Clinical Trials /

A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

NCT02924038

Description:

This is a pilot, randomized, two arm neoadjuvant vaccine study in human leukocyte antigen-A2 positive (HLA-A2+) adults with World Health Organization (WHO) grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety of the novel combination of subcutaneously administered IMA950 peptides and poly-ICLC (Hiltonol) and i.v. administered CDX-1127 (Varlilumab) in the neoadjuvant approach; and 2) whether addition of i.v. CDX-1127 (Varlilumab) increases the response rate and magnitude of CD4+ and CD8+ T-cell responses against the IMA950 peptides in post-vaccine peripheral blood mononuclear cell (PBMC) samples obtained from participating patients.

Related Conditions:
  • Diffuse Astrocytoma
  • Oligoastrocytoma
  • Oligodendroglioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)
  • Official Title: Pilot Randomized Neo-adjuvant Evaluation of Agonist Anti-CD27 Monoclonal Antibody Varlilumab on Immunologic Activities of IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

Clinical Trial IDs

  • ORG STUDY ID: 15108
  • SECONDARY ID: NCI-2017-01369
  • NCT ID: NCT02924038

Conditions

  • Glioma
  • Malignant Glioma
  • Astrocytoma, Grade II
  • Oligodendroglioma
  • Glioma, Astrocytic
  • Oligoastrocytoma, Mixed

Interventions

DrugSynonymsArms
IMA950IMA950 peptidesIMA950/poly-ICLC subQ only
poly-ICLCHiltonolIMA950/poly-ICLC subQ only
VarlilumabCDX-1127IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV

Purpose

This is a pilot, randomized, two arm neoadjuvant vaccine study in human leukocyte antigen-A2 positive (HLA-A2+) adults with World Health Organization (WHO) grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety of the novel combination of subcutaneously administered IMA950 peptides and poly-ICLC (Hiltonol) and i.v. administered CDX-1127 (Varlilumab) in the neoadjuvant approach; and 2) whether addition of i.v. CDX-1127 (Varlilumab) increases the response rate and magnitude of CD4+ and CD8+ T-cell responses against the IMA950 peptides in post-vaccine peripheral blood mononuclear cell (PBMC) samples obtained from participating patients.

Detailed Description

      Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse
      astrocytomas, and oligodendrogliomas are a diverse family of central nervous system (CNS)
      neoplasms that occur in children and adults. Based on data from the American Cancer Society
      and Central Brain Tumor Registry of the United States (CBRTUS), approximately 1,800 LGG were
      diagnosed in 2006, thus representing approximately 10% of newly diagnosed primary brain
      tumors in the United States. Pilocytic astrocytomas (WHO grade I) are the most common brain
      tumor in children 5 to 19 years of age. Diffuse astrocytomas and oligodendrogliomas are all
      considered WHO grade II low grade gliomas (LGG) and are more common in adults. Pilocytic
      astrocytomas are generally well circumscribed histologically and radiographically and
      amenable to cure with gross total resection. In contrast, the diffuse astrocytomas and
      oligodendrogliomas are more infiltrative and less amenable to complete resection. From a
      molecular genetics standpoint, the most common alterations in LGG are IDH1 mutations and
      mutations in the tumor suppressor gene TP53, located on chromosome 17, the gene product of
      which is a multifunctional protein involved in the regulation of cell growth, cell death
      (apoptosis), and transcription. Additionally, several molecular factors are of favorable
      prognostic significance, particularly the presence of 1p/19q co-deletion and isocitrate
      dehydrogenase (IDH) mutations.

      WHO grade II LGGs are at risk to undergo malignant transformation into more aggressive and
      lethal WHO grade III or IV high-grade glioma (HGG). Even with a combination of available
      therapeutic modalities (i.e., surgery, radiation therapy [RT], chemotherapy), the invasive
      growth and resistance to therapy exhibited by these tumors results in recurrence and death in
      most patients. Although postoperative RT in LGG significantly improves 5-year
      progression-free survival (PFS), it does not prolong overall survival (OS) compared with
      delayed RT given at the time of progression. Early results from a randomized trial of
      radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy for
      supratentorial adult LGG (RTOG 9802) demonstrated improved PFS in patients receiving PCV plus
      RT compared RT alone. Nonetheless, PCV is considerably toxic and currently not widely used
      for management of glioma patients. Although chemotherapy with temozolomide (TMZ) is currently
      being investigated in LGG patients, it is unknown whether it confers improved OS in these
      patients. Further, our recent study has indicated that 6 of 10 LGG cases treated with TMZ
      progressed to HGG with markedly increased exome mutations and, more worrisome, driver
      mutations in the RB and AKT-mTOR pathways, with predominant C>T/G>A transitions at CpC and
      CpT dinucleotides, strongly suggesting a signature of TMZ-induced mutagenesis; this study
      also showed that in 43% of cases, at least half of the mutations in the initial tumor were
      undetected at recurrence, while IDH mutations were the only type of mutations that persisted
      in the initial and recurrent tumors. These data suggests the possibility that treatment of
      LGG patients with TMZ may enhance oncogenic mutations and genetic elusiveness of LGG,
      therefore calling for development of safer and effective therapeutic modalities such as
      vaccines.

