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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate number of adverse events with the addition of ADXS11-001 to standard chemoradiation for patients with anal cancer.
Every week during treatment, for an average of 6 months. Once off study annually, for an average of 5 years.
Howard Safran, MD
Brown University Oncology Research Group
United States: Food and Drug Administration
|Rhode Island Hospital||Providence, Rhode Island 02903|
|Boston Medical Center||Boston, Massachusetts 02118|
|Montefiore Medical Center||Bronx, New York 10467-2490|
|University of Pennsylvania School of Medicine||Philadelphia, Pennsylvania 19104|
|MD Anderson||Houston, Texas 77230|
|The Miriam Hospital||Providence, Rhode Island 02903|
|The James Cancer Center Hospital, Ohio State||Colombus, Ohio 43210|