Clinical Trials /

DNA Plasmid-encoding Interleukin-12/HPV DNA Plasmids Therapeutic Vaccine INO-3112 and Durvalumab in Treating Patients With Recurrent or Metastatic Human Papillomavirus Associated Cancers

NCT03439085

Description:

This phase II trial studies how well deoxyribonucleic acid (DNA) plasmid-encoding interleukin-12/human papillomavirus (HPV) DNA plasmids therapeutic vaccine INO-3112 and durvalumab work in treating patients with human papillomavirus associated cancers that have come back or spread to other places in the body. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving DNA plasmid-encoding interleukin-12/HPV DNA plasmids therapeutic vaccine INO-3112 and durvalumab may work better in treating patients with human papillomavirus associated cancers.

Related Conditions:
  • Anal Carcinoma
  • Cervical Carcinoma
  • Penile Carcinoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vaccine + Durvalumab in Human Papilloma Virus (HPV) Cancers
  • Official Title: A Phase 2, Open-Label Study to Evaluate Efficacy of Combination Treatment With MEDI0457 (INO-3112) and Durvalumab (MEDI4736) in Patients With Recurrent/Metastatic Human Papilloma Virus Associated Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2017-0302
  • SECONDARY ID: NCI-2018-00914
  • NCT ID: NCT03439085

Conditions

  • Malignant Neoplasms of Digestive Organs
  • Malignant Neoplasms of Female Genital Organs
  • Malignant Neoplasms of Male Genital Organs
  • Human Papilloma Virus

Interventions

DrugSynonymsArms
MEDI0457HPV-16/18 Cervical Cancer
DurvalumabMEDI4736HPV-16/18 Cervical Cancer

Purpose

The goal of this clinical research study is to learn if the combination of MEDI0457 and durvalumab can help to control cancers related to the Human Papilloma Virus (HPV). The safety of this combination therapy will also be studied. MEDI0457 is given using a procedure called electroporation, or EP. EP is the delivery of low-voltage electric pulses to the muscle tissue after injection of the MEDI0457. EP is designed to make MEDI0457 more effective. This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of urothelial cancer. It is not approved for use in patients with the types of cancer that are being enrolled on this study. Neither MEDI0457 nor the use of EP are FDA approved or commercially available for the types of cancer in this study. They are currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work. Up to 77 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      If you are found to be eligible to take part in this study, you will receive MEDI0457 at
      Weeks 1, 3, 7, 12, and then every 8 weeks after that. You will receive it as an injection
      into the muscle in your shoulder. After the injection, you will receive the EP around the
      site of the injection. The EP will take a few seconds and you may feel some discomfort (pain
      or tenderness) which typically goes away within 1 hour.

      If needed, the area may be numbed with a topical numbing agent or you may be offered a mild
      sedative for anxiety related to the EP procedure. If you receive a mild sedative, you must
      not operate a motor vehicle for 3-4 hours after receiving medication and must have
      transportation to leave MD Anderson. You will also be offered a pain reliever after the EP
      procedure. You may ask the study staff for information about how these drugs are given and
      their risks.

      About 30 to 60 minutes after the treatment, the site will be checked for any possible
      reactions to the injection and/or the EP.

      You will receive durvalumab by vein over about 1 hour every 4 weeks, beginning with Week 4.

      Length of Study:

      You may continue to receive the study drugs for as long as the doctor thinks it is in your
      best interest. You will be taken off study if the disease gets worse, if intolerable side
      effects occur, or if you are unable to follow study directions.

      Study Visits:

      On Day 1 of Week 1:

        -  You will have a physical exam.

        -  Blood (about 6 tablespoons) will be drawn for routine tests, research tests (which in
           this study will include tests of the immune system and HPV), and biomarker tests. If you
           can become pregnant, part of this sample will be used for a pregnancy test.

        -  You will have an EKG to check your heart function.

      On Day 1 of Weeks 3 and 7:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

      On Day 1 of Week 4:

        -  You will have a physical exam.

        -  Blood (about 7 tablespoons) will be drawn for routine, research, and biomarker tests. If
           you can become pregnant, part of this sample will be used for a pregnancy test.

      On Day 1 of Week 8:

        -  You will have a physical exam.

        -  Blood (about 7 tablespoons) will be drawn for routine, research, and biomarker tests. If
           you can become pregnant, part of this sample will be used for a pregnancy test.

        -  You will have an EKG to check your heart function.

        -  You will have an MRI or a CT scan to check the status of the disease.

