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

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ClinicalTrials.gov Identifier: NCT03386500
Recruitment Status : Recruiting
First Posted : December 29, 2017
Last Update Posted : December 29, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Anal Cancer, Squamous Cell Carcinoma Radiation Exposure Drug: BMX-001 Phase 1

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial for Patients With Newly Diagnosed Anal Cancer Treated With Concurrent Radiation Therapy, 5FU, Mitomycin and BMX-001
Actual Study Start Date : November 28, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anal Cancer
Drug Information available for: Mitomycin
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Concurrent Radiation Therapy, 5FU, Mitomycin and BMX-001
One arm includes all enrolled patients.
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.
Other Names:
  • MnTnBuOE-2-PyP5+
  • manganese butoxyethyl pyridyl porphyrin


Outcome Measures

Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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).

  11. 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).

  12. 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).


Other Outcome Measures:
  1. Effect of study treatment on patient-reported outcomes of health-related quality of life (HRQoL) [ Time Frame: Pre-treatment baseline, once every 10 fractions of RT and then 1, 4 and 10 months post RT ]
    To evaluate patient-reported outcomes (EORTC QLQ C30 and CR29)

  2. Effect of study treatment on urine levels of 4-hydroxynonenal (4-HNE) [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure 4-hydroxynonenal (4-HNE) in the urine.

  3. Effect of study treatment on plasma levels of 4-hydroxynonenal (4-HNE) [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure 4-hydroxynonenal (4-HNE) in the plasma.

  4. Effect of study treatment on serum level of 8-OHdG [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure 8-OHdG in the serum.

  5. Effect of study treatment on blood cells level of 8-OHdG [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure 8-OHdG in the blood cells.

  6. Effect of study treatment on urine level of 8-OHdG [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure 8-OHdG in the urine

  7. Effect of study treatment on urine levels of malondialdehyde (MDA) [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure malondialdehyde (MDA) in the urine.

  8. Effect of study treatment on plasma levels of malondialdehyde (MDA) [ Time Frame: Pre-treatment baseline, week 4 of RT and then 1 and 4 months post RT. ]
    To measure malondialdehyde (MDA) in the plasma.

  9. Single-dose and repeated-dose pharmacokinetic profiles of BMX-001 [ Time Frame: On days 1, 8, 22 and 36 of the chemoradiation phase. Measures will be obtained at time -1 hr, 0 hr, 0.5 hr, 4 hr, 24 hr. ]
    To measure serum drug concentration of BMX-001 after single-dose and repeated-dose BMX-001 delivery.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03386500


Contacts
Contact: Amy Study coordinator, RN, BSN 402-552-2790 afillerkatz@unmc.edu
Contact: Peggy Project Coordinator, BA, RD 402-559-4596 peggy.heires@unmc.edu

Locations
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Amy Study Coordinator, RN, BSN    402-552-2790    afillerkatz@unmc.edu   
Contact: Peggy Project Coordinator, BS, RD    402-559-4596    peggy.heires@unmc.edu   
Sponsors and Collaborators
Chi Lin, MD
BioMimetix JV, LLC
University of Nebraska
Investigators
Principal Investigator: Chi Lin, MD University of Nebraska
More Information

Responsible Party: Chi Lin, MD, Associate Professor of Medicine, University of Nebraska Medical Center
ClinicalTrials.gov Identifier: NCT03386500     History of Changes
Other Study ID Numbers: 247-17
First Posted: December 29, 2017    Key Record Dates
Last Update Posted: December 29, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Anus Neoplasms
Neoplasms, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Anus Diseases
Rectal Diseases
Mitomycins
Mitomycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors