Safety Study of BMX-001 (Radio-protector) in Patients With Newly Diagnosed Anal Cancer

Overview

In this Phase 1 study, the investigators will conduct a dose-escalation study of the combination of BMX-001 with standard radiation therapy (RT) and concurrent 5-fluorouracil (5FU)/mitomycin in newly diagnosed Anal Squamous Cell Carcinoma (ASCC) patients. The primary objective is to determine the maximum tolerated dose (MTD) of BMX-001 in ASCC patients receiving RT and concurrent 5FU/mitomycin chemotherapy.

Full Title of Study: “A Phase 1 Trial for Patients With Newly Diagnosed Anal Cancer Treated With Concurrent Radiation Therapy, 5FU, Mitomycin and BMX-001″

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2019

Detailed Description

In this Phase 1 study, the investigators will conduct a dose-escalation study of the combination of BMX-001 with standard radiation therapy (RT) and concurrent 5-fluorouracil (5FU)/mitomycin in newly diagnosed Anal Squamous Cell Carcinoma (ASCC) patients. The dose escalation will be a Rolling-6 design, which is an efficient phase I trial design, to determine the maximum tolerated dose (MTD) of BMX-001 in combination with concurrent 5FU/mitomycin and RT. Subjects will be administered BMX-001 subcutaneously first as a loading dose at least 2 hours before the initiation of chemoradiation and then at a maintenance dose (50% of the loading dose) twice a week for up to seven weeks.

Based on Rolling-6 design (1), cohorts of 2-6 patients are concurrently enrolled onto a dose level, beginning with 0.1 mg/kg, until the maximum tolerated dose (MTD) is defined. The average number of subjects required for this Phase 1 is estimated to be 20, and the maximum estimated to be 24. The maximum tolerated dose (MTD) is the highest dose level at which ≤ 1 out of 6 subjects experienced DLT. If no DLT has been identified at the highest dose proposed (loading dose of 0.6 mg/kg followed by 0.3 mg/kg twice per week) this will be accepted as the MTD.

In order to evaluate the pharmacokinetics (PK) of BMX-001 in combination with current chemoradiation, blood samples will be drawn for analysis. Blood will be drawn for PK on the following days: Day 1 (before and after loading dose), Day 8, Day 22 and Day 36. Measures will be obtained at approximately the following times: -1 to 0 hour (before loading dose), 30 minutes after the drug is given, 4 hours post-dose, and 24 hours post-dose.

Rectal, GI, and GU symptoms will be measured on the day of screening, weekly during RT, 1 months, 4 months and 10 months after the completion of RT. Perianal skin will be assessed weekly during RT, 1 month, 4 months, and 10 months after completion of RT. Further follow up will be per standard of care.

Interventions

  • Drug: BMX-001
    • BMX-001 at escalating doses in combination with standard RT, 33 fractions to 59.4 Gy, plus Mitomycin at the standard dosing of 10 mg/m2 administered IV bolus at day 1 and day 29 as well as 5FU 1g/m2/d day 1-4 and 29-32.

Arms, Groups and Cohorts

  • Other: Concurrent Radiation Therapy, 5FU, Mitomycin and BMX-001
    • One arm includes all enrolled patients.

Clinical Trial Outcome Measures

Primary Measures

  • Maximum tolerated dose (MTD) of BMX-001
    • Time Frame: Within year 1 of the two year study
    • MTD is defined as the highest dose level at which ≤ 1 out of 6 experienced DLT.

Secondary Measures

  • Impact of study treatment on acute rectal bleeding
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 rectal bleeding per CTCAE 4.0
  • Impact of study treatment on acute rectal pain
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 rectal pain per CTCAE 4.0
  • Impact of study treatment on bowel movements
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 diarrhea per CTCAE 4.0
  • Impact of study treatment on acute dysuria
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 dysuria per CTCAE 4.0
  • Impact of study treatment on acute hematuria
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 hematuria per CTCAE 4.0
  • Impact of study treatment on acute urinary frequency
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To examine acute grade 3 urinary frequency per CTCAE 4.0
  • Impact of study treatment on acute perianal grade 3 radiation dermatitis per CTCAE 4.0
    • Time Frame: Pre-treatment baseline, once every 5 fractions of RT and then 1, 4 and 10 months post RT
    • To evaluate rate of acute perianal grade 3 radiation dermatitis per CTCAE 4.0
  • Impact of study treatment on late rectal bleeding
    • Time Frame: at 10 months and 24 months post RT
    • To examine grade 3 late rectal bleeding per CTCAE 4.0
  • Impact of study treatment on rectal fibrosis
    • Time Frame: at 10 months and 24 months post RT
    • To examine grade 3 rectal fibrosis by endoscopy
  • Effect of study treatment on local control survival (PFS).
    • Time Frame: at 10 months and 24 months post RT
    • To assess local recurrence rate survival (PFS).
  • Effect of study treatment on overall survival (OS) survival (PFS).
    • Time Frame: at 10 months and 24 months post RT
    • To assess OS rate survival (PFS).
  • Effect of study treatment on locoreginal progression free survival survival (PFS).
    • Time Frame: at 10 months and 24 months post RT
    • To assess locoreginal progression free survival rate survival (PFS).

Participating in This Clinical Trial

Inclusion Criteria

  • Patients with pathologically confirmed locally advanced anal squamous cell carcinoma (including oligometastatic disease) who will be receiving concurrent chemoradiation with standard 5FU/Mitomycin regimen with curative intent.
  • Any cancer stage that will require a dose of 59.4 cGy.
  • Age ≥ 19 years
  • Karnofsky Performance Status (KPS) ≥ 60%
  • Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 /dl, platelets ≥ 100,000 /dl (The use of transfusion or other intervention to achieve Hgb > 9.0 g/dl is acceptable)
  • Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of normal
  • Signed, written informed consent
  • 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
  • PET/CT/ pelvic MRI done within 8 weeks of trial initiation

Exclusion Criteria

  • Breast-feeding
  • Active infection requiring IV antibiotics 7 days before enrollment
  • Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ, basal cell or carcinoma of the skin, invasive cancers with a 5-year disease-free interval, resected cancer of the bladder or low-grade (Gleason 6 or less) prostate cancer
  • Prior history of ASCC
  • Prior history of pelvic radiotherapy for any other type of malignancy
  • Known hypersensitivity to 5FU and/or mitomycin
  • Because corticosteroids are anti-inflammatory and could interrupt oxidative stress, patients will be required to be on stable or decreasing corticosteroids dose at the time of the study.
  • Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)
  • Active or history of postural hypotension and autonomic dysfunction within the past year
  • Known hypersensitivity to BMX-001
  • Clinically significant (i.e. active) cardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, 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 potentially interfering with protocol treatment
  • History or evidence upon physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment
  • A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >480 milliseconds (ms) (CTCAE grade 1) using the specific/usual choice by clinical center for correction factor.
  • A history of additional risk factors for Torsades de Pointes (TdP) (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome).

Gender Eligibility: All

Minimum Age: 19 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Chi Lin, MD
  • Collaborator
    • BioMimetix JV, LLC
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Chi Lin, MD, Associate Professor of Medicine – University of Nebraska
  • Overall Official(s)
    • Chi Lin, MD, Principal Investigator, University of Nebraska
  • Overall Contact(s)
    • Amy Study coordinator, RN, BSN, 402-552-2790, afillerkatz@unmc.edu

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