Industry sponsor decision

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.

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 Isocitrate dehydrogenase 1 (IDH1) mutations and mutations in the tumor suppressor gene tumor protein 53 (TP53), located on chromosome 17, the gene product of which is a multi-functional 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 retinoblastoma tumor suppressor (RB) and Protein kinase B (AKT)-Mechanistic target of rapamycin (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.

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