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

Information source: Brown University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Anal Cancer

Intervention: Advaxis (Biological)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Brown University

Official(s) and/or principal investigator(s):
Howard Safran, MD, Principal Investigator, Affiliation: Brown University Oncology Research Group

Overall contact:
kayla Rosati, EdM, Phone: 401-863-3000, Email: Kayla_rosati@brown.edu

Summary

The main purpose of this study is to study the safety and effectiveness of ADXS11-001 when combined with standard chemotherapy and radiation treatment for anal cancer. ADXS11-001 is an investigational agent that is not approved by the FDA to treat anal cancer or any other cancer.

Clinical Details

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

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

Primary outcome:

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

To evaluate the 6-month clinical complete response rate for patients with anal cancer treated with ADXS11-001 mitomycin, 5-FU and IMRT.

Secondary outcome:

To evaluate progression-free and overall survival for patients with anal cancer treated with ADXS11-001, mitomycin, 5-FU and IMRT.

To assess peripheral and histologic markers of immune response including measuring immunohistochemistry of biopsies for T cell infiltration, following ADXS11-001 in patients

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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: 3. 1.2. 1 History/physical examination within 14 days prior to registration; 3. 1.2. 2 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 study. 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: 3. 2.5. 1 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; 3. 2.5. 2 Transmural myocardial infarction within the last 6 months; 3. 2.5. 3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 3. 2.5. 4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; 3. 2.5. 5 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 use). 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

Locations and Contacts

kayla Rosati, EdM, Phone: 401-863-3000, Email: Kayla_rosati@brown.edu

Rutgers- Robert Wood Johnson University Hospital, New Brunswick, New Jersey 08901, United States; Recruiting
kayla Rosati, Edm, Phone: 401-863-3000, Email: kayla_rosati@brown.edu
Salma Jabbour, MD, Principal Investigator

Montefiore Medical Center, New York, New York 10467, United States; Recruiting
kayla rosati, Phone: 401-863-3000
Madhur Garg, MD, Principal Investigator

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting
Howard Safran, MD, Email: Hsafran@lifespan.org
Howard Safran, MD, Principal Investigator

The Miriam Hospital, Providence, Rhode Island 02906, United States; Recruiting
Howard Safran, MD
Howard Safran, MD, Principal Investigator

Additional Information

Starting date: April 2013
Last updated: July 21, 2015

Page last updated: August 23, 2015

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