      On Day 1 of Week 10:

        -  You will have a physical exam.

        -  Blood (about 6 tablespoons) will be drawn for routine, research, and biomarker tests.

        -  If you are one of the first 10 patients on this study to get to Week 10, you will have a
           core tumor biopsy for immune system testing and for biomarker testing, which may include
           genetic biomarkers. If you are not one of the first 10 patients, this procedure will be
           optional. The study doctor will tell you if you are one of these patients.

      On Day 1 of Week 12:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests. If you can become pregnant,
           part of this sample will be used for a pregnancy test.

        -  You will have an EKG to check your heart function.

      On Day 1 of Week 16 and then every 4 weeks:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests. If you can become pregnant,
           part of this sample will be used for a pregnancy test. After you have participated on
           this study for more than a year, these routine tests will be done every 3 months until
           you finish the study. Pregnancy tests will continue every 4 weeks.

      The following procedures will be performed on Day 1 of Week 16 and then every 8 weeks:

        -  You will have an MRI or a CT scan to check the status of the disease.

        -  Blood (about 5 tablespoons) will be drawn for routine, research, and biomarker tests.

        -  On Day 1 of Week 20 and then every 12 weeks, you will have an EKG to check your heart
           function.

      End of Treatment Visit:

      After you have received your last dose of the study drugs:

        -  You will have a physical exam.

        -  Blood (about 6 tablespoons) will be drawn for routine, research, and biomarker tests. If
           you can become pregnant, part of this sample will be used for a pregnancy test.

        -  You will have an EKG to check your heart function.

        -  You will have an MRI or a CT scan to check the status of the disease.

      Follow-Up:

      About 30 days after your last dose of the study drugs:

        -  You will have a physical exam.

        -  Blood (about 6 tablespoons) will be drawn for routine, research, and biomarker tests.

      If the disease has not gotten worse, you will have an MRI or a CT scan to check the status of
      the disease about 90 days after your last dose of the study drug, then every 3 months for a
      year, and then every 6 months until the end of study (about 5 years after the last
      participant stops receiving the study drugs).
    

Trial Arms

NameTypeDescriptionInterventions
HPV-16/18 Cervical CancerExperimentalParticipants receive MEDI0457 at Weeks 1, 3, 7, 12, and then every 8 weeks after that. After the injection, participant receives electroporation (EP) around the site of the injection. Participants receive Durvalumab by vein over about 1 hour every 4 weeks, beginning with Week 4.
  • Durvalumab
HPV-16/18 Rare Tumors (Anal, Penile, Vulvar, Vaginal)ExperimentalParticipants receive MEDI0457 at Weeks 1, 3, 7, 12, and then every 8 weeks after that. After the injection, participant receives electroporation (EP) around the site of the injection. Participants receive Durvalumab by vein over about 1 hour every 4 weeks, beginning with Week 4.
  • Durvalumab
HIV (+) HPV-16/18 Malignancies (Any Site)ExperimentalParticipants receive MEDI0457 at Weeks 1, 3, 7, 12, and then every 8 weeks after that. After the injection, participant receives electroporation (EP) around the site of the injection. Participants receive Durvalumab by vein over about 1 hour every 4 weeks, beginning with Week 4.
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent in accordance with institutional guidelines.

          2. Male and female patients age 18 years or older who are able and willing to comply with
             all study procedures.

          3. For patients who are not HIV positive, cervical, anal, penile, vulvar, or vaginal
             cancer positive for HPV-16 and/or HPV-18 by the Cervista assay. For patients who are
             HIV positive, histologically or cytologically confirmed diagnosis of cancer at any
             site that is positive for HPV-16 and/or HPV-18 by the Cervista assay. Tumors may be
             positive for more than 1 HPV subtype as long as HPV-16 and/or HPV-18 is present. Note:
             For the first 6 patients, only cervical, vulvar, or vaginal cancers will be enrolled.

          4. Patients with cancer that is refractory to standard therapy, that have either relapsed
             after standard therapy or has no standard therapy that increases survival by at least
             three months, and/or that are not curable by salvage approaches including resection
             and/or re-irradiation.

          5. Has measurable disease, defined as at least one lesion that can be accurately measured
             in at least one dimension (longest diameter to be recorded) with a minimum size of 10
             mm by computed tomography (CT) scan, except lymph nodes which must have minimum short
             axis size of 15 mm (CT scan slice thickness no greater than 5 mm in both cases).
             Indicator lesions must not have been previously treated with surgery, radiation
             therapy, or radiofrequency ablation unless there is documented Response Evaluation
             Criteria In Solid Tumors (RECIST) version 1.1 progression in the lesion after such
             therapy.

