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BrUOG 276: A Phase I/II Evaluation of ADXS11-001, Mitomycin,5-fluorouracil (5-FU) and IMRT for Anal Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Anal Cancer

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Trial Information

BrUOG 276: A Phase I/II Evaluation of ADXS11-001, Mitomycin,5-fluorouracil (5-FU) and IMRT for Anal Cancer

Novel treatments are needed in anal cancer. An important percentage of patients with locally
advanced anal cancer will have persistent loco-regional disease or develop systemic
metastases. Virtually all cases of anal cancer are related to infection by HPV. Anal cancer
cells infected with HPV have the tumor associated antigen HPV E7. ADXS11-001 causes antigen
presenting cells to be stimulated to facilitate immune cells to attack cancer cells
expressing HPV E7. ADXS11-001, at the phase II dose of 1x109 CFU, has been shown to be safe
in patients with advanced cervical cancer which also is caused by HPV infection. Anti-tumor
activity and safety have been demonstrated in cervical cancer to single agent ADXS11-001 and
the combination of ADXS11-001 and cisplatin chemotherapy. Data presented at ASCO 2012
ADXS11-001 is currently being evaluated in women in the United States with cervical
intraepithelial neoplasia. Radiation may augment the activity of ADXS11-001 increasing the
exposure of tumor related antigens thereby increasing the chance for loco-regional disease
eradication and preventing systemic recurrence. Therefore, ADXS11-001 may increase complete
response, prevent recurrence disease and increase disease-free and overall survival in anal
cancer. This protocol will develop sufficient preliminary safety and efficacy data to
facilitate the investigation of ADXS11-001 in anal cancer within "NRG", the newly formed
cooperative group based on the merger of the RTOG, NSABP and GOG.

As described above, Phase I studies and preliminary data from phase II studies have
demonstrated that ADXS11-001, 1x109 CFU, can be safely administered as a single agent and in
combination with chemotherapy. For example in over 200 patients treated at the dose of
1x109CFU there have been no cases of severe listeria bacteremia or grade 3 cardiopulmonary
toxicity. However, since ADXS11-001 has not previously been administered with radiation, the
primary objective of this study will be to establish the safety of the addition of
ADXS11-001 to chemoradiation for anal cancer. The following schedules will be assessed.

- Treatment Schedule #1: The first dose will be given 10-14 days prior to the initiation
of chemoradiation. The 2nd-4th dosages of ADXS11-001will not be until after completion
of all chemoradiation. The second dosage of ADXS11-001 will not be administered until a
minimum of 10 days after completion of chemoradiation, ANC > 1,000 cells/mm3, serum
creatinine < 1.5 mg/dl and all toxicities from chemoradiation have resolved to grade 2
or less. The subsequent third and fourth treatment with of ADXS11 will be administered
at 28 day intervals. This will provide the needed safety data to evaluate Treatment
Schedule #2.

- Treatment Schedule #2: If dose limiting toxicities (defined below) are not exceeded
during Treatment Schedule #1, then Treatment Schedule #2 will investigate
administration of the second dose of ADXS11-001 on day 21 of chemoradiation.
Administration of ADXS11-001 on day 21 of chemoradiation would only be administered if
ANC > 1,000 cells/mm3, serum creatinine < 1.5mg/dl and all toxicities from ongoing
chemoradiation were grade 2 or less. The third treatment with ADXS11-001 would be
administered no less than 10 days after completion of all chemoradiation, if ANC >
1,000 cells/mm3, serum creatinine < 1.5mg/dl and all toxicities from ongoing
chemoradiation were grade 2 or less. The fourth treatment would be 28 days later.

Standard treatment with mitomycin, 5-FU and radiation for anal cancer has substantial
toxicity. In RTOG 9811, 74% of patients had grade 3/4 nonhematologic toxicity and 61% of
patients had grade 3 or grade 4 hematologic toxicity from this regimen. Therefore, the
toxicities of standard chemoradiation with mitomycin, 5-FU and radiation are well above the
conventionally accepted parameters in a phase I study even prior to adding ADXS11-001.
However, it is critical that the addition of ADXS-11-001 does not compromise the delivery of
potentially curative standard chemoradiation for anal cancer.

