/dL

               -  INR ≤ 1.5

               -  Creatinine Clearance ≥ 60 mg/mL as calculated by the modified Cockraft-Gault
                  formula:

        Calculated Creatinine Clearance = [(140-age) X (actual body weight in kg) X (0.85 if
        female)]/(72 X serum creatinine)

          -  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 with poorly controlled diabetes mellitus, defined as FPG > 140 mg/dL or 7.8
             mmol/L

          -  Patient has a history of another malignancy within 2 years prior to starting study
             treatment, except for excised and cured: carcinoma-in-situ of breast or cervix;
             non-melanomatous skin cancer; T1-2, N0, M0 differentiated thyroid carcinoma;
             superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected
             tissue with normal PSA since resection.

          -  The presence of distant metastatic disease

          -  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.

          -  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 AV-blockage

               -  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 ECG

          -  Patient who has any severe and/or uncontrolled medical conditions such as:

               -  Active or uncontrolled severe infection requiring systemic antibiotics or
                  antifungals

               -  Liver disease such as cirrhosis, decompensated liver disease, and chronic
                  hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)

               -  Known severely impaired lung function (spirometry and DLCO 50% or less of normal
                  and O2 saturation 88% or less at rest on room air),

               -  Active bleeding diathesis

          -  Chronic treatment with corticosteroids or other immunosuppressive agents

          -  Chronic treatment with warfarin or other coumarin derived anti-coagulant, for
             treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
             heparin (LMWH), or fondaparinux is allowed

          -  Grade ≥ 2 peripheral neuropathy

          -  Grade ≥ 2 sensorineural hearing loss

          -  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 is currently receiving treatment with drugs known to be moderate or strong
             inhibitors or inducers of isoenzymes CYP34A or CYP2C8. The patient must have
             discontinued moderate and strong inducers of either enzyme for at least one week and
             must have discontinued strong and moderate inhibitors before the start of treatment.
             Switching to a different medication prior to start of treatment is allowed.

          -  Patient with impaired gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of oral BYL719 (e.g. ulcerative disease,
             malabsorption syndrome, or small bowel resection).

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

          -  Pregnant or nursing woman, 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 drug
                  and for 12 weeks after completion of all protocol treatment and should not father
                  a child in this period. A condom is required to be used also by vasectomized men
                  in order to prevent delivery of the drug via seminal fluid, during the period of
                  BYL719 treatment (induction chemotherapy) and for 4 weeks following completion of
                  BYL719.

               -  Women of child-bearing potential, defined as all women physiologically capable of
                  becoming pregnant, unless they are using highly effective methods of
                  contraception during dosing and 12 weeks after completion of all study treatment.
                  Highly effective contraception methods include:

                    -  Total abstinence (when this is in line with the preferred and usual
                       lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
                       symptothermal, post-ovulation 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 (at least 6 months prior to screening). For
                       female subjects on the study the vasectomized male partner should be the
                       sole partner for that subject.

                    -  Combination of the following methods:

               -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete clinico-radiologic response of primary tumor following induction therapy
Time Frame:10-11 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Pathologic response of primary tumor and lymph nodes following induction therapy
Time Frame:16-19 weeks
Safety Issue:
Description:
Measure:2 year recurrence-free survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Duration of survival
Time Frame:5 years
Safety Issue:
Description:
Measure:Proportion of patients with genomic PI3K pathway activation who have a complete clinico-radiologic and/or pathologic response to induction therapy
Time Frame:10-13 weeks
Safety Issue:
Description:Genomic activation defined as: PIK3CA mutation, PIK3CA amplification, and/or PTEN deletion in baseline tumor
Measure:Number of participants with adverse events
Time Frame:10-13 weeks
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Julie E. Bauman, MD, MPH

Trial Keywords

  • Carcinoma
  • Squamous
  • Oropharyngeal
  • HPV
  • Resectable

Last Updated

July 5, 2016