Safety and Efficacy Study of SL-701, a Glioma-Associated Antigen Vaccine To Treat Recurrent Glioblastoma Multiforme

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

The purpose of this study is to determine the safety and efficacy of SL-701 as a treatment for recurrent glioblastoma multiform (GBM).

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Adult Brain Glioblastoma
• Intervention / Treatment: Drug: Bevacizumab; Drug: SL-701 + GM-CSF; Drug: Imiquimod; Drug: SL-701; poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose)

Detailed Description

This is a multicenter, open-label Phase 1/2 study evaluating the efficacy and safety of SL-701 as a treatment for recurrent GBM, divided into 2 stages. Seventy-four (74) participants were treated in the study, 46 in Stage 1 and 28 in Stage 2, men and women at least 18 years of age, all of whom showed unequivocal evidence of either a first tumor recurrence or progression during or following an initial treatment regimen before enrollment in this study. At least 54 of the 74 treated participants had measurable disease based on contrast-enhanced magnetic resonance imaging or computed tomography scans.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Tucson, Arizona, United States, 85718
      • Center for Neurosciences
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20052
      • George Washington University
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60208
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New York
    • New York, New York, United States, 10027
      • Columbia University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Charles A Sammons Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years of age or older.
• Histologically confirmed GBM or World Health Organization (WHO) Grade IV variants (gliosarcoma, glioblastoma with oligodendroglial features, or giant cell glioblastoma).
• 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 temozolomide chemotherapy, as assessed by MRI or CT scan of the brain with or 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. Participants unable to undergo MRI because of non-compatible devices can be enrolled, provided CT scans are obtained and are of sufficient quality. For each participant, the same imaging technique should be performed throughout the study, for purposes of assessing tumor response or PD.

• For participants 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 hours (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.
• Participants who have not had resection of recurrent or progressive disease must have measurable disease.
• At least 56 of the approximately 76 participants 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).
• 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 two consecutive scans.
• Recovery from prior therapy toxicity, defined as resolution of all treatment-related adverse events (AEs) to Grade ≤ 1 or pre-treatment baseline (except alopecia and lymphopenia).
• 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.
• No chemotherapy or investigational agent for at least 3 weeks prior to the start of SL-701.
• Human leukocyte antigen (HLA)-A2 positive.
• 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. Participants 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.
• Karnofsky performance status (KPS) score ≥ 70%.

• Adequate organ function, including the following:

  • Absolute neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 100,000/μL.
  • Serum creatinine < 1.5 × the upper limit of normal (ULN).
  • Bilirubin < 1.5 × ULN.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN.
• Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to the start of SL-701 treatment.
• Female participants of childbearing potential and sexually active male participants must agree to use an acceptable form of contraception for heterosexual activity (that is, 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.
• Female participants 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.
• Able and willing to comply with protocol requirements, in the opinion of the investigator.
• A written and voluntarily signed informed consent must be obtained from the participant or legally authorized representative, in accordance with local regulations, before the initiation of any study related procedures. The participant or legally authorized representative must be able to read and understand the informed consent form (ICF).

Exclusion Criteria:

• Prior cancer chemotherapy, bevacizumab (or other vascular endothelial growth factor [VEGF]/VEGF receptor [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).

• Contrast-enhancing tumor that is any of the following:

