sEphB4-HSA in Combination with Chemotherapy or Cetuximab and Radiation Therapy for the Treatment of High Risk, Stage III-IVB Head and Neck Squamous Cell Carcinoma
This phase I/Ib trial studies the side effects and best dose of sEphB4-HSA when given together with chemotherapy or cetuximab and radiation therapy in treating patients with high risk, stage III-IVB head and neck squamous cell carcinoma. sEphB4-HSA works by blocking one way tumors get a blood supply. Chemotherapy drugs, such as cisplatin or carboplatin, 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. Monoclonal antibodies, such as cetuximab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving sEphB4-HSA with chemotherapy or cetuximab and radiation therapy may work better in treating patients with head and neck squamous cell carcinoma compared to cetuximab and radiation therapy alone.
Inclusion Criteria
- Provision to sign and date the consent form
- 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
- Pathologically confirmed (from the primary lesion and/or regional lymph nodes) squamous cell carcinoma of the oropharynx, hypopharynx, oral cavity, unknown primary, or larynx
- Intermediate to high risk, locally advanced HNSCC which may include any of the following by American Joint Committee on Cancer (AJCC) 8th edition: * Stage III Hypopharyngeal Carcinoma AJCC version (v) 8 * Stage III Laryngeal Cancer AJCC v8 * Stage III Lip and Oral Cavity Cancer AJCC v8 * Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8 * Stage II Oropharyngeal (p16-positive) Carcinoma >= 10 pack-years history of smoking * Stage III Oropharyngeal (p16-positive) Carcinoma >= 10 pack-years history of smoking * Stage III Sinonasal Carcinoma AJCC v8 * Stage IVA Sinonasal Carcinoma AJCC v8 * 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 * 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
- Patient is not a candidate for definitive surgical resection
- Hemoglobin >= 9.0 g/dL (within 28 days prior to administration of study treatment)
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study treatment)
- White blood cells (WBC) > 3 x 10^9/L (within 28 days prior to administration of study treatment)
- Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study treatment)
- Total bilirubin < 1.5 x institutional upper limit of normal (within 28 days prior to administration of study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal (within 28 days prior to administration of study treatment)
- 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)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Be deemed eligible by a medical oncologist to receive cetuximab or chemotherapy at the discretion of the treating medical oncologist
- 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 * For males of reproductive potential: use of condoms from time of screening through 12 weeks following the final dose of study treatment
- Pretreatment imaging to include the following within 28 days of treatment initiation: * Computed tomography (CT) neck (with contrast unless contraindicated) with CT chest OR positron emission tomography (PET)-CT. Magnetic resonance imaging (MRI) of the neck with contrast (unless contraindicated) can replace CT neck ** Nota bene (N.B.): a CT neck performed for radiation planning and read by a radiologist may serve as appropriate staging and planning tools
- General history and physical examination by a radiation or medical oncologist within 28 days prior to enrollment
- Examination by an ear, nose, and throat (ENT) or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 56 days prior to enrollment
- Eligible for definitive therapy
Exclusion Criteria
- Pregnant, attempting to conceive, lactating, or declining to use appropriate contraception for duration of study
- Hypertension that is uncontrolled (requiring 3+ antihypertensive medications to control). If the systolic blood pressure (SBP) >= 140mmHg or diastolic blood pressure (DBP) >= 90mmHg, corresponding to Stage 2 according to Joint National Committee (JNC) 7, then it should be treated. If the blood pressure (BP) is untreated, or SBP remains > 140mmHg despite proper treatment, then patient will not be eligible
- Prior history of allergic or infusion reaction to cetuximab, chemotherapy, or sEphB4
- Febrile illness within 7 days prior to enrollment
- Concomitant use of EGFR-directed therapies (besides cetuximab given as part of this trial), including erlotinib, gefitinib
- Major surgery (excluding tumor biopsy) within 4 weeks prior to start of study treatment
- 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 National Comprehensive Cancer Network [NCCN] criteria)
- Treatment with another investigational drug or other intervention within 30 days of treatment start
- Resectable oral cavity primary site
- p16-positive carcinoma of the oropharynx that is stage I (AJCC 8th Edition) OR =< 10 pack-year smoking history
- Stage IVC (M1) disease per AJCC 8th edition for HPV-negative (p16 negative) disease or any AJCC 8th edition stage IV for HPV-positive disease
- 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
- 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 human immunodeficiency virus (HIV) positive or have active viral hepatitis, defined as positive hepatitis C virus (HCV) quantitative titers and/or positive (+) hepatitis (Hep) B surface antigen (sAg) and + immunoglobulin M (IgM) anti-HepB. Confirmatory testing is not required for the study.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04091867.
PRIMARY OBJECTIVE:
I. To determine the safety and maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of recombinant ephB4-HSA fusion protein (sEphB4-HSA) in conjunction with radiation therapy (RT) and chemotherapy or cetuximab for patients with intermediate to high risk locally-advanced squamous cell carcinoma of the head and neck (LAHNSCC).
SECONDARY OBJECTIVE:
I. To assess the effect of adding sEphB4-HSA to radiation and chemotherapy or cetuximab in newly-diagnosed intermediate to high risk LAHNSCC on locoregional disease control (LRC), distant control (DC), disease-free survival (DFS), and overall survival (OS).
EXPLORATORY OBJECTIVE:
I. To elucidate the drug's properties, a dose expansion cohort, once the trial has identified the MTD will be enrolled.
OUTLINE: This is a dose-escalation study of recombinant ephB4-HSA fusion protein.
Patients receive recombinant ephB4-HSA fusion protein intravenously (IV) over 1 hour on days 1, 15, 29, and 43. Patients may receive or standard of care chemotherapy consisting of cisplatin IV or carboplatin IV over 30 minutes - 2 hours or cetuximab IV over 2 hours on day 8 and over 1 hour on days 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. Beginning on day 15, radiation therapy via intensity-modulated radiation therapy (IMRT) or volume modulated arc therapy (VMAT) for 33 fractions over 6.5 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 and 8 weeks, then every 12 weeks for 2 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Colorado
Principal InvestigatorSana D Karam
- Primary ID16-2575
- Secondary IDsNCI-2019-06321
- ClinicalTrials.gov IDNCT04091867