Clinical Trials /

sEphB4-HSA With Cetuximab and RT in Patients With High Risk, LAHNSCC and Heavy Smoking Histories

NCT04091867

Description:

This is a Phase I dose-escalation study of sEphB4-HSA in combination with cetuximab and radiotherapy (RT). The purpose is to estimate the maximum tolerated dose (MTD) that can be administered concurrently with Cetuximab and radiation in patients with locally advanced, Stage III or IV A-B squamous cell carcinomas of the head or neck with a history of at least ten pack-years of smoking.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: sEphB4-HSA With Cetuximab and RT in Patients With High Risk, LAHNSCC and Heavy Smoking Histories
  • Official Title: A Phase I/Ib Study of sEphB4-HSA in Combination With Cetuximab and Radiation Therapy in Patients With High Risk, Locally-Advanced Squamous Cell Carcinomas of the Head and Neck

Clinical Trial IDs

  • ORG STUDY ID: 16-2575.cc
  • SECONDARY ID: P30CA046934
  • NCT ID: NCT04091867

Conditions

  • High Risk, Locally-advanced Squamous Cell Carcinoma of Head and Neck

Interventions

DrugSynonymsArms
sEphB4-HSA with cetuximab and radiationsEphB4-HSA in combination with Cetuximab and Radiation Therapy

Purpose

This is a Phase I dose-escalation study of sEphB4-HSA in combination with cetuximab and radiotherapy (RT). The purpose is to estimate the maximum tolerated dose (MTD) that can be administered concurrently with Cetuximab and radiation in patients with locally advanced, Stage III or IV A-B squamous cell carcinomas of the head or neck with a history of at least ten pack-years of smoking.

Detailed Description

      RT combined with the EGFR-targeted agent cetuximab represents a valuable alternative to
      platinum-based CRT and is FDA-approved for initial treatment of LAHNSCC, but outcomes remain
      unfavorable. Recently, EphB4 has emerged as another rational target. While minimally
      expressed in normal tissue, it is highly expressed in LAHNSCC and has been implicated in
      resistance to both EGFR-targeted therapy and to RT. Suppression of EphB4 in the preclinical
      setting has enhanced tumor death and enhanced radiosensitivity. The novel agent sEphB4-HSA is
      a fusion protein that binds the ligand for EphB4 and leads to inhibition of tumor
      proliferation and angiogenesis. It was well-tolerated as monotherapy in a phase I trial but
      has yet to be explored in combination with radiotherapy or EGFR-directed treatments. A
      combined modality approach adding sEphB4-HSA to standard-of-care RT plus cetuximab represents
      a rational, targeted approach for investigation in patients with high risk LAHNSS
      p16-negative or any patient with heavy smoking histories. Moreover, a short window period of
      sEphB4-HSA monotherapy between baseline biopsy and repeat biopsy prior to initiation of
      cetuximab with RT will both minimize potential treatment delay and allow for the
      identification of potential biomarkers of response to sEphB4-HSA. Finally, a third optional
      biopsy, to be done if feasible after initiation of cetuximab-radiation, will allow us to
      identify radiosensitization markers and potential markers for treatment de-escalation. MTD.
    

Trial Arms

NameTypeDescriptionInterventions
sEphB4-HSA in combination with Cetuximab and Radiation TherapyExperimentalsEphB4-HSA: Loading dose at fixed dose of 10mg/Kg per below schema on D1 Concurrent dose per below schema D15-43 and given on an every other week basis Cetuximab: Loading dose 400 mg/m2 on D9 Concurrent dose 250mg/m2 weekly D15± 3 day window RT: 6930 cGy IMRT starting D15-D18
  • sEphB4-HSA with cetuximab and radiation

Eligibility Criteria

        Inclusion Criteria:

          1. Provision to sign and date the consent form.

          2. Stated willingness to comply with all study procedures and be available for the
             duration of the study.

          3. Patients must be willing to consent for two mandatory biopsies to be collected at
             baseline and again one week after the loading dose of sEphB4-HSA. A third optional
             biopsy will be collected if feasible 5-10 days after initiation of radiation
             treatment.

