Clinical Trials /

Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With HPV Positive, KRAS-Variant Stage III-IV Oropharyngeal Squamous Cell Carcinoma

NCT04106362

Description:

This phase II trial studies how well radiation therapy and cisplatin with or without cetuximab works in treating patients with human papillomavirus (HPV) positive, KRAS-variant stage III-IV oropharyngeal squamous cell carcinoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, 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. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy, cisplatin, and cetuximab may work better in treating patients with HPV positive, KRAS-variant oropharyngeal squamous cell carcinoma compared to radiation therapy and cisplatin alone.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With HPV Positive, KRAS-Variant Stage III-IV Oropharyngeal Squamous Cell Carcinoma
  • Official Title: Randomized Phase II Trial of Radiotherapy With Concurrent Cisplatin +/- Concurrent Cetuximab for HPV-Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) in KRAS-Variant Patients

Clinical Trial IDs

  • ORG STUDY ID: 19-000543
  • SECONDARY ID: NCI-2019-03636
  • SECONDARY ID: 19-000543
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04106362

Conditions

  • Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
  • Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
  • KRAS Protein Variant
  • Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
  • Pathologic Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8

Interventions

DrugSynonymsArms
CetuximabCetuximab Biosimilar CDP-1, Cetuximab Biosimilar CMAB009, Cetuximab Biosimilar KL 140, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Arm II (cetuximab, radiation therapy, cisplatin)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm I (radiation therapy, cisplatin)

Purpose

This phase II trial studies how well radiation therapy and cisplatin with or without cetuximab works in treating patients with human papillomavirus (HPV) positive, KRAS-variant stage III-IV oropharyngeal squamous cell carcinoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, 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. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy, cisplatin, and cetuximab may work better in treating patients with HPV positive, KRAS-variant oropharyngeal squamous cell carcinoma compared to radiation therapy and cisplatin alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant oropharyngeal squamous cell carcinoma (OPSCC) patients
      in terms of overall survival (OS) at 2 years.

      SECONDARY OBJECTIVES:

      I. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of patterns of failure at 6
      months and 2 years.

      II. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of progression-free survival
      (PFS) at 2 years.

      III. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of locoregional control (LRC) at
      2 years.

      IV. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of distant metastasis-free
      survival (DMFS) at 2 and 5 years.

      V. To determine the efficacy of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of OS at 5 years.

      VI. To determine the safety of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of acute toxicity profiles at
      the end of radiation, at 1 month, and at 6 months.

      VII. To determine the safety of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of late toxicity profiles at 1
      and 2 years.

      VIII. To determine the safety of radiation therapy with concurrent cisplatin combined with
      concurrent cetuximab in KRAS-variant OPSCC patients in terms of patient-reported swallowing
      outcomes at 6 months and 1 and 2 years.

      IX. To assess the predictive value of fludeoxyglucose (FDG)-positron emission tomography
      (PET) at 10-14 weeks post-treatment.

      X. To assess the predictive value of additional blood and tissue biomarkers for disease
      outcomes at 2 years.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the impact of cetuximab on the immune response as well as treatment outcome
      and toxicity.

      II. To evaluate biomarkers for immune response in HPV-associated OPSCC through saliva and
      blood samples to be collected prior to treatment and at each follow-up visit.

      III. To evaluate for additional checkpoint targets through tumor tissue taken at the time of
      initial biopsy and profiled for tumor infiltrating lymphocytes, activation markers, and
      antigen-specific T-cell receptor (TCR) utilization/diversity.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Beginning on day 0, patients undergo radiation therapy over 6 weeks for a total of 35
      fractions. Patients also receive cisplatin intravenously (IV) over 1-2 hours on days 0 and
      21.

      ARM II: Patients receive cetuximab IV over 120 minutes 5-7 days prior to start of radiation
      therapy and then IV over 60 minutes weekly on Monday or Tuesday for 7 weeks. Patients also
      undergo radiation therapy and receive cisplatin as in Arm I.