          6. All patients must consent to pre-treatment biopsy of the tumor if it can be done
             safely (as judged by the investigator) during screening. Week 10 on-treatment biopsies
             will be required for a minimum 10 patients. After 10 paired biopsies have been
             obtained then Week 10 on-treatment biopsy will be made optional.

          7. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance
             status of 0 or 1.

          8. Adequate organ and bone marrow function within 28 days of Day 0. Criteria a. to c.
             cannot be met with recent (within 28 days of screening test except as noted below)
             blood transfusions or require ongoing growth factor support: a. Hemoglobin >/= 9 g/dL
             (Note: No Transfusion within 56 days. Ongoing growth factor support is acceptable if
             on a stable dose for the past 56 days.), b. Absolute neutrophil count >/= 1,000/mm^3,
             c. Platelet count >/= 100,000/mm^3 and no transfusion in prior 4 weeks, d. Total
             bilirubin (TBL) </= 1.5 × upper limit of normal (ULN) except patients with documented
             Gilbert's syndrome (> 3 × ULN), e. Alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) </= 3 × ULN, f. Serum creatinine </= 2.0 mg/dL or creatinine
             clearance >/= 40 mL/min (measured or calculated according to the method of Cockcroft
             and Gault), and g. For Human Immunodeficiency Virus (HIV)+ patients: Documented HIV-1
             infection with CD4 count > 200 cells/mm^3 and viral load < 75 copies/mL.

        Exclusion Criteria:

          1. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal
             therapy for cancer treatment; receipt of any investigational or approved anticancer
             therapy (chemotherapy, targeted therapy, biologic therapy, monoclonal antibodies,
             etc.) within 21 days or 5 half lives, whichever is shorter, prior to the first dose of
             MEDI0457; concurrent enrollment in another clinical study, unless it is an
             observational (non-interventional) clinical study or during the follow-up period of an
             interventional study.

          2. Major surgical procedure or significant traumatic injury within 28 days before the
             first dose of study drug or anticipation of the need for major surgery during the
             course of study treatment.

          3. 3. Any unresolved toxicity (National Cancer Institute Common Terminology Criteria for
             Adverse Event [CTCAE] version 4.03 [v4.03]) Grade 2 or greater from previous
             anticancer therapy with the exception of alopecia, and the laboratory values defined
             in the inclusion criterion 8. Hearing loss of Grade 3 or lower and peripheral
             neuropathy of Grade 2 or lower is allowed. Subjects with Grade >/= 2 neuropathy will
             be evaluated on a case-by-case basis after consultation with the Study Physician.
             Subjects with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with durvalumab may be included only after consultation with the Study
             Physician.

          4. Current or prior use of immunosuppressive medication within 14 days prior to first
             study dose, with the exception of intranasal and inhaled corticosteroids or systemic
             corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
             equivalent. Steroids as premedication for hypersensitivity reactions due to
             radiographic contrast agents are allowed.

          5. Patients requiring therapeutic anticoagulation and irreversible platelet inhibitors
             (e.g. clopidogrel, prasugrel, or ticagrelor). Low dose aspirin for cardiac prophylaxis
             is allowed.

          6. History of primary immunodeficiency.

          7. Patients who have had prior exposure to immune-mediated therapy defined as prior
             exposure to T-cell and natural killer cell directed therapy (e.g. anti-PD-1,
             anti-PD-L1, anti-CD137, and anti-CTLA4, etc).

          8. History of allogeneic organ transplantation.

          9. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g. colitis, ulcerative colitis or Crohn's disease],
             diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,
             Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'
             disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are
             exceptions to this criterion: Patients with vitiligo or alopecia, Patients with
             hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement, Any
             chronic skin condition that does not require systemic therapy, Patients without active
             disease in the last 5 years may be included but only after consultation with the study
             physician, and Patients with celiac disease controlled by diet alone.

         10. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active
             infection, uncontrolled hypertension, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring adverse events, or compromise the ability of the patient to give
             written informed consent.

