Clinical trial NCT03386500: Safety Study of BMX-001 (Radio-protector) in Patients With Newly Diagnosed Anal Cancer
Official title: A Phase 1/2 Trial for Patients With Newly Diagnosed Anal Cancer Treated With Concurrent Radiation Therapy, 5FU, Mitomycin and BMX-001
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Anal Cancer, Squamous Cell Carcinoma
Radiation Exposure
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: BioMimetix JV, LLC
First posted: 2017-12-29
Enrollment: 24
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Over 80% of anal cancers are squamous cell carcinoma (SCC). Current standard treatment for locally advanced squamous cell carcinoma of the anal canal is a combination of radiation therapy (RT) and concurrent chemotherapy. This allows for organ preservation in approximately 75% of patients. The use of concurrent radiation and chemotherapy with infusional 5-fluorouracil (5-FU) and mitomycin results in locoregional relapse rates of 20-32 and 5-year overall survival rates of 58-78%. However, while mitomycin significantly increases the rate of grade 4 toxicities, it improves local outcomes and has been considered a necessary agent in the care of anal cancer. Oxidative stress induced by radiotherapy and chemotherapy tends to protect tumor cells and promote normal tissue damage. A recently developed compound, BMX-001 (MnTnBuOE-2- PyP5+), is among the most highly potent metalloporphyrin compounds which reduce oxidative stress, thereby protecting normal tissues and augmenting tumor killing.

In this Phase 1/2 study, the investigators will conduct a safety and efficacy study of the combination of BMX-001 with standard radiation therapy and concurrent (5FU)/mitomycin in newly diagnosed Anal Squamous Cell Carcinoma (ASCC) patients. The primary Phase 1 objective is to determine the maximum tolerated dose (MTD) of BMX-001 in ASCC patients receiving RT and concurrent 5FU/mitomycin chemotherapy. Three participants will be treated at Dose Level 1 and three at Dose Level 2, then three at Dose Level 3. Dose Limiting Toxicities (DLT) experienced by any participant will be used to determine the MTD. The Phase II objective is to examine the impact of BMX-001 on the overall acute ≥ grade 3 toxicity rate of the normal tissue including rectum, bladder, and skin in combination with RT and concurrent 5FU/mitomycin in treatment of newly diagnosed ASCC patients. These will be determined by participant reports, biological materials (blood, tissue, urine) sampling and imaging. Participant health-related quality of life will be assessed by two questionnaires.

Detailed description: Over 80% of anal cancers are squamous cell carcinoma (SCC). Current standard treatment for locally advanced squamous cell carcinoma of the anal canal is a combination of radiation therapy (RT) and concurrent chemotherapy. This allows for organ preservation in approximately 75% of patients. The use of concurrent radiation and chemotherapy with infusional 5-fluorouracil (5-FU) and mitomycin results in locoregional relapse rates of 20-32 and 5-year overall survival rates of 58-78%. However, while mitomycin significantly increases the rate of grade 4 toxicities, it improves local outcomes and has been considered a necessary agent in the care of anal cancer. Oxidative stress induced by radiotherapy and chemotherapy tends to protect tumor cells and promote normal tissue damage. A recently developed compound, BMX-001 (MnTnBuOE-2- PyP5+), is among the most highly potent metalloporphyrin compounds which reduce oxidative stress, thereby protecting normal tissues and augmenting tumor killing.

In this Phase 1/2 study, the investigators will conduct a safety and efficacy 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) participant. A recently completed Phase 1 study using BMX-001 with concurrent chemotherapy and radiation therapy in patient with newly diagnosed high-grade gliomas (BMX-HGG-001) demonstrated no adverse effects in subcutaneous dosing up to 28 mg/subject load with half the loading dose (14 mg/subject) given biweekly for 8 weeks in 12 participants. One of three participants dosed with 42 mg/subject load with half the loading dose given biweekly for 8 weeks experienced dose-limiting toxicity (DLT) of grade 3 tachycardia and grade 3 hypotension at loading dose. These resolved with treatment within 24 hours and the participant returned to the study with no recurrence for the maintenance does. The sponsor determined that the Recommended Phase 2 Dose (RP2D) of BMX-001 is 28 mg/subject load followed by 14 mg/subject twice a week for up to eight weeks as the maximum dose that was tolerated with no adverse effects. The most common related toxicity seen in this study grade 1 injection site reaction. There is no apparent toxicity to end organ tissues or bone marrow.

