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Molgramostim

Sargramostim

Monatide (IMS 3015)

500 mcg (1 mL) SurVaxM emulsion with Montanide ISA 51. Sargramostim dose is 3.33 mcg/kg/dose for patients \< 30 kg, and 100 mcg for patients ≥ 30 kg.

Priming Phase: patients will get one dose of SurVaxM combined with Montanide ISA 51 through a subcutaneous injection at the start of the study and every 2 weeks for 6 weeks (for a total of 4 doses). At each SurVaxM/Montanide ISA 51 injection, patients will also get an injection of sargramostim.

Maintenance Phase: the patient will get a SurVaxM/Montanide ISA 51 dose along with a sargramostim dose about every 8 weeks for up to two years.

After finishing study treatment, patients will be followed for up to 3 years following the last dose of SurVaxM/Montanide ISA 51. Patients will be followed in clinic every 3 months during the follow-up.

500 mcg (1 mL) SurVaxM emulsion with Montanide ISA 51. Sargramostim dose is 3.33 mcg/kg/dose for patients \< 30 kg, and 100 mcg for patients ≥ 30 kg.

SurVaxM for patients with relapsed or progressive MB, HGG or ependymoma ages ≥10 and ≤21 years

SurVaxM for patients with relapsed or progressive MB, HGG or ependymoma ages ≥1 and <10 years

SurVaxM for patients with non-relapsed DIPG post radiation-therapy ages ≥1 and ≤21 years

Anneliese Rosdil, MSN

Nina Butingan, MBS

Nathan Robison, MD

Sonia Partap, MD, MS

Cynthia Campen, MD

Eugene Hwang, MD

Elias Sayour, MD

Jennifer King, RN

Jason Fangusaro, MD

Alicia Lenzen, MD

Clare Twist

Ira Dunkel, MD

Natasha Pillay Smiley, DO

James Felker, MD

Patricia Baxter, MD

Vijay Ramaswamy, MD

Aiman Siddiqi

Clare Twist, MD

Patients will receive a vaccine called SurVaxM on this study. While vaccines are usually thought of as ways to prevent diseases, vaccines can also be used to treat cancer. SurVaxM is designed to tell the body's immune system to look for tumor cells that express a protein called survivin and destroy them. The survivin protein can be found on up to 95% of glioblastomas and other types of cancer but is not found in normal cells. If the body's immune system knows to destroy cells that express survivin, it may help to control tumor growth and recurrence.

SurVaxM will be mixed with Montanide ISA 51 before it is given. Montanide ISA 51 is an ingredient that helps create a stronger immune response in people, which helps the vaccine work better.

This study has two phases: Priming and Maintenance. During the Priming Phase, patients will get one dose of SurVaxM combined with Montanide ISA 51 through a subcutaneous injection (a shot under the skin) at the start of the study and every 2 weeks for 6 weeks (for a total of 4 doses). At the same time that patients get the SurVaxM/Montanide ISA 51 injection, they will also get a second subcutaneous injection of a medicine called sargramostim. Sargramostim is given close to the SurVaxM//Montanide ISA 51 injection and works to stimulate the immune system to help the SurVaxM/Montanide ISA 51 work more effectively.

If a patient completes the Priming Phase without severe side effects and his or her disease stays the same or improves, he or she can continue to the Maintenance Phase. During the Maintenance Phase, the patient will get a SurVaxM/Montanide ISA 51 dose along with a sargramostim dose about every 8 weeks for up to two years.

After a patient finishes the study treatment, the doctor and study team will continue to follow his/her condition and watch for side effects up to 3 years following the last dose of SurVaxM/Montanide ISA 51. Patients will be seen in clinic every 3 months during the follow-up period.

This is a multicenter pilot study of SurVaxM (SVN53-67/M57-KLH) for children and young adults with progressive or relapsed medulloblastoma, high grade glioma, ependymoma and newly diagnosed diffuse intrinsic pontine glioma.

Survivin (BIRC5) is an inhibitor of apoptosis (IAP) protein that is highly expressed in many cancers. Survivin's high level of expression in certain pediatric malignancies makes it an attractive molecular target for new therapies, including active specific vaccination-based immunotherapy.

The design of the SurVaxM vaccine employs several strategies to create an effective antitumor immunogen, including: 1) incorporation of multiple MHC class I epitopes, 2) peptide modification to enhance binding to certain MHC class I molecules, 3) cytokine helper support, and 4) antibody-mediated tumor cell killing. All of these effects would not be expected with the unmodified class-I restricted short survivin peptides employed in previously studied glioma vaccines.