         11. Patients with spinal cord compression or a history of leptomeningeal carcinomatosis.
             At the time of Day 1 of the study, patients with central nervous system metastases
             must have been treated and must be asymptomatic and meet the following criteria. 1. No
             concurrent treatment, inclusive of, but not limited to, surgery, radiation, and/or
             corticosteroids. (Note: patients are allowed on systemic steroids as detailed in
             Exclusion Criterion 4 unless these are being administered to manage central nervous
             system metastases.); 2. Neurologic stability (lack of signs or symptoms greater than
             baseline prior to radiotherapy) until the time of dosing of MEDI0457; (Continued in
             next criterion)

         12. (Continued from Criterion 11) 3. For radiation treatment, patients must be: At least
             14 days between last day of stereotactic radiosurgery or gamma-knife treatment and Day
             1 of protocol treatment, At least 28 days between last day of whole brain radiation
             therapy and Day 1 of protocol treatment, and/or At least 14 days since last dose of
             corticosteroids and Day 1 of protocol treatment.

         13. Patients with cardiovascular (CV) disease conditions including New York Heart
             Association Class 3 or 4 congestive heart failure, unstable angina pectoris, or
             clinically important cardiac arrhythmias OR a recent (< 3 months) CV event, including
             myocardial infarction, unstable angina pectoris, or stroke.

         14. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from ECG using
             Fridericia's Correction by manual read.

         15. Active tuberculosis (clinical evaluation that includes clinical history, physical
             examination and radiographic findings, and tuberculosis testing in line with local
             practice) infection.

         16. Presence of acute or chronic hepatitis B (HBV) or active hepatitis C (HCV). Patients
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV
             antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

         17. Receipt of live, attenuated vaccine within 30 days prior to study entry or the first
             dose of MEDI0457. Note: Patients, if enrolled, should not receive live vaccine during
             the study and up to 30 days after the last dose of IP.

         18. Other untreated coexisting HIV related malignancies.

         19. History of another primary malignancy except for: malignancy treated with curative
             intent and with no known active disease >/= 2 years before the first dose of IP and of
             low potential risk for recurrence, adequately treated non-melanoma skin cancer or
             lentigo maligna without evidence of disease, or adequately treated carcinoma in situ
             without evidence of disease.

         20. Pregnant or breastfeeding female patients.

         21. Known allergy or hypersensitivity to study treatment or any of the study drugs
             excipients.

         22. Any medical condition that, in the opinion of the investigator, would interfere with
             evaluation of the study treatment or interpretation of patient safety or study
             results.

         23. Patients with active or prior digestive tract bleeding.

         24. Patients with uncontrolled seizures.

         25. Fewer than two acceptable sites exist for intramuscular (IM) injection and
             electroporation (EP) between the deltoid and lateral quadriceps muscles. Note: A site
             for injection/EP is not acceptable if there are tattoos or scars within 2 cm of the
             proposed injection/EP site or if there is implanted metal within the same limb. Any
             device implanted in the chest (e.g. cardiac pacemaker or defibrillator) excludes the
             use of the deltoid muscle on the same side of the body.

         26. Patients who are unable to provide informed consent, are incarcerated, or are unable
             to follow protocol requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR) of MEDI0457 in Combination with Durvalumab Measured by RECIST v1.1
Time Frame:Start of drug combination up to 30 days after drug combination stopped up to 5 years.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) of MEDI0457 in Combination with Durvalumab
Time Frame:Start of drug combination up to 30 days after drug combination stopped up to 5 years.
Safety Issue:
Description:ORR assessed using RECIST version 1.1 and irRECIST.
Measure:Progression Free Survival (PFS) Based on RECIST v1.1
Time Frame:30 days after last dose of study drug combination up to 5 years.
Safety Issue:
Description:PFS defined as the time from the date of start of IP treatment until the date of objective disease progression or death (+1 day) (by any cause) whichever occurs first.
Measure:Disease Control Rate (DCR)
Time Frame:24 weeks
Safety Issue:
Description:DCR defined as N (%) patients with complete response (CR), partial response (PR), or stable disease (SD) using RECIST version 1.1.
Measure:Overall Survival (OS)
Time Frame:30 days after last dose of study drug combination up to 5 years.
Safety Issue:
Description:OS defined as the time from the date of start of IP treatment until death (+1 day) due to any cause.
Measure:Adverse Events (AE) of MEDI0457 in Combination with Durvalumab
Time Frame:Start of study drugs up to 30 days after study drug combination stopped.
Safety Issue:
Description:AE graded according to the NCI CTCAE v4.03.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant Neoplasms of Digestive Organs
  • Malignant neoplasms of female genital organs
  • Malignant neoplasms of male genital organs
  • Human Papilloma Virus
  • MEDI0457
  • Durvalumab
  • MEDI4736
  • Electroporation
  • EP

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