Details

Details

Title A Phase 1/2 Study of SL-701, a Subcutaneously Injected Multivalent Glioma-Associated Antigen Vaccine, in Adult Patients with Recurrent Glioblastoma Multiforme

IRB STML1314

CC 14-698

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Brain, Glioblastoma

Drug SL-701

Description

Description

Primary Objectives
  1. Characterize the safety and tolerability of SL-701 and SL-701 in combination with bevacizumab.
  2. Estimate the percent of patients alive 12 months after the initiation of SL-701 (OS-12).
  3. Estimate the ORR.
Secondary Objectives
  1. Estimate the duration of response (DR).
  2. Estimate the percent of patients alive and PFS-6 after the initiation of SL-701.
  3. Estimate the distributions of PFS and OS.
Exploratory Objectives
  1. Estimate the relationships between measures of immunogenicity and anti-tumor efficacy.
  2. Evaluate available post-vaccine tumor tissue for GAA expression status and infiltration of GAA-specific T-cells.
Inclusion Criteria

Inclusion Criteria

  1. 18 years of age or older.
  2. Histologically confirmed GBM or WHO Grade IV variants (gliosarcoma, glioblastoma with oligodendroglial features, or giant cell glioblastoma).
  3. Unequivocal evidence of a first tumor recurrence or progression on the initial treatment regimen (prior to enrollment on this study), consisting of surgical intervention (biopsy and/or resection), radiation, and TMZ chemotherapy, as assessed by MRI or CT scan of the brain with and without contrast within 14 days prior to the start of SL-701. If receiving corticosteroids, the dose must be stable or decreasing for at least 5 days prior to the scan. Patients unable to undergo MRI because of non-compatible devices can be enrolled, provided CT scans are obtained and are of sufficient quality. Patients without non-compatible devices may not have CT scans performed to meet this requirement. For each patient, the same imaging technique should be performed throughout the study for purposes of assessing tumor response or PD.
  4. For patients who have undergone resection of recurrent or progressive tumor prior to study enrollment, the following conditions must apply:
    • Recovery from the effects of surgery.
    • Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, an MRI should be performed:
      • No later than 96 h in the immediate post-operative period; or
      • At least 4 weeks post-craniotomy (7 days for stereotactic biopsy), within 14 days prior to the start of SL-701, and on a corticosteroid dosage that has been stable or decreasing for at least 5 days.
  5. Patients who have not had resection of recurrent or PD must have measurable disease.
  6. At least 56 of the approximately 76 patients treated must have measurable disease, defined as at least one, contrast-enhancing lesion measuring at least 1 cm in 2 planes (axial, coronal, or sagittal).
  7. No evidence of hemorrhage on the baseline MRI or CT scan other than those that are Grade ≤ 1 and either post-operative or stable on at least 2 consecutive scans.
  8. Recovery from prior therapy toxicity, defined as resolution of all treatment related AEs to Grade ≤ 1 or pre-treatment baseline (except alopecia and lymphopenia).
  9. At least 12 weeks from prior radiotherapy to the start of SL-701 unless there is new enhancement outside of the radiation field or unequivocal histopathologic evidence of recurrent tumor subsequent to radiotherapy.
  10. No chemotherapy or investigational agent for at least 3 weeks prior to the start of SL-701.
  11. HLA-A2 positive.
  12. A tumor tissue sample is provided for immunohistochemical analysis of relevant antigens, immune markers and potential prognostic factors. Preferably a paraffin block or 10-12 unstained slides will be submitted prior to study entry. Patients for whom tumor samples are unavailable or inadequate are permitted to participate in the study, however the absence of available/adequate tumor specimen must be documented..
  13. KPS score ≥ 70%.
  14. Adequate organ function, including the following:
    • ANC ≥ 1,000/μL, platelets ≥ 100,000/μL.
    • Serum creatinine < 1.5 x the ULN.
    • Bilirubin < 1.5 x ULN.
    • ALT and AST < 2.5 x ULN.
  15. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to the start of SL-701 treatment.
  16. Female patients of childbearing potential and sexually active male patients must agree to use an acceptable form of contraception for heterosexual activity (ie, oral contraceptives, double-barrier methods, hormonal injectable, transdermal, or implanted contraceptives, tubal ligation, or vasectomy of their sexual partner(s) for > 40 days before Screening, during the study, and for 60 days after the last dose of study drug. Men should not donate semen during the study and for 60 days after the last dose of study drug.
  17. Female patients without childbearing potential (spontaneous amenorrhea for > 12 months or surgically sterilized by tubal ligation, hysterectomy, or bilateral oophorectomy > 6 months before Screening) are eligible for inclusion without contraceptive use restriction.
  18. Able and willing to comply with protocol requirements, in the opinion of the Investigator.
  19. A written and voluntarily signed informed consent must be obtained from the patient or legally authorized representative, in accordance with local regulations, before the initiation of any study-related procedures. The patient or legally authorized representative must be able to read and understand the ICF.
Exclusion Criteria

Exclusion Criteria

  1. Prior cancer chemotherapy, bevacizumab (or other VEGF/VEGFR-directed agent), or an investigational agent for recurrent/progressive GBM or prior bevacizumab as part of initial therapy (prior chemotherapy or investigational agents are permitted as part of initial therapy; VEGF/VEGFR-directed agents are not permitted).
  2. A contrast-enhancing brain tumor that is any of the following:
    • Multi-focal (defined as 2 separate areas of contrast enhancement measuring at least 1 cm in 2 planes that are not contiguous on either fluid-attenuated inversion recovery [FLAIR] or T2 sequences;
    • Associated with either diffuse subependymal or leptomeningeal dissemination; or
    • ≥ 4 cm in any dimension.
  3. Requirement of systemic corticosteroid therapy > 4 mg/day of dexamethasone or equivalent or requirement of increasing dose of systemic corticosteroids during the 7 days prior to the start of SL-701 treatment.
  4. Surgical resection or major surgical procedure within 4 weeks prior to the start of SL-701, or stereotactic biopsy within 7 days prior to the start of SL-701.
  5. Radiation therapy, local therapy (except for surgical re-resection), or systemic therapy following first recurrence or PD. Excluded local therapies following first recurrence/PD include stereotactic radiation boost, implantation of carmustine, biodegradable wafers (Gliadel), intratumoral or convection-enhanced delivery administered agents, etc.
  6. Active infection requiring IV antibiotics.
  7. History of cancer (other than GBM) within the past 2 years that has substantial metastatic or local recurrence potential and could negatively impact survival and/or potentially confound tumor response assessments within this study.
  8. Clinically significant cardiovascular disease (eg, uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
  9. Known immunosuppressive disease or active systemic autoimmune disease such as systemic lupus erythematosus, human immunodeficiency virus infection, active or chronic Hepatitis B, or Hepatitis C, or has taken an immunosuppressive agent within 4 weeks prior to the start of SL-701 treatment. Patients with vitiligo, type 1 diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement therapy, psoriasis not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  10. Any condition that in the Investigator's opinion makes the patient unsuitable for study participation.
  11. Requires therapeutic anticoagulation with warfarin at baseline; patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study drug; however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed.
  12. Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug.
  13. Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than those that are ≤Grade 1 and either post-operative or stable on at least 2 consecutive MRI scans.
  14. Has gastrointestinal bleeding or any other hemorrhage/bleeding event National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) >Grade 3 within 6 months of start of study drug.