For this study, after completion of Phase 1 and establishment of a RP2D for the treatment regimen in participants undergoing radiation therapy and chemotherapy, the protocol will proceed to Dose Level 3, after completion of Dose Level 1 and Dose Level 2. Up to 20 participants will be enrolled with a safety lead-in of 6 participants to confirm safety in subjects in this cohort receiving radiation therapy and 5FU/mitomycin. To evaluate the pharmacokinetics (PK) of BMX-001 in combination with current chemoradiation, blood samples will be drawn for analysis in three to six participants in enrolled in the safety lead-in. Next, the first dose of BMX-001 will be administered subcutaneously from 4 days up to 1 hour prior to the start of radiation treatment. 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. Samples will be analyzed for BMX-001 using validated analytical methods. Skin, gastrointestinal (GI), and genitourinary (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.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed locally advanced anal squamous cell carcinoma (including oligometastatic disease) with concurrent chemoradiation with standard Fluorouracil (5FU)/mitomycin regimen with curative intent
* Any cancer stage requiring a dose of 59.4 cGy
* 19 years of age or older
* Karnofsky Performance Status (KPS) ≥ 60%
* Hemoglobin ≥ 9.0 g/dl (a transfusion or other intervention to achieve Hgb \> 9.0 g/dl is acceptable)
* Absolute neutrophil count (ANC) ≥ 1,500 /dl
* Platelets ≥ 100,000 /dl
* Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of normal
* Negative pregnancy test for women of child-bearing potential within 48 hours prior to first dose of BMX-001
* Use of a medically effective means of birth control until 12 months following the last study treatment for women of childbearing potential and male participants
* Positron Emission Tomography (PET)/ Computed Tomography (CT)/pelvic magnetic resonance imaging (MRI) done within 8 weeks of trial initiation

Exclusion Criteria:

* Breast-feeding
* Active infection requiring IV antibiotics within 7 days before enrollment
* Prior, unrelated malignancy requiring current active treatment, exception: 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 prostate cancer (Gleason 6 or less)
* Prior history of Acantholytic squamous cell carcinoma (ASCC)
* Prior history of pelvic radiotherapy for any other type of malignancy
* Known hypersensitivity to Fluorouracil (5FU) and/or mitomycin
* Current corticosteroid use unless dose is stable or decreasing at study enrollment (anti-inflammatory properties could interrupt oxidative stress)
* Inadequately controlled hypertension (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 (active) cardiovascular disease or cerebrovascular disease, (e.g., 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 from physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer, potentially interfering with protocol treatment unless adequately controlled by medication
* Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment
* 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
* History of additional risk factors for Torsades de Pointes (TdP) (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome)

Primary outcomes:
measure: Maximum Tolerated Dose of BMX-001
timeFrame: Within first year of the study
measure: Count of Adverse Events, Serious Adverse Events and Dose Limiting Toxicities
timeFrame: 10 months post-radiation therapy
Secondary outcomes:
measure: Impact of Study Treatment on Acute Rectal Bleeding
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Acute Rectal Pain
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Bowel Movements
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Acute Dysuria
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Acute Hematuria
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Acute Urinary Frequency
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Acute Perianal Grade 3 Radiation Dermatitis
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Late Rectal Bleeding
timeFrame: 10 months post-radiation therapy
measure: Impact of Study Treatment on Rectal Fibrosis
timeFrame: 10 months post-radiation therapy
measure: Effect of Study Treatment on Local Control
timeFrame: 10 months post-radiation therapy
measure: Effect of Study Treatment on Overall Survival
timeFrame: 10 months post-radiation therapy
measure: Effect of Study Treatment on Locoreginal Progression-free Survival
timeFrame: 10 months post-radiation therapy
Other outcomes:
measure: Effect of Study Treatment on Urine Levels of 4-hydroxynonenal
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Plasma Levels of 4-hydroxynonenal
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Serum Level of 8-OHdG
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Blood Cells Level of 8-OHdG
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Urine Level of 8-OHdG
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Urine Levels of Malondialdehyde
timeFrame: 4 months post-radiation therapy
measure: Effect of Study Treatment on Plasma Levels of Malondialdehyde
timeFrame: 4 months post-radiation therapy
measure: Single-dose and Repeated-dose Pharmacokinetic Profiles of BMX-001
timeFrame: Up to 36 days of the chemoradiation phase
measure: Effect of Study Treatment on Participant-reported Outcomes of Health-related Quality of Life
timeFrame: 10 months post-radiation therapy
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Chi Lin, MD
role: PRINCIPAL_INVESTIGATOR
References: