Clinical Trials /

Avelumab With Valproic Acid in Virus-associated Cancer

NCT03357757

Description:

Up to 20% of all cancers may be associated with a bacterial or viral infection. In some instances, the infection may be one of the reasons why the cancer developed in the first place. One such example is infection with the human papilloma virus (HPV) and the development of cervical or oral cavity cancer. A viral infection that is chronic may not cause a person symptoms, and may be able to escape detection by a person's own immune system. One of the medications being studied in this clinical trial (Valproic acid) may be able to unmask a chronic viral infection from a person's own immune system, therefore making the virus susceptible to attack by the immune system. In this study Valproic acid is being combined with an immune therapy, Avelumab. Avelumab is an antibody that targets a person's own immune cells, or lymphocytes. Lymphocytes must be activated to fight infections or cancer, but after activation they are deactivated. Avelumab prevents the deactivation of a lymphocyte, in effect "turning off the off-switch." This leads to a re-energizing of a person's immune system, hopefully leading to an attack by the immune system on a person's cancer. Avelumab is known to be an effective treatment for a variety of cancers, although it has not yet been tested in all cancers. By combining Valproic acid, a treatment which targets the virus that contributed to the development of this type of cancer with Avelumab the investigators hope to enhance the ability of Avelumab to restore the body's own immune defense against the cancer.

Related Conditions:
  • Anal Squamous Cell Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Hodgkin Lymphoma
  • Nasopharyngeal Carcinoma
  • Non-Hodgkin Lymphoma
  • Squamous Cell Carcinoma of Unknown Primary
  • Squamous Cell Carcinoma of the Penis
  • Vulvar/Vaginal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab With Valproic Acid in Virus-associated Cancer
  • Official Title: The LATENT Trial: Lytic Activation To Enhance Neoantigen-directed Therapy A Study to Evaluate the Feasibility and Efficacy of the Combined Use of Avelumab With Valproic Acid for the Treatment of Virus-associated Cancer

Clinical Trial IDs

  • ORG STUDY ID: LATENT
  • NCT ID: NCT03357757

Conditions

  • Cancer That is Associated With a Chronic Viral Infection
  • p16 Positive SCCHN
  • Squamous Cell Carcinoma of the Cervix
  • p16 Positive Squamous Cell Carcinoma of the Vagina or Vulva
  • p16 Positive Squamous Cell Carcinoma of the Penis
  • p16 Positive Squamous Cell Carcinoma of the Anus or Anal Canal
  • EBER Positive NPC
  • EBER Positive Hodgkins and Non-hodgkins Lymphona

Interventions

DrugSynonymsArms
Valproic AcidAvelumab with VPA
AvelumabAvelumab with VPA

Purpose

Up to 20% of all cancers may be associated with a bacterial or viral infection. In some instances, the infection may be one of the reasons why the cancer developed in the first place. One such example is infection with the human papilloma virus (HPV) and the development of cervical or oral cavity cancer. A viral infection that is chronic may not cause a person symptoms, and may be able to escape detection by a person's own immune system. One of the medications being studied in this clinical trial (Valproic acid) may be able to unmask a chronic viral infection from a person's own immune system, therefore making the virus susceptible to attack by the immune system. In this study Valproic acid is being combined with an immune therapy, Avelumab. Avelumab is an antibody that targets a person's own immune cells, or lymphocytes. Lymphocytes must be activated to fight infections or cancer, but after activation they are deactivated. Avelumab prevents the deactivation of a lymphocyte, in effect "turning off the off-switch." This leads to a re-energizing of a person's immune system, hopefully leading to an attack by the immune system on a person's cancer. Avelumab is known to be an effective treatment for a variety of cancers, although it has not yet been tested in all cancers. By combining Valproic acid, a treatment which targets the virus that contributed to the development of this type of cancer with Avelumab the investigators hope to enhance the ability of Avelumab to restore the body's own immune defense against the cancer.

Trial Arms

NameTypeDescriptionInterventions
Avelumab with VPAExperimentalValproic Acid (VPA, 12.5 mg/kg) once per day and Avelumab (10 mg/kg IV) every 2 weeks for up to 2 years.
  • Valproic Acid

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be 18 years of age or older.

          -  Patients with the following histologically confirmed diagnoses will be eligible for
             enrolment: p16 positive SCCHN; squamous cell carcinoma of the cervix; p16 positive
             squamous cell carcinoma of the vagina or vulva; p16 positive squamous cell carcinoma
             of the penis; p16 positive squamous cell carcinoma of the anus or anal canal; EBER
             positive NPC; EBER positive Hodgkins and non-hodgkins lymphoma.

          -  Note: patients with p16 positive SCC of unknown primary origin meeting the minimum
             life expectancy and performance status requirements will also be eligible for
             enrollment, as the majority of these patients may be assumed to represent
             HPV-associated disease.

          -  Patients must be capable of providing consent to enrolment and treatment.

          -  Patients with a performance status of ECOG 0-1(51) will be eligible for enrolment (see
             appendix 1).

          -  Measurable disease must be present according to irRECIST criteria(50).

          -  Women of child bearing potential (WOCBP) must have a negative serum (or urine)
             pregnancy test at the time of screening.

          -  Patients of childbearing / reproductive potential should use highly effective birth
             control methods, as defined by the investigator, during the study treatment period and
             for a period of 60 days after the last dose of study drug. A highly effective method
             of birth control is defined as those that result in low failure rate (i.e. less than
             1% per year) when used consistently and correctly.

          -  Note: abstinence is acceptable if this is established and preferred contraception for
             the patient and is accepted as a local standard.

          -  Female patients who are breast-feeding should discontinue nursing prior to the first
             dose of study treatment and until 120 days after the last dose of study drug.

          -  Absence of any condition hampering compliance with the study protocol and follow- up
             schedule; those conditions should be discussed with the patient before registration in
             the trial.

          -  The following adequate organ function laboratory values must be met:

          -  Hematological:

               -  Absolute neutrophil count (ANC) >1.5 x109/L

               -  Platelet count >100 x109/L

               -  Hemoglobin >9 g/dL (may have been transfused)

          -  Renal:

             o Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
             (or local institutional standard method)

          -  Hepatic:

               -  Total serum bilirubin <1.5x ULN

               -  AST and ALT <2.5x ULN (or ≤ 5 x ULN for subjects with documented metastatic
                  disease to the liver)

               -  Serum albumin > 25 g/L

          -  Coagulation:

               -  International Normalized Ratio (INR) <1.5x ULN (unless patient is receiving
                  anticoagulant therapy as long as PT or PTT is within therapeutic range of
                  intended use of anticoagulants)

               -  Activated Partial Thromboplastin Time (aPTT) <1.5x ULN (unless patient is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants)

        Exclusion Criteria:

          -  History of pneumonitis requiring treatment with steroids.

          -  History of interstitial lung disease.

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
             Association Classification Class II), or serious cardiac arrhythmia requiring
             medication.

          -  History of another malignancy or a concurrent malignancy;

          -  Exceptions include patients who have been disease-free for 5 years, or patients with a
             history of completely resected non-melanoma skin cancer or successfully treated in
             situ carcinoma are eligible, for example cervical cancer in situ.

          -  Active brain metastases or leptomeningeal disease.

          -  Patients with treated brain metastases that are stable for 6 weeks will be eligible
             for enrolment.

          -  Diagnosis of immunodeficiency.

          -  Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
             inhaled, topical steroids, or local steroid injection (e.g., intra-articular
             injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone
             or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
             scan premedication).

          -  Prior organ transplantation including allogenic stem-cell transplantation.

          -  Known history of human immunodeficiency virus (HIV).

          -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).

          -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
             agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
             diseases not requiring immunosuppressive treatment are eligible.

          -  Patients with hyperthyroidism or hypothyroidism but that are stable on hormone
             replacement will not be excluded.

          -  Active infection requiring systemic therapy.

          -  Vaccination within 4 weeks of the first dose of Avelumab and while on trials is
             prohibited except for administration of inactivated vaccines.

          -  Patient will not be eligible if the patient is or has an immediate family member
             (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or
             sponsor staff directly involved with this trial, unless prospective IRB approval (by
             chair or designee) is given allowing exception to this criterion for a specific
             subject.

          -  Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,
             alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety
             risk based on investigator's judgment are acceptable.

          -  Known prior severe hypersensitivity to investigational product or any component in its
             formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (NCI CTCAE v4.03 Grade ≥ 3).

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of Avelumab and VPA
Time Frame:1 year after enrolment of last patient
Safety Issue:
Description:• Assessment of the clinical response rate according to the immune-related RECIST criteria (iRECIST)

Secondary Outcome Measures

Measure:Overall survival
Time Frame:5 years from final study drug dose
Safety Issue:
Description:defined as the time from the date of enrollment to the date of death, whatever the cause.
Measure:Progression free survival
Time Frame:5 years from final study drug dose
Safety Issue:
Description:Progression free survival is defined as the time between the date of treatment initiation and the date of disease progression or death (whatever the cause), whichever occurs first.
Measure:Number of participants with adverse events
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:• Incidence of adverse events (assessed as the incidence and severity of adverse events, including immune-related adverse events, and the number of discontinuations due to adverse events).
Measure:Identify specific virus-associated cancers as candidates for subsequent study
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:Measurement of Immuno-score
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:AffymetriX Micro-array (Immuno-score)
Measure:Measurement of MHC expression
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:Measurement of cell-free tumoral DNA in blood
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:Phenotyping of Tumour Infiltrating Lymphocytes
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:DNA viral load
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:DNA Quantitative PCR (viral load)
Measure:Expression of lytic viral genes
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:Cytotoxic T-Lymphocyte immunophenotyping
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:T-cell receptor sequencing
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:
Measure:Hsp90 concentration in serum
Time Frame:Through study completion, up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AHS Cancer Control Alberta

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