  • Multi-focal (defined as two 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.
• 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.
• 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.
• Radiation therapy, local therapy (except for surgical re-resection), or systemic therapy following first recurrence/progressive disease. Excluded local therapies include stereotactic radiation boost, implantation of carmustine biodegradable wafers (Gliadel), intratumoral or convection-enhanced delivery administered agents, etc.
• Active infection requiring intravenous antibiotics.
• History of cancer (other than GBM) within the past 2 years that has metastatic or local recurrence potential and could negatively impact survival and/or potentially confound tumor response assessments within this study.
• Clinically significant cardiovascular disease (for example, 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).
• Known immunosuppressive disease or active systemic autoimmune disease such as systemic lupus erythematosus, human immunodeficiency virus infection, Hepatitis B, or Hepatitis C, or has taken an immunosuppressive agent within 4 weeks prior to the start of SL-701 treatment. Participants 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.
• Any condition which in the investigator's opinion makes the participant unsuitable for study participation.
• Requires therapeutic anticoagulation with warfarin at baseline; participants 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.
• 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.
• 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
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SL-701 + GM-CSF + Imiquimod; Participants will receive SL-701 with the vaccine adjuvants granulocyte macrophage-colony stimulating factor (GM-CSF) injection and imiquimod topical cream. A complete dose of study drug consists of the administration of a sequence of 3 agents, SL-701 emulsion SC injection, GM-CSF SC injection, and imiquimod topical cream, within a 5-minute time frame. Topical application of imiquimod cream at the injection site is repeated at 24 hours after each SL-701 emulsion injection. For each participant, SL-701 emulsion (SL-701 in Montanide) will be administered by SC injection beginning on Day 1 with imiquimod topical cream 5% applied immediately (within 5 minutes of SL-701 emulsion injection) to the SL-701 emulsion injection site. In addition to the SL-701 emulsion injection, the participant will receive a SC injection of GM-CSF 150 μg close to the injection site of SL-701 emulsion. An additional dose of imiquimod cream will be applied at the same site by the participant 24 hours later.	Drug: SL-701 + GM-CSF; 1.0 mL injection taken from 0.7 mL of SL-701 mixed at a 1:1 (v/v) ratio with 0.7 mL of Montanide. Preferred site of SC injection is in the right or left upper arms. 150 μg GM-CSF should be administered as a SC injection immediately after SL-701 emulsion administration and within 1 cm from the center of the SL-701 emulsion injection site.; Drug: Imiquimod; Within 5 minutes following the administration of the SL-701 emulsion, approximately 125 mg of imiquimod cream will be applied topically on the injection site. The imiquimod cream should be rubbed in until the cream is no longer visible.
Experimental: SL-701; poly-ICLC 1.6 mg; bevacizumab; SL-701 emulsion and the adjuvant poly-ICLC will be administered twice weekly for the initial 2 weeks, every 7 days during the subsequent 3 doses, and subsequently every 14 days for the subsequent 9 doses (16 doses total) through Week 22, and every 4 weeks thereafter. Bevacizumab will be administered every 2 weeks, subsequent to the administration of SL-701/poly-ICLC.	Drug: Bevacizumab; Following the administration of SL-701 and poly-ICLC, bevacizumab will be administered IV at a dose of 10 mg/kg. Bevacizumab infusions may occur over 30, 60 or 90 minutes in accordance with institutional practices and guidelines.; Drug: SL-701; poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose); 1.0 mL injection taken from 0.7 mL of SL-701 mixed at a 1:1 (v/v) ratio with 0.7 mL of Montanide. Preferred site of SC injection is in the right or left upper arms. Within 20 minutes following the administration of the SL-701 emulsion, poly-ICLC should be administered as an IM injection in the same extremity (within 3 cm whenever possible) as was administered the SL-701 (deltoid muscle, unless contraindicated).; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Regimen-limiting Toxicity (RLT)	RLT included any events that occurred anytime through the first 12 doses of study treatment that were considered possibly, probably, or definitely related to investigational therapy and ranged from Grade ≥3 bronchospasm or Grade 2 bronchospasm that did not resolve within 24 hours despite appropriate medical treatment to cerebral edema associated with severe clinical manifestations (Grade 4) that were considered related to study therapy by the investigator.	Approximately 24 weeks
Number of Participants Experiencing Sudden or Unexpected Death Related to SL-701 or SL-701 in Combination With Bevacizumab	A safety review occurred following each sudden or unexpected death that was not considered by the investigator to be a disease-related mortality and was considered to be related to SL-701.	Day 1 through Month 12
Overall Survival at 12 Months (OS-12)	OS-12 was defined as the number of participants surviving at 12 months after the first injection of SL-701 and was calculated using the Clopper-Pearson Method.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR was the percentage of participants who had at least 1 overall tumor response of complete response (CR) or partial response (PR) documented on 2 consecutive magnetic resonance images (MRIs) ≥4 weeks apart by modified response assessment in neuro-oncology (RANO) criteria.	3 years
Disease Control Rate (DCR)	DCR was the percentage of participants whose best response was either CR, PR, or stable disease (SD) documented on 2 consecutive MRIs ≥4 weeks apart by modified RANO criteria.	3 years
Duration of Response (DoR)	DoR was defined as the time from the date measurement criteria were first met for objective response (either CR or PR) until the first date that the criteria for progressive disease (PD) was met, or death due to any cause, whichever occurred first, by modified RANO. If a participant did not progress or die after a response of CR or PR, then the participant's DoR was censored at the date of the participant's last tumor assessment. Only participants who attained a confirmed response of either CR or PR were included in the estimation of DoR (calculated using the Kaplan-Meier method).	3 years
Duration of Disease Control (DDC)	DDC was defined as the time from the date measurement criteria were first met for objective response (either CR, PR, or SD) until the first date that the criteria for PD were met, or death due to any cause, whichever occurs first, by modified RANO. If a participant did not progress or die after a response of CR, PR or SD, then the participant's DDC was censored at the date of the participant's last tumor assessment. Only participants who attained a confirmed response of either CR, PR or SD were included in the estimation of DDC.	3 years
Progression-free Survival at 6 Months (PFS-6)	PFS-6 was defined as the time from the date of the first injection of SL-701 to the date of disease progression or death from any cause, whichever occurred first, by modified RANO. Participants who had not progressed or died at the time of the analysis were censored at the date of their latest tumor assessment or survival assessment.	Up to 6 months
Progression-free Survival at 12 Months (PFS-12)	PFS-12 was defined as the time from the date of the first injection of SL-701 to the date of disease progression or death from any cause, whichever occurred first, by modified RANO. Participants who had not progressed or died at the time of the analysis were censored at the date of their latest tumor assessment.	Up to 12 months
Progression-free Survival (PFS)	PFS was defined as the time from the date of the first injection of SL-701 to the date of disease progression or death from any cause, whichever occurred first, by modified RANO. Participants who had not progressed or died at the time of the analysis were censored at the date of their latest tumor assessment.	3 years
Overall Survival (OS)	OS was the time from the date of the first SL-701 injection to the date of death from any cause. If a participant did not die during the study, the participant's overall survival time was censored at the date at which the participant was last known to be alive.	3 years

Collaborators and Investigators

• Sponsor: Stemline Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): January 22, 2018

Study Registration Dates

• First Submitted: February 20, 2014
• First Submitted That Met QC Criteria: March 3, 2014
• First Posted (Estimated): March 5, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Vaccine; Immunotherapy; Recurrent Glioblastoma; Adult; Glioma Associated Antigen
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Antineoplastic Agents, Immunological; Toll-Like Receptor Agonists; Immunomodulating Agents; Anti-Infective Agents; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Antiviral Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Adjuvants, Immunologic; Interferon Inducers; Laxatives; Bevacizumab; Imiquimod; Poly I-C; Carboxymethylcellulose Sodium; Poly ICLC
• Other Study ID Numbers: STML-701-0114