There are no prior clinical trials of SurVaxM in pediatric patients; however, SurVaxM has been studied in several adult trials, including a phase I study conducted at Roswell Park Comprehensive Cancer Center. Following the single-institution phase I trial, a multicenter phase IIa trial (NCT024455557) was conducted in 63 patients with newly diagnosed glioblastoma. All patients in this study underwent surgical resection of their tumors. Patients then underwent chemoradiation with temozolomide according to the Stupp protocol. This was followed by a one-month hiatus from chemotherapy, during which priming doses of SurVaxM were initiated. The priming phase of vaccination was then followed by initiation of standard adjuvant chemotherapy with temozolomide and maintenance doses of SurVaxM as an add-on to standard chemotherapy. There have been no regimen-limiting toxicities (RLT) or grade ≥ 3 SAE attributable to SurVaxM, with most toxicities being related to temozolomide. The most common AE was grade 1-2 injection site reaction with 2 patients experiencing Montanide-related granulomatous panniculitis with local skin ulceration at vaccine injection sites, both of which resolved. Humoral and survivin-specific CD8+ T cell responses were observed in almost all patients. Twelve-month overall survival (OS12) was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Although not a randomized trial, these results are superior to overall survival reported in various studies in which patients received standard of care treatment for this disease. A randomized phase IIb clinical trial of standard therapy plus SurVaxM is currently being developed with intent for drug registration, if successful.

The primary objective of this trial is to assess the toxicity profile of SurVaxM in emulsion with Montanide plus sargramostim in children with relapsed or progressive medulloblastoma and high-grade glioma, ependymoma and non-recurrent diffuse intrinsic pontine glioma post-radiation therapy. Patients will be enrolled into three separate strata based on age and diagnosis. Enrollment will be staged to allow for safety evaluations between strata.

Each patient will receive 500 micrograms SurVaxM as a 1:1 mixture with Montanide ISA 51 in a water-in-oil emulsion. The SurVaxM-Montanide emulsion injection will be followed immediately by sargramostim (or biosimilar) given via a second separate subcutaneous injection in close proximity to the vaccine injection site. Patients will receive four injections administered over a 6-week period, followed by 14 days of follow-up, called the Priming Phase (8 weeks total). Beginning 8 weeks after the fourth priming dose, a maintenance dose of SurVaxM with Montanide ISA 51 may be given every 8 weeks (± 2 weeks) for two years or until an off-treatment criterion is met.

All participants receive the same intervention/treatment in disease specific or age stratified fashion.

A Pilot Study of SurVaxM in Children Progressive or Relapsed Medulloblastoma, High Grade Glioma, Ependymoma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma

A Pilot Study of Safety, Tolerability, and Immunological Effects of SurVaxM in Pediatric Patients With Progressive or Relapsed Medulloblastoma, High Grade Glioma, Ependymoma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma

The Pediatric Brain Tumor Consortium (PBTC) ensures that high dimensional molecular data generated from PBTC samples will be submitted to the NIH Database of Genotypes and Phenotypes (dbGaP) or other NIH-designated data repository. PBTC is required to make data available to other investigators for use in research projects. An investigator requesting data from published PBTC studies will submit a proposal describing the studies from which data are requested, the requested data, and a list of investigators in the project and their affiliated institutions, along with the investigator's CV to the PBTC Steering Committee for review. Once approved, the requesting investigator will be asked to complete a Data Transfer Agreement before the release of deidentified data. Requests for data are typically only considered once the primary study manuscript has been published though exceptions may be made in the event of long delays in the primary study data publication.

Overall response assessment takes into account response (complete response, partial response, stable disease, progressive disease) in both target and non-target lesion, and the appearance of new lesions, where applicable, according to the criteria described in the protocol. Best radiographic response observed while on treatment will be reported for each patient and percentage of patients that fall in each response category will be reported.

Interval of time between date of initiation of protocol treatment and minimum date of documentation of Progressive Disease

Time between date of initiation of protocol treatment and minimum date of death due to any cause or date of last follow-up.

The RLT rate during the first 8 weeks (14 days after the 4th priming dose of vaccine) will be used as the primary endpoint for safety monitoring and for determining when enrollment can begin in the next sub-cohort.

A separate RLT assessment window for risk of pseudoprogression will encompass the 6 weeks for administration of 4 priming doses + 8 weeks of follow-up after administration of the 4th priming dose. Pseudoprogression RLTs during this interval will be included in the primary safety monitoring rules and analysis.

Differences in estimated rCBV and ktrans values between patients with pseudoprogression vs. true progression will be reported.

Roswell Park Cancer Institute

National Cancer Institute (NCI)

American Lebanese Syrian Associated Charities (ALSAC)

Pediatric Brain Tumor Consortium

Spots Global Cancer Trial Database for survaxm for patients with relapsed or progressive mb, hgg or ependymoma ages ≥10 and ≤21 years