      After completion of study treatment, patients are followed up at 2-4 weeks, every 12 weeks
      for 2 years, and then every 3-12 months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (radiation therapy, cisplatin)Active ComparatorBeginning on day 0, patients undergo radiation therapy over 6 weeks for a total of 35 fractions. Patients also receive cisplatin IV over 1-2 hours on days 0 and 21.
  • Cisplatin
Arm II (cetuximab, radiation therapy, cisplatin)ExperimentalPatients receive cetuximab IV over 120 minutes 5-7 days prior to start of radiation therapy and then IV over 60 minutes weekly on Monday or Tuesday for 7 weeks. Patients also undergo radiation therapy and receive cisplatin as in Arm I.
  • Cetuximab
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent obtained from the patient/legal representative prior to
             performing any protocol-related procedures, including screening evaluation

          -  Newly diagnosed, untreated, biopsy-proven HPV+ squamous cell carcinoma of the
             oropharynx. Cytologic diagnosis from a cervical lymph node is sufficient in the
             presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence
             should be documented, may consist of palpation, imaging, or endoscopic evaluation and
             should be sufficient to estimate the size of the primary (for T stage). HPV-positivity
             will be defined as tumors that are p16-positive by immunohistochemistry

          -  Selective stage III-IV disease (T3-T4 or N2-N3 disease) by American Joint Committee on
             Cancer (AJCC) 8th edition as determined by a computed tomography (CT) scan or magnetic
             resonance imaging (MRI) of the head and neck, CT neck, chest, abdomen, pelvis or a PET
             =< 6 weeks of registration

          -  Confirmation of KRAS-variant status as assessed by genotyping from a cheek swab sample
             at MiraDx

          -  Lifetime cumulative smoking history of < 10 pack-years. The cumulative total of the
             number of pack-years during each period of active smoking is the lifetime cumulative
             history

               -  Note: Investigators are discouraged from enrolling patients with a history of
                  very sustained use (such as several years or more) of non-cigarette tobacco
                  products alone given that the effect of non-cigarette tobacco products on the
                  survival of patients with p16-positive oropharyngeal cancers is undefined

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 ? 1 within 60 days
             prior to registration

          -  Hemoglobin >= 9 g/dL (5.58 mmol/L) (within 2 weeks prior to registration)

          -  Absolute neutrophil count (ANC) >= 1500/uL (cells/mm^3) (within 2 weeks prior to
             registration)

          -  Platelet count >= 100,000/uL (cells/mm^3) (within 2 weeks prior to registration)

          -  Total bilirubin =< 1.5 mg/dL (25.65 umol/L) or =< 3.0 mg/dL if the patient has a
             history of Gilbert?s disease (within 2 weeks prior to registration)

          -  Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2 x the institutional upper
             limit of normal (ULN) (within 2 weeks prior to registration)

          -  Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance (measured via
             24-hour urine collection) >= 50 ml/min (that is, if serum creatinine is > 1.5 times
             the ULN, a 24-hour urine collection to calculate creatinine clearance must be
             performed) (within 2 weeks prior to registration)

          -  Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
             history: >= 60 years old and no menses for at least 1 year without an alternative
             medical cause, OR history of hysterectomy, OR history of bilateral tubal ligation, OR
             history of bilateral oophorectomy) or must have a negative serum pregnancy test within
             7 days prior to enrollment

          -  Female subjects of child bearing potential and male subjects with partners of child
             bearing potential must agree to adequate contraceptive measures (hormonal or barrier
             methods) during treatment and for 2 months after the last dose of cetuximab

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment, scheduled visits, and examinations including follow up

        Exclusion Criteria:

          -  Patients with biopsy-proven metastatic, HPV-negative, KRAS-variant negative, or
             recurrent head and neck squamous cell carcinoma (HNSCC)

          -  Patients with primary site of tumor outside of the oropharynx, specifically of the
             oral cavity, salivary glands, nasal cavity, paranasal sinuses, larynx, hypopharynx, or
             nasopharynx