      Taken together, LGG are considered a premalignant condition for HGG, such that novel
      interventions to prevent malignant transformation need to be evaluated in patients with LGG.
      Immunotherapeutic modalities, such as vaccines, may offer a safe and effective option for
      these patients due to the slower growth rate of LGG (in contrast with HGG), which should
      allow sufficient time for multiple immunizations and hence high levels of anti-glioma
      immunity. Because patients with LGGs are generally not as immuno-compromised as patients with
      HGG, they may also exhibit greater immunological response to and benefit from the vaccines.
      Further, the generally mild toxicity of vaccines may improve quality of life compared with
      chemotherapy or RT.
    

Trial Arms

NameTypeDescriptionInterventions
IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IVExperimentalIMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously followed immediately by a Varlilumab 3mg/kg infusion (intravenously) -23±2 days (about 3 weeks) before the date of scheduled standard-of-care surgery to remove the WHO grade II glioma. Patients will continue receiving IMA950/poly-ICLC subcutaneous injections every week leading up to surgery (Days -16±2, -9±2 and 24-48 hours prior to scheduled surgery) and every 3 weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). After surgery, patients will continue receiving a Varlilumab infusion every 6 weeks immediately following the IMA950/poly-ICLC injection (Weeks A1, A7, A13, and A19).
  • IMA950
  • poly-ICLC
  • Varlilumab
IMA950/poly-ICLC subQ onlyExperimentalIMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously every week leading up to standard-of-care surgery to remove the WHO grade II glioma (Days -23±2, -16±2, -9±2 and 24-48 hours prior to scheduled surgery) and every three weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). Patients will not receive Varlilumab.
  • IMA950
  • poly-ICLC

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be >= 18 years old.

          -  Pathological criteria - Participants must have a newly diagnosed or recurrent WHO
             grade II astrocytoma, oligoastrocytoma or oligodendroglioma that has been
             histologically confirmed by prior biopsy or surgical resection. If the pathological
             diagnosis ws made outside of University of California, San Francisco (UCSF), the
             pathology must be reviewed and confirmed at UCSF.

          -  Patients must be positive for HLA-A2 based on flow-cytometry or genotyping

          -  Before enrollment, patients must show non-enhancing T2-FLAIR lesions lesions that are
             amenable to surgical resection. Surgical resection of at least 0.3 grams of tumor is
             expected to ensure adequate evaluation of the study endpoints

          -  Prior radiation therapy (RT) after the initial diagnosis will be allowed but there
             must be at least 6 months from the completion of RT (or radiosurgery) to signed
             informed consent.

          -  Prior chemotherapy and any systemic molecularly targeted anti-tumor therapy will be
             allowed, and there must be at least 28 days from the last temodar chemotherapy, 42
             days for nitrosourea; at least 14 days from the last dose for chemotherapy regimens
             given continuously or on a weekly basis with limited potential for delayed toxicity.

          -  Patients must have a Karnofsky performance status (KPS) of >= 70%.

          -  Off or low dose (<= 4 mg/day by Decadron) corticosteroid at least two weeks before the
             first pre-surgical vaccine

          -  Adequate organ function within 28 days of study registration including: 1) Adequate
             bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) >=1.0 x
             10^9/L, absolute lymphocyte count >=4.0 x 10^8/L, platelets >=100 x 10^9/L; hemoglobin
             >=8 g/dL; 2) Hepatic: - Total bilirubin <= 1.5 x upper limit of normal (ULN) and Serum
             glutamic pyruvic transaminase(SGPT)/ (alanine aminotransferase (ALT)) <=2.5 x upper
             limit of normal (ULN), and 3) Renal: Normal serum creatinine or creatinine clearance
             >=60 ml/min/1.73 m^2

          -  Must be free of systemic infection. Subjects with active infections (whether or not
             they require antibiotic therapy) may be eligible after complete resolution of the
             infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days
             before beginning treatment.

