A Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-001 in Locally Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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This is a Phase 1 / Phase 2 study of newly diagnosed patients with biopsy-proven head and neck cancer (squamous cell carcinoma) who are undergoing standard radiation therapy and treatment with cisplatin. BMX-001 added to radiation therapy and cisplatin is expected to reduce radiation-induced mucositis and xerostomia and also has the potential to benefit the survival of head and neck cancer patients. In Phase 1, safety and tolerability of BMX-001 will be assessed using a Continual Reassessment Method (CRM) and a maximum tolerated dose (MTD) will be determined. BMX-001 will be given subcutaneously first with a loading dose zero to four days prior to the start of chemoradiation and followed by twice a week doses at one-half of the loading dose for the duration of radiation therapy plus two weeks. In Phase 2 both safety and efficacy of BMX-001 will be evaluated. Impact on mucositis and xerostomia will also be assessed. A maximum of 48 patients will be enrolled to the MTD dose determined in Phase 1 to confirm the MTD. The investigators hypothesize that BMX-001 when added to standard radiation therapy and cisplatin will be safe at pharmacologically relevant doses in patients with newly diagnosed head and neck cancer. The investigators also hypothesize that in Phase 2 of this study the addition of BMX-001 will reduce the severity of radiation-induced mucositis and xerostomia in patients receiving head and neck radiation therapy.

Official Title
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A Phase 1 / Phase 2 Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-001 in Locally Advanced Head and Neck Cancer

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: BMX-001
* Radiation: Radiation Therapy
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of squamous cell carcinoma of the oropharynx, larynx, hypopharynx, or oral cavity with clinical or pathologic high-risk features for whom cisplatin and radiation would be considered appropriate care. Treatment plan to receive a continuous course of IMRT delivered as single daily fractions of 2.0 to 2.1 Gy with a cumulative radiation dose between 60 Gy and 70 Gy depending on whether patients are considered post-operative high risk or unresectable/organ preservation high risk. Planned radiation treatment fields must include at least two oral sites buccal mucosa, retromolar trigone, floor of mouth, oral tongue, soft palate, hard palate) with a portion of each site receiving a minimum total of 50 Gy. Patients who are to undergo definitive chemoradiation must have clinically or radiographically evident measurable disease at the primary site and/or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted. Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions. Fine needle aspirations of the neck that are positive for squamous cell carcinoma are sufficient for diagnosis pending pathology review at participating institutions. For patients undergoing curative intent resection the following criteria are required: Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma Patients must have undergone gross total surgical resection within 42 days prior to registration and beginning of therapy under the clinical trial. Note: Patients may have biopsy under general anesthesia in an operating room followed by definitive ablative cancer surgery representing gross total resection. Clinical or pathologic stage Stage III-IVb per the American Joint Committee on Cancer (AJCC), 7th edition. General history and physical examination by a radiation oncologist and medical oncologist within 4 weeks prior to enrollment. Examination by an ear/nose/throat (ENT) or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to enrollment. Zubrod Performance Status 0-2 within 4 weeks prior to enrollment Complete blood count (CBC)/differential obtained within 7 days prior to starting the study drug with adequate bone marrow function, defined as follows: Hemoglobin ≥ 9.0 g/dl; Platelets ≥ 100,000 cells/mm3; Absolute neutrophil count (ANC) > 1,500 cell/mm3. Adequate hepatic function as defined as follows: Total bilirubin < 2x institutional upper limit of normal (ULN) within 7 days prior to starting the study drug; Aspartate aminotransferase (AST) and AST <3x institutional ULN within 7 days prior to starting the study drug. Adequate renal function defined as follows: Serum creatinine < 1.5 mg/dl within 7 days prior to starting the study drug or creatinine clearance rate (CCr) ≥ 50 mL/min within 7 days prior to starting the study drug determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male) Negative pregnancy test for women of child-bearing potential within 48 hours prior to first dose of BMX-001. Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study and until 12 months following the last study treatment. Exclusion Criteria: Stage I or II; T1N1 and T2N1 stage III presentations per AJCC 7th edition Distant metastasis Hypertension requiring 3 or more anti-hypertensive medications to control Grade ≥2 hypotension at screening Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment of the treating investigator, create a risk for a precipitous decrease in blood pressure History of syncope within the last 6 months Patients receiving, or unable to stop use at least 1 week prior to receiving the first dose of BMX-001, medications listed in Section 12.2 of the protocol are not eligible. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic Women who are breast feeding are not eligible Prior allergic reaction to cisplatin Known hypersensitivity to compounds of similar chemical composition to BMX-001 Grade 3-4 electrolyte abnormalities (CTCAE v 4.03) except sodium, which must be ≥126 mmol/L. Prior unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ, basal cell carcinoma of the skin, resected T1-2N0M0 differentiated thyroid cancers, invasive cancers with a 3-year disease-free interval, Ta bladder cancers, or low and favorable intermediate risk prostate cancer. Prior history of HNSCC receiving radiation or chemo-radiation. Prior systemic chemotherapy for the study cancer (including neoadjuvant chemotherapy); note that prior chemotherapy for a different cancer is allowable. Prior radiotherapy that would result in overlap of radiation treatment fields with planned treatment for study cancer. Severe, active co-morbidity, 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation Therapy, Cisplatin and BMX-001<br>In Phase 1, safety and tolerability of BMX-001 will be assessed using a Continual Reassessment Method and a maximum tolerated dose (MTD) will be determined using a single arm design. In Phase 2, the severity of radiation-induced mucositis and xerostomia will be assessed using a single arm design. | Drug: BMX-001<br>* Subcutaneous injection.<br>Radiation: Radiation Therapy<br>* Patients will receive standard dose intensity modulated radiation therapy (IMRT).<br>Drug: Cisplatin<br>* Cisplatin will be administered per institution's standard of care practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Safety of the Study Drug by Calculating the Proportion of Patients Who Experience Grade 4 or 5 Study Drug Related Adverse Events, as Assessed by CTCAE v 4.03. | This outcome is to confirm the safety and tolerability of escalating doses of BMX-001 in conjunction with RT and concurrent cisplatin in a cohort of newly diagnosed patients with locally advanced head and neck cancers. Each dose will be reported separately. | 1 year | 
| Incidence Radiation-induced Mucositis by Clinician Scoring | Mucositis will be scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Higher scores are indicative of worse symptoms. Grade 0-5. We are reporting the incidence of the patients that had mucositis grade 1-5. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Radiation-induced Xerostomia by Stimulated Saliva Production | Xerostomia will also be assessed by measurement of stimulated saliva production posttreatment. | 6 months | 
| Incidence of Radiation-induced Xerostomia by Unstimulated Saliva Production | Xerostomia will also be assessed by measurement of unstimulated saliva production post treatment. | 6 months | 
| Incidence of Radiation-induced Xerostomia by Clinician Scoring | Xerostomia will be assessed using Maximum Xerostomia Clinical Score Common Terminology Criteria for Adverse Events (CTCAE) 4.03. Scores range from 0 to 5 with 0 being no xerostomia and 5 being the worst. Mean maximum xerostomia grade of patients assessed is reported. | 6 months | 
| Duration of Radiation-induced Mucositis | Mucositis will be scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Duration of Oral Mucositis WHO Grade 3 or higher measured as the days of severe oral mucositis. | 6 month 6 months | 
| To Examine the Impact on Radiation Dermatitis When Adding BMX-001 to Treatment | To examine the impact on radiation dermatitis of BMX-001 in combination with RT and concurrent cisplatin at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of radiation dermatitis, and evaluation of radiation dermatitis-related patient-reported outcomes | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucositis, Xerostomia