          -  Patients with prior radiation therapy (RT) that would result in overlap of radiation
             therapy treatment fields (superficial x-ray of skin lesions excluded)

          -  Gross total excision (ex. tonsillectomy) of the primary tumor; however, partial
             removal of the tumor to alleviate an impending airway obstruction does not make the
             patient ineligible. Initial surgical treatment, excluding diagnostic biopsy of the
             primary site or nodal sampling of neck disease, as well as radical or modified neck
             dissection is not permitted

          -  Prior systemic chemotherapy or biologic therapy for the study cancer; note that prior
             chemotherapy or biologic therapy for a different cancer is allowable

          -  Prior therapy that specifically and directly targets the EGFR pathway

          -  History of another primary invasive malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease >= 3
                  years before the first dose of study drug and of low potential risk for
                  recurrence

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated low risk prostate cancer without evidence of disease

               -  Adequately treated carcinoma in situ without evidence of disease e.g., cervical
                  cancer in situ, and ductal breast carcinoma in situ (DCIS)

          -  History of infusion reaction or hypersensitivity to cetuximab OR allergic reactions
             attributed to compounds of chemical or biologic composition similar to those of
             cetuximab

          -  Documented uncontrolled intercurrent illness or co-morbidity including, but not
             limited to, ongoing or active bacterial or fungal infection requiring intravenous
             antibiotics, uncontrolled congestive heart failure, cardiomyopathy, uncontrolled
             hypertension, unstable angina pectoris, cardiac arrhythmia, acquired immune deficiency
             syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC)
             definition, or psychiatric illness/social situations that would limit compliance with
             study requirements or compromise the ability of the subject to give written informed
             consent

          -  Female subjects who are pregnant or breastfeeding as well as male or female patients
             of reproductive potential who are not employing an effective method of birth control

          -  Patients with clinically relevant coronary artery disease or history of myocardial
             infarction in the last 12 months or high-risk of uncontrolled arrhythmia or
             uncontrolled cardiac insufficiency

          -  Patients with uncontrolled or poorly-controlled hypertension (> 180 mmHg systolic or >
             130 mmHg diastolic)

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Involvement in the planning and/or conduct of the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From time of randomization to death due to any cause, assessed at 2 years
Safety Issue:
Description:OS will be estimated in each study arm by Kaplan-Meier estimate. Summaries of the number and percentage of patients who have died, are still in survival follow-up, are lost to follow-up and have withdrawn consent will be provided along with median OS. Furthermore, a binomial test of proportions will be used to test difference in 2-year OS between the two arms. Exact tests and continuity correction strategies will be considered when appropriate.

Secondary Outcome Measures

Measure:Primary tumor control
Time Frame:Up to 5 years
Safety Issue:
Description:Will be determined by Response Evaluation Criteria in Solid Tumors version (v). 1.1. Kaplan-Meier estimate will be used to describe primary control rate for each arm. Furthermore, log-rank test will be used to test the difference between primary tumor control between the two arms.
Measure:Locoregional recurrence rate
Time Frame:Up to 5 years
Safety Issue:
Description:Will be determined by surveillance imaging, with failure defined as appearance of new disease in the head and neck from the date of randomization. Kaplan-Meier estimate will be used to describe locoregional recurrence rate for each arm. Furthermore, log-rank test will be used to test difference in locoregional recurrence rates between the two arms.
Measure:Acute toxicity
Time Frame:Up to 5 years
Safety Issue:
Description:Will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The safety analysis set will be used for safety analyses. The overall safety and tolerability will be assessed throughout the study period. All adverse event (AE) data will be listed individually by treatment group and patient identifier.
Measure:Late toxicity
Time Frame:Up to 5 years
Safety Issue:
Description:Will be evaluated using the CTCAE v5.0. The safety analysis set will be used for safety analyses. The overall safety and tolerability will be assessed throughout the study period. All AE data will be listed individually by treatment group and patient identifier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

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