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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02924038
Recruitment Status : Recruiting
First Posted : October 5, 2016
Last Update Posted : January 31, 2020
Celldex Therapeutics
Information provided by (Responsible Party):
Nicholas Butowski, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glioma Malignant Glioma Astrocytoma, Grade II Oligodendroglioma Glioma, Astrocytic Oligoastrocytoma, Mixed Biological: IMA950 Biological: poly-ICLC Biological: Varlilumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 13, 2017
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV
IMA950 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).
Biological: IMA950
IMA950 vaccine
Other Name: IMA950 peptides

Biological: poly-ICLC
poly-ICLC vaccine
Other Name: Hiltonol

Biological: Varlilumab
Intravenous solution
Other Name: CDX-1127

Experimental: IMA950/poly-ICLC subQ only
IMA950 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.
Biological: IMA950
IMA950 vaccine
Other Name: IMA950 peptides

Biological: poly-ICLC
poly-ICLC vaccine
Other Name: Hiltonol

Primary Outcome Measures :
  1. Adverse Events [ Time Frame: up to 2 years ]
    CTCAE v5.0

  2. CD4+ and CD8+ T-cell responses [ Time Frame: up to 2 years ]
    flow-cytometry-based 2D ex vivo assay system

Other Outcome Measures:
  1. IMA950-reactive T-cell infiltration and CXCL9/10 expression in tumor [ Time Frame: up to 2 years ]
    Multi-color flow cytometry

  2. CXCL9/10 expression [ Time Frame: up to 2 years ]
    Reverse transcription polymerase chain reaction (RT-PCR)

  3. IMA950-reactive T-cell receptor (TCR) clonotypes [ Time Frame: up to 2 years ]

  4. Overall survival (OS) [ Time Frame: minimum of 2 years ]
    Response Assessment in Neuro-Oncology (RANO) response criteria

  5. Progression-free survival (PFS) [ Time Frame: minimum of 2 years ]
    Response Assessment in Neuro-Oncology (RANO) response criteria

  6. PBMC responses [ Time Frame: up to 2 years ]

  7. Objective response rate (ORR) [ Time Frame: up to 2 years ]

  8. Leukocyte phenotypes in peripheral blood mononuclear cell (PBMC) samples [ Time Frame: up to 2 years ]

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must be ≥ 18 years old.
  • Pathological criteria - Participants must have WHO grade II astrocytoma, oligoastrocytoma or oligodendroglioma that has been histologically confirmed by prior biopsy or surgical resection. If patients have already undergone biopsy and have pathological diagnosis in a non-UCSF institute, pathology must be reviewed and confirmed at University of California, San Francisco (UCSF).
  • Patients must be positive for HLA-A2 based on flow-cytometry or genotyping
  • Before enrollment, patients must show non-enhancing T2-FLAIR lesions that need to be surgically resected and are likely WHO grade II glioma.
  • Surgical resection of at least 0.5 grams of tumor
  • Both newly diagnosed (with available pathological diagnosis) and recurrent patients can be eligible. 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.
  • 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 14 days of study registration including: 1) Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.0 x 10^9/L, absolute lymphocytes ≥400/μL, 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.
  • 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) or gliomas. If a patient who received pre-surgical vaccines is diagnosed as high-grade glioma (HGG), 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. Pregnancy testing will be performed on all menstruating females within 14 days prior to study enrollment
  • 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).
  • Receiving ongoing treatment with immunosuppressive drugs, or dexamethasone > 4mg

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02924038

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Contact: Nicholas Butowski, MD 877-827-3222
Contact: Jane Rabbitt, BSN (415) 353-2652

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United States, California
University of California Recruiting
San Francisco, California, United States, 94143
Contact: Meghan Tedesco, BS   
Contact: Jane Rabbitt, BSN    (415) 353-2652   
Sponsors and Collaborators
Nicholas Butowski
Celldex Therapeutics
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Principal Investigator: Hideho Okada, MD, PhD University of California, San Francisco
Principal Investigator: Nicholas Butowski, MD University of California, San Francisco

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Responsible Party: Nicholas Butowski, MD, University of California, San Francisco Identifier: NCT02924038    
Other Study ID Numbers: 15108
NCI-2017-01369 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: October 5, 2016    Key Record Dates
Last Update Posted: January 31, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nicholas Butowski, University of California, San Francisco:
low-grade glioma
WHO grade II
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Poly I-C
Carboxymethylcellulose Sodium
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Interferon Inducers
Gastrointestinal Agents
Antiviral Agents
Anti-Infective Agents