          4. Be a male or female aged 18-100.

          5. Pathologically confirmed (from the primary lesion and/or regional lymph nodes)
             squamous cell carcinoma of the oropharynx, hypopharynx, oral cavity, unknown primary,
             or larynx.

          6. High risk, locally advanced HNSCC which may include any of the following by AJCC 8th
             Edition:

               -  Stage III Hypopharyngeal Carcinoma AJCC v8

               -  Stage III Laryngeal Cancer AJCC v8

               -  Stage III Lip and Oral Cavity Cancer AJCC v8

               -  Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage III
                  Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking

               -  Stage IVA Hypopharyngeal Carcinoma AJCC v8

               -  Stage IVA Laryngeal Cancer AJCC v8

               -  Stage IVA Lip and Oral Cavity Cancer AJCC v8

               -  Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage IVA
                  Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking

               -  Stage IVB Hypopharyngeal Carcinoma AJCC v8

               -  Stage IVB Laryngeal Cancer AJCC v8

               -  Stage IVB Lip and Oral Cavity Cancer AJCC v8

               -  Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8 or Stage IVB
                  Oropharyngeal (p16-positive) Carcinoma ≥ 10 pack-years history of smoking

          7. Patient is not a candidate for definitive surgical resection

          8. Patients must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined below:

               -  Hemoglobin ≥ 9.0 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  White blood cells (WBC) > 3 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Total bilirubin < 1.5 x institutional upper limit of normal

               -  AST and ALT < 2.5 x institutional upper limit of normal

          9. For women of childbearing potential, a negative serum pregnancy test within 28 day
             screening to confirm eligibility. (Note: Pregnancy test will be repeated within 48
             hours prior to the first dose of sEphB4-HAS) .

         10. ECOG performance status ≤ 2.

         11. Be deemed ineligible by a medical oncologist to receive concurrent platinum-based
             chemotherapy with radiotherapy or patient refusal of platinum-based chemotherapy.

         12. Be deemed eligible by a medical oncologist to receive cetuximab.

         13. Agreement to exercise appropriate use of contraception, as indicated.

               -  For females of reproductive potential: use of highly effective contraception from
                  time of screening through 12 weeks following the final dose of study treatment
                  (see section 8.5).

               -  For males of reproductive potential: use of condoms from time of screening
                  through 12 weeks following the final dose of study treatment.

         14. Pretreatment imaging to include the following within 28 days of treatment initiation:

             CT Neck (with contrast unless contraindicated) with CT chest OR PET-CT. MRI of the
             neck with contrast (unless contraindicated) can replace CT neck.

             N.B.: a CT Neck performed for radiation planning and read by a radiologist may serve
             as appropriate staging and planning tools.

         15. General history and physical examination by a radiation or medical oncologist within
             28 days prior to enrollment.

         16. Examination by an ENT or head and neck surgeon, including laryngopharyngoscopy (mirror
             and/or fiberoptic and/or direct procedure) within 56 days prior to enrollment.

         17. Dental evaluation and, if applicable, prophylaxis per NCCN guidelines performed within
             84 days of treatment initiation.

         18. Eligible for definitive therapy.

        Exclusion Criteria:

          1. Pregnant, attempting to conceive, lactating, or declining to use appropriate
             contraception for duration of study.

          2. Hypertension that is uncontrolled (requiring 3+ antihypertensive medications to
             control).

          3. Hypertension at screening (SBP ≥140mmHg or DBP ≥90mmHg, corresponding to Stage 2
             according to JNC 7).

          4. Prior history of allergic or infusion reaction to cetuximab or sEphB4.

          5. Febrile illness within 7 days prior to enrollment.

          6. Concomitant use of EGFR-directed therapies (besides cetuximab given as part of this
             trial), including erlotinib, gefitinib.