Inclusion Criteria:

3.1.1 Histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma
of the anal canal; 3.1.2 AJCC 2009 TN Stage: T1N1-N3, T2(< 4cm)N1-N3, T2(> 4cm)N0,T3N0-3,
T4N0-3;based upon the following minimum diagnostic workup: History/physical
examination within 14 days prior to registration; Within 42 days prior to
registration, the patient must have an anal examination by any of the following:
colonoscopy, sigmoidoscopy, or rigid proctoscopy, with documentation of primary anal
lesion size, distance from anal verge.

3.1.3 Groin examination within 42 days prior to registration with documentation of any
groin adenopathy and lymphadenopathy (location: right vs. left; medial vs. lateral; mobile
vs. fixed; and size); 3.1.4 X-ray (PA and lateral), CT scan, or PET/CT scan of the chest
within 42 days prior to registration; 3.1.5 CT scan, MRI, or PET/CT of the abdomen and
pelvis within 42 days prior to registration; 3.1.6 Zubrod Performance Status 0-1; 3.1.7
Age ≥ 18; 3.1.8 Laboratory data obtained ≤ 14 days prior to registration on study, with
adequate bone marrow, hepatic and renal function defined as follows:

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

- Platelets ≥ 100,000 cells/mm3;

- Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve
Hgb ≥ 8.0 g/dl is acceptable.);

- Serum creatinine ≤ 1.5 mg/dl;

- Bilirubin < 1.4mg/dl;

- ALT/AST < 3 x ULN;

- Negative serum pregnancy test for women of child-bearing potential; 3.1.9 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

3.1.10 Patients must sign a study-specific informed consent prior to study entry.

3.1.11 Patients with a history of clinically significant pulmonary disease must have PFTs
demonstrating a DLCO ≥ 40%. This testing is considered standard of care prior to
mitomycin, 5-FU and radiation.

3.1.12 Patients with a history of clinically significant cardiac disease must have a
LVEF ≥ 30% by ECHO. (MUGA scan may also be used to determine LVEF) This testing is
considered standard of care prior to mitomycin, 5-FU and radiation.

Exclusion Criteria:

3.2.1 Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free
for a minimum of 2 years; 3.2.2 Prior systemic chemotherapy for anal cancer; 3.2.3 Prior
allergic reaction to the study drugs involved in this protocol. 3.2.4 Prior radiotherapy
to the pelvis that would result in overlap of radiation therapy fields; 3.2.5 Severe,
active co-morbidity, defined as follows: Patients with uncontrolled intercurrent
illness including, but not limited to ongoing or active infection, symptomatic congestive
heart failure, unstable angina pectoris and cardiac arrhythmia are ineligible.
Furthermore, patients with unstable angina and/or congestive heart failure requiring
hospitalization within the past 6 months are ineligible; Transmural myocardial
infarction within the last 6 months; Acute bacterial or fungal infection requiring
intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary
Disease exacerbation or other respiratory illness requiring hospitalization or precluding
study therapy at the time of registration; Hepatic insufficiency resulting in
clinical jaundice and/or coagulation defects; 3.2.6 Patients known to be seropositive for
HIV and/or active hepatitis, even if liver function studies are in the eligible range.

3.2.7 Other immunocompromised status (e.g., organ transplant or chronic glucocorticoid

3.2.8 Women who are pregnant or lactating are ineligible because the treatment involved in
this study may be significantly teratogenic and there is the potential for transmission of
listeria to the infant.

3.2.9 Patients allergic to penicillin, trimethoprim-sulfa and quinolones (including
history of rash or anaphylaxis).

3.2.10 Patients allergic to naproxen. 3.2.11 Patients receiving oral or IV antibiotics
3.2.11 Patients with a prior history of a splenectomy and/or sickle cell trait/disease

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate number of adverse events with the addition of ADXS11-001 to standard chemoradiation for patients with anal cancer.

Outcome Time Frame:

Every week during treatment, for an average of 6 months. Once off study annually, for an average of 5 years.

Safety Issue:


Principal Investigator

Howard Safran, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Brown University Oncology Research Group


United States: Food and Drug Administration

Study ID:

BrUOG 276



Start Date:

April 2013

Completion Date:

May 2018

Related Keywords:

  • Anal Cancer
  • Anal Cancer
  • Mitomycin
  • 5-Fluorouracil
  • 5-FU
  • IMRT
  • ADXS11-001
  • Anus Neoplasms



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