          -  Sexually active females of child bearing potential must agree to use adequate
             contraception (diaphragm, birth control pills, injections, intrauterine device (IUD),
             surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration
             of the vaccination period. Sexually active males must agree to use barrier
             contraceptive for the duration of the vaccination period.

          -  Women of child-bearing potential and men must agree to use adequate contraception (ex.
             Hormonal or barrier method of birth control or abstinence) prior to study entry and
             for the duration of study participation (until one month after the last vaccine) since
             the effects of the current regimen on the developing human fetus are unknown. Should a
             woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately

          -  Patient must sign an informed consent document indicating that they are aware of the
             investigational nature of this study, which includes an authorization for the release
             of their protected health information

        Exclusion Criteria:

          -  Presence of gliomatosis cerebri, cranial or spinal leptomeningeal metastatic disease

          -  Presence of T1 Gadolinium (Gd)-enhancing lesions (on MRI) suggestive of high-grade
             glioma

          -  Pathological diagnosis for the resected tumor demonstrates transformation to higher
             grade (i.e. WHO grade III or IV) gliomas. If a patient is diagnosed as HGG upon
             resection after receiving the pre-surgical treatment, the patient will be withdrawn
             from the study and considered for therapeutic options for HGG (trials for HGG or
             standard of care). The tumor tissue of such a case would be brought to the lab before
             the pathological diagnosis is made; and thus would be processed before the lab is
             informed of the final HGG diagnosis. Because HGG tissue may still reflect the vaccine
             effects, we will evaluate the tumor tissue to help us develop future approaches for
             HGG.

          -  Pregnant women are excluded from this study because IMA950 and poly-ICLC are drugs
             with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with IMA950 plus poly-ICLC (IMA950-poly-ICLC hereafter)
             vaccine, breastfeeding should be discontinued if the mother is treated with IMA950-
             poly-ICLC vaccine

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection (e.g. active or chronic hepatitis B and C), symptomatic congestive heart
             failure, unstable angina pectoris, or psychiatric illness/social situations that would
             limit compliance with study requirements

          -  History or current status of immune system abnormalities such as hyperimmunity (e.g.,
             autoimmune diseases) that needed to be treated by systemic therapy, such as
             immuno-suppressants and hypoimmunity (e.g., myelodysplastic disorders, marrow
             failures, AIDS, transplant immunosuppression).

          -  Any isolated laboratory abnormality suggestive of a serious autoimmune disease (e.g.
             hypothyroidism): Antinuclear antibody, thyroid-stimulating hormone (TSH), free
             thyroxine (FT4), rheumatoid factor

          -  Any condition that could potentially alter immune function (AIDS, multiple sclerosis,
             diabetes, renal failure)

          -  Receiving ongoing treatment with immunosuppressive drugs or dexamethasone > 4mg

          -  Use of any of the following concurrent treatment or medications:

               -  radiation therapy

               -  chemotherapy

               -  interferon (e.g. Intron-A)

               -  allergy desensitization injections

               -  growth factors (e.g. Procrit, Aranesp, Neulasta)

               -  Interleukins (e.g. Proleukin)

               -  any investigational therapeutic medication

          -  Prior cancer diagnosis except the following:

               -  squamous cell cancer of the skin without known metastasis

               -  basal cell cancer of the skin without known metastasis

               -  carcinoma in situ of the breast (DCIS or LCIS)

               -  carcinoma in situ of the cervix

          -  Any other acute or chronic medical or psychiatric condition or laboratory abnormality
             that could increase the risk associated with trial participation or trial drug
             administration or could interfere with the interpretation of trial results and, in the
             judgment of the investigator, would make the patient inappropriate for entry into the
             trial.

          -  Participants with known addiction to any drugs
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Treatment-related Adverse Events (AE)
Time Frame:up to 2 years
Safety Issue:
Description:Incidence and severity of treatment-related adverse events, using standard criteria as well as close clinical follow-up as would be performed normally in this group of participants following vaccinations. All reported or observed toxicities and adverse events at all clinic visits will be graded, documented and reported according to a standard toxicity table, the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nicholas Butowski

Trial Keywords

  • low-grade glioma
  • glioma
  • immunotherapy
  • vaccine
  • WHO grade II

Last Updated

June 12, 2020