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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Brown University
Sponsor:
Collaborators:
Rhode Island Hospital
The Miriam Hospital
Montefiore Medical Center
Boston Medical Center
M.D. Anderson Cancer Center
Rutgers Cancer Institute of New Jersey
Ohio State University Comprehensive Cancer Center
Information provided by (Responsible Party):
howard safran, Brown University
ClinicalTrials.gov Identifier:
NCT01671488
First received: August 7, 2012
Last updated: August 29, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Anal Cancer
Biological: Advaxis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: BrUOG 276: A Phase I/II Evaluation of ADXS11-001, Mitomycin,5-fluorouracil (5-FU) and IMRT for Anal Cancer

Resource links provided by NLM:


Further study details as provided by Brown University:

Primary Outcome Measures:
  • To evaluate number of adverse events with the addition of ADXS11-001 to standard chemoradiation for patients with anal cancer. [ Time Frame: Every week during treatment, for an average of 6 months. Once off study annually, for an average of 5 years. ] [ Designated as safety issue: Yes ]
  • To evaluate the 6-month clinical complete response rate for patients with anal cancer treated with ADXS11-001 mitomycin, 5-FU and IMRT. [ Time Frame: Tumor evaluation 6 months after coming off study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To evaluate progression-free and overall survival for patients with anal cancer treated with ADXS11-001, mitomycin, 5-FU and IMRT. [ Time Frame: Follow up and survival status at 6 months and 1 year post coming off study and annually until patient has been off for 5 years ] [ Designated as safety issue: No ]
  • To assess peripheral and histologic markers of immune response including measuring immunohistochemistry of biopsies for T cell infiltration, following ADXS11-001 in patients [ Time Frame: Prior to study procedures, within 3 days of beginning radiation and 6 months after coming off study therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 25
Study Start Date: April 2013
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Advaxis Schedule 1
Treatment Schedule #1: The first dose will be given 10-14 days prior to the initiation of chemoradiation. The 2-4th dosages of ADXS11-001 will 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, Platelets ≥ 50,000 cells/mm3, serum creatinine < 1.5 mg/dl and all non-hematologic 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. ADXS11-001 administration may be +/- 72 hours. The second cycle of chemotherapy may be +/- 72 hours.
Biological: Advaxis
ADXS11-001 will be given at a dose of 1x109 cfu intravenously once every 28 days for 4 total doses. All 4 doses of ADXS11-001 will be 1x109 cfu. The drug will be given as an 500ml infusion over 15 minutes.
Other Name: ADXS11-001
Experimental: Advaxis Schedule 2
Schedule #2: Once all patients have completed Schedule #1 and have been observed for 28 days Schedule #2 will proceed. Schedule #2 will investigate the second dose of ADXS11-001 D21 of chemoradiation. Administration on day 21 of chemoradiation would only be administered if ANC > 1,000 cells/mm3, serum creatinine < 1.5mg/dl and all non-heme toxicities were grade 2 or less. The third txt with ADXS11-001 would be no less than 10 days after chemoradiation, if ANC > 1,000 cells/mm3, PLTs ≥ 50,000 cells/mm3, serum creatinine < 1.5mg/dl and all toxicities were grade 2 or less. The fourth txt would be 28 days later. If the second dose in Schedule #2, can't be given on D21 (+/- 72 hrs) then Schedule #1 will be used for the second dose.
Biological: Advaxis
ADXS11-001 will be given at a dose of 1x109 cfu intravenously once every 28 days for 4 total doses. All 4 doses of ADXS11-001 will be 1x109 cfu. The drug will be given as an 500ml infusion over 15 minutes.
Other Name: ADXS11-001

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01671488

Contacts
Contact: kayla Rosati, EdM 401-863-3000 Kayla_rosati@brown.edu

Locations
United States, Massachusetts
Boston Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02118
Contact: Lisa Kachnic, MD       Lisa.Kachnic@bmc.org   
Principal Investigator: Lisa Kachnic, MD         
United States, New York
Montefiore Medical Center Recruiting
New York, New York, United States, 10467
Contact: kayla rosati    401-863-3000      
Principal Investigator: Madhur Garg, MD         
United States, Ohio
Ohio State University Comprehensive Cancer Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Kayla Rosati, EdM    401-863-3000      
Principal Investigator: Evan Wuthrick, MD         
United States, Rhode Island
Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Howard Safran, MD       Hsafran@lifespan.org   
Principal Investigator: Howard Safran, MD         
The Miriam Hospital Recruiting
Providence, Rhode Island, United States, 02906
Contact: Howard Safran, MD         
Principal Investigator: Howard Safran, MD         
Sponsors and Collaborators
Brown University
Rhode Island Hospital
The Miriam Hospital
Montefiore Medical Center
Boston Medical Center
M.D. Anderson Cancer Center
Rutgers Cancer Institute of New Jersey
Ohio State University Comprehensive Cancer Center
Investigators
Principal Investigator: Howard Safran, MD Brown University Oncology Research Group
  More Information

No publications provided

Responsible Party: howard safran, Principal Investigator, Brown University
ClinicalTrials.gov Identifier: NCT01671488     History of Changes
Other Study ID Numbers: BrUOG 276
Study First Received: August 7, 2012
Last Updated: August 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Brown University:
Anal Cancer
Mitomycin
5-Fluorouracil
5-FU
IMRT
ADXS11-001

Additional relevant MeSH terms:
Anus Neoplasms
Anus Diseases
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Rectal Neoplasms
Fluorouracil
Mitomycin
Mitomycins
Alkylating Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014