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

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Brief Title

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

Official Title

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

Brief 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

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: 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.

      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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

To Evaluate the Safety of the Addition of ADXS11-001 to Standard Chemoradiation for Patients With Anal Cancer.

Secondary Outcome

 To Evaluate Progression-free and Overall Survival for Patients With Anal Cancer Treated With ADXS11-001, Mitomycin, 5-FU and IMRT.


Anal Cancer



Study Arms / Comparison Groups

Description:  The first dose will be given 10-14 days prior to the initiation of chemoradiation.
Patient will then receive 5-FU: 1 gm/m2/day x 96 hours beginning on day 1-4 and day 29-32 + 7 days and Mitomycin: 10 mg/m2, day 1 and 29 with IMRT radiation: 54 Gy in 30 fractions at 1.8 Gy per fraction.
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. The subsequent third and fourth treatment with of ADXS11 will be administered at 28 day intervals.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 2013

Completion Date

February 2018

Primary Completion Date

February 2018

Eligibility 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: 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 2 forms of medically
             effective means of birth control (such as a condom and spermicide) throughout their
             participation in the treatment phase of the study and for 90 days post last dose of
             study drug.

        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.

        3.1.13 Patients must be able to swallow pills.

        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; Patients with active infection requiring
        systemic therapy (oral or IV) or those currently receiving antibiotics that cannot
        discontinue prior to dosing 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
        use).If patient has diagnosis of immunodeficiency, is dependent on or has received systemic
        steroids therapy or any form of immunosuppressive therapy within 7 days prior to the first
        dose of ADXS11-001 they are ineligible. Topical corticosteroid or occasional inhaled
        corticosteroids are allowed.

        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 or with a sensitivity to penicillin, ampicillin,
        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
        3.2.12 Patients with a prior history of a splenectomy and/or sickle cell trait/disease
        3.2.13 Patient has implanted medical device(s) that pose a high risk for colonization
        and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves,
        pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous
        implant(s)). NOTE: More common devices and prosthetics which include arterial and venous
        stents, dental and breast implants and venous access devices (e.g. Port-a-Cath or Mediport)
        are permitted. Sponsor must be contacted prior to consenting any subject who has any other
        device and/or implant. Site is required to submit to BrUOG ALL surgical implants patient
        has ever had in their medical history and ALL surgeries regardless of link to this cancer

        3.2.14 Patients who are receiving or may receive future treatment with PI3K or TNFα
        inhibitors. To be confirmed by treating medical oncologist in writing 3.2.15 Has undergone
        a major surgery, including surgery for a new artificial implant and/or device, within 6
        weeks prior to the initiation of ADXS11-001 treatment. NOTE: if patient underwent surgery >
        6 weeks from start of ADSX11-001, all toxicities and/or complications must have recovered
        to baseline or Grade 1 prior to the initiation of ADXS11-001 study therapy.

        3.2.16 Patient not being willing to have new infusion line placed for each infusion of
        ADXS11-001 as existing or newly placed central venous catheter or infusion ports are not
        allowed to be used for ADXS11-001 administration. Must be confirmed as discussed with
        patient and that they agreed.

        3.2.17 Patient not willing to comply with requirement of central venous catheter or
        infusion port must not be used for 72 hours following the completion of the ADXS11-001
        infusion and the patient receives the first post-treatment dose of oral antibiotics. Must
        be confirmed as discussed with patient and that they agreed.

        3.2.18 Live vaccines within 30 days prior to the first dose of trial treatment and while
        participating in the trial. Examples of live vaccines include, but are not limited to, the
        following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid
        (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus
        vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
        attenuated vaccines and are not allowed. All recent vaccines (within 30 days) to be listed
        on conmed log 3.2.19 Patient has a history of listeriosis or prior ADXS11-001 therapy.




18 Years - N/A

Accepts Healthy Volunteers



Howard Safran, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID

BrUOG 276

Responsible Party

Principal Investigator

Study Sponsor

Brown University


 Rhode Island Hospital

Study Sponsor

Howard Safran, MD, Principal Investigator, Brown University

Verification Date

February 2020