          7. Major surgery (excluding tumor biopsy) within 4 weeks prior to start of study
             treatment.

          8. Prior unrelated malignancy requiring current active treatment within 3 years prior to
             enrollment with exceptions of cervical carcinoma in situ, basal cell carcinoma of
             skin, resected T1-T2N0M0 differentiated thyroid cancers, Ta bladder cancer, prostatic
             adenocarcinoma of low or intermediate risk (per NCCN criteria).

          9. Treatment with another investigational drug or other intervention within 30 days of
             treatment start.

         10. Resectable oral cavity primary site

         11. p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC
             8th Edition) AND ≤ 10 pack-year smoking history

         12. Stage IVC (M1) disease per AJCC 8th edition.

         13. Prior receipt of systemic chemotherapy for the study cancer (including "induction" or
             "neoadjuvant" chemotherapy) within 60 days of diagnosis; prior chemotherapy for a
             different cancer diagnosis is allowed.

         14. Any severe, active comorbidity, defined as follows:

               -  Cardiovascular disease or cerebrovascular disease, for example cerebrovascular
                  accidents or myocardial infarction ≤ 6 months prior to study enrollment, unstable
                  angina, New York Heart Association (NYHA) Grade II or greater congestive heart
                  failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or with
                  the potential to interfere with protocol treatment;

               -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
                  recent arterial thrombosis) within 6 months prior to enrollment;

               -  History or evidence upon physical/neurological examination of central nervous
                  system disease (e.g., seizures) unrelated to cancer unless adequately controlled
                  by medication;

               -  Acute bacterial or fungal infection requiring intravenous antibiotics within 7
                  days of enrollment;

               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy within 30 days of
                  registration;

               -  Patients known to be HIV positive or have active viral hepatitis, defined as
                  positive HCV quantitative titers and/or +Hep B sAg and +IgM anti-HepB.
                  Confirmatory testing is not required for the study.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary endpoint is whether a dose-limiting toxicity (DLT) occurs
Time Frame:13 weeks
Safety Issue:
Description:Severe cetuximab-associated rash is defined as per Lacouture 2010 criteria69, namely > 20 papules or pustules OR > 5 areas of erythema or edema < 1 cm (this is grade 3A) or > 20 papules/pustules OR > 5 areas of erythema or edema < 1 cm AND pain, pruritus, or effect on emotions or functioning (this is a commonly used criteria for grading of rash specifically related to EGFR inhibitors, such as cetuximab).

Secondary Outcome Measures

Measure:To assess the effect of adding sEphB4-HSA to radiation and cetuximab in newly-diagnosed EGFR-expressing LAHNSCC and heavy smoking histories on Locoregional disease
Time Frame:13 weeks
Safety Issue:
Description:Tumor response will be assessed in participants with measurable disease at start of therapy by measuring change in size (and/or FDG avidity) on CT (and/or PET/CT). LRC will be calculated as the time from completion of locoregional therapy until disease recurrence at the primary site or in the neck.
Measure:To assess the effect of adding sEphB4-HSA to radiation and cetuximab in newly-diagnosed EGFR-expressing LAHNSCC and heavy smoking histories on Distant Control
Time Frame:13 weeks
Safety Issue:
Description:DC will be calculated as the time from completion of locoregional therapy until disease recurrence at a site other than the primary site or neck.
Measure:To assess the effect of adding sEphB4-HSA to radiation and cetuximab in newly-diagnosed EGFR-expressing LAHNSCC and heavy smoking histories on Disease Free Survival
Time Frame:13 weeks
Safety Issue:
Description:DFS will be calculated as the time from completion of locoregional therapy until either disease recurrence at any site or until death.
Measure:Overall Survival
Time Frame:13 weeks
Safety Issue:
Description:OS will be calculated as the time from diagnosis of LAHNSCC to death

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Colorado, Denver

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