QUILT-3.011 Phase 2 Yeast-Brachyury Vaccine Chordoma

A Randomized, Double-Blind, Phase 2 Trial of GI-6301 (Yeast-Brachyury Vaccine) Versus Placebo in Combination With Standard of Care Definitive Radiotherapy in Locally Advanced, Unresectable, Chordoma

TRIAL SUMMARY Researchers at the National Cancer Institute (NCI) are now enrolling patients in a phase 2 clinical trial to determine whether the yeast-brachyury vaccine GI-6301 improves the effectiveness of radiation for patients with localized chordoma. Chordoma patients with inoperable or residual tumor who do not have metastases and are planning to be treated with definitive (>70Gy) radiation are eligible to participate. Patients will initially be randomized to receive radiation plus the vaccine or radiation plus a blinded placebo. Those randomized to receive radiation plus placebo will have the option to receive vaccine if their tumor grows while on the study. The study will compare the outcomes of patients treated with radiation with and without the vaccine to determine whether the vaccine can increase the chances of shrinking the tumor and/or preventing further tumor growth. WHY THIS TRIAL IS BEING DONE The primary treatment options for chordoma currently consist of surgery and high dose radiation. Radiation has been shown to improve patient outcomes following surgery. Radiation is also sometimes used instead of surgery when surgery would carry unacceptable risks. The chance of tumor growth after radiation is significantly higher for patients who have residual tumor than for those whose tumor is completely removed. Unfortunately for patients with a tumor that cannot be completely removed, there tends to be a short time until the tumor grows back and eventually causes death. For this reason, our team at the NCI seeks to identify a therapy that can reduce the risk of recurrence and improve survival after radiation for patients who have residual tumor. One approach we are pursuing is treating patients with a therapeutic vaccine that is intended to stimulate the immune system to fight cancer cells that express the brachyury protein. Brachyury is present at very high levels in nearly all chordomas but is not present in the vast majority of normal tissues, making it a promising target for immune therapy. Research in other cancers suggests that radiation in combination with immune therapy can provide powerful antitumor effects. We have recently completed a phase 1 clinical trial of a therapeutic vaccine targeting brachyury called GI-6301 in which 11 chordoma patients participated. Through that phase I trial, we learned that this vaccine can be given safely without serious adverse reactions. In that study, the vaccine was also capable of inducing immune responses against brachyury and one patient had his tumor shrink more than 30% while on study. Some other patients (7 of 10 evaluable) also had stable disease for more than 5 months while on study. However, these clinical findings are not definitive and further clinical testing is required to determine the benefit of this vaccine in chordoma. To that end, we have designed a larger phase 2 clinical trial intended to determine if this vaccine, when given in combination with radiation, improves outcomes for patients with chordoma compared to those who only have radiation. WHO CAN PARTICIPATE We have designed this trial for patients who have residual tumor remaining after surgery, who are unable to have surgery, or who have a local recurrence following previous treatment. To be eligible for enrollment on this study, patients must: Have a confirmed diagnosis of chordoma Have only localized tumor (no metastases) Be able to receive at least 70 Gy of radiation to their localized tumor Be willing to travel to Bethesda, MD for treatment and follow-up visits HOW THE TRIAL WILL WORK The trial is taking place at the National Institutes of Health Clinical Center in Bethesda, MD. The NCI will pay for transportation costs (including airfare) and a portion of lodging costs for patients after enrollment in this study. The process of participating in the trial is as follows: Patients travel to NIH to receive injections of the vaccine (or placebo) every other week for three doses prior to starting radiation (approximately 4 weeks) Patients then complete their radiation treatment with their home radiation oncologist (typically over a 1-2 month timespan) Following completion of radiation treatment plan, patients travel back to NIH to resume vaccine (or placebo) injections every 2 weeks until 6 total doses have been given (3 doses after radiation, another 4 weeks) At that point, doses spread out to every 4 weeks for 4 doses, and then 1 dose every 3 months until disease progression. Between all doses of vaccine, patients may return home and travel back for the next visit. There is no requirement to stay locally in Bethesda at any point in the study outside of clinic visits and dosing days. Repeat imaging studies will be performed about 3 months after completion of radiatio...

BACKGROUND: Chordoma is a rare disease, affecting about 3,000 people in the United States, with about 300 new cases diagnosed per year. Brachyury is a member of the T-box family of transcription factors, characterized by a highly conserved DNA-binding domain designated as T-domain. Brachyury is expressed universally in chordoma cells. GI-6301 (Yeast-brachyury vaccine) has demonstrated immunogenicity with a tolerable and acceptable safety profile in a phase 1 trial. Brachyury specific T cells can lyse human cancer cells expressing brachyury in an MHC restricted manner. There have been indications of clinical benefit in patients with chordoma enrolled on the phase I trial of GI-6301. A) 1 Partial Response B) 1 Mixed Response in Chordoma patients who received Radiation C) 6 of 9 patients with progressive disease at enrollment had Stable Disease at Day 85 restaging -In vitro, chordoma cell lines are killed significantly better by brachyury-specific T cells after radiation exposure using either proton beam or gamma radiation. ENDPOINTS: PRIMARY OBJECTIVES: -To determine if there is a difference in overall response rate (ORR) defined as complete response (CR) or partial response (PR) by RECIST 1.1 after up to 24 months among patients with Chordoma who are treated with radiation plus placebo vs. radiation plus vaccine. ELIGIBILITY: Patients at least 18 years old with locally advanced (unresectable, non-metastatic) chordoma who are eligible for definitive radiotherapy treatment. No history of autoimmune disease Measurable disease as defined by RECIST 1.1 Adequate organ function DESIGN: Randomized, double-blind, placebo controlled phase 2 clinical trial of radiation plus placebo vs. radiation plus yeast-brachyury vaccine in patients with chordoma. Participants will be randomized on a 1:1 basis to the two arms Participants assigned to the placebo arm will be allowed to cross-over at time of confirmed disease progression. Participants will be evaluated for objective response, progression free survival and overall survival Up to 55 participants will be accrued to the study

Overall Response Rate, Immune Activation, Tumor Infiltrating Lymphocytes, T Cell Response, Cross-Over

GI-6301 Placebo will consist of USP-grade or equivalent 0.9% Sodium Chloride for Injection. Doses of GI-6301 placebo will be drawn into labeled syringes by an independent, unblinded pharmacist or designee.

GI-6301 Vaccine is a heat-killed, recombinant yeast-based vaccine engineered to express the transcription factor, Brachyury. The Brachyury gene is used to transfect the parental yeast strain (S. cerevisiae W303 - a haploid strain with known mutations from wildtype yeast) to produce the final recombinant vaccine product.

wGT3X-BT is small, non-invasive, portable watch accelerometer worn on the subject's wrist for Cycle 1 through Cycle 9

Difference in overall response rate among patients with Chordoma who are treated with radiation plus placebo vs. radiation plus vaccine.

INCLUSION CRITERIA: Participants must meet the following criteria for participation: Diagnosis: Patients must have histologically confirmed chordoma by the Laboratory of Pathology, NCI, which is localized (no evidence of metastatic disease), unresectable and they must have planned radiation therapy, to at least one targeted lesion with evidence of growth prior to enrollment. The tentative radiation plan at enrollment must be in compliance with the required radiation doses. This can be given in standard or hypofractionated dosing with any technique deemed most appropriate by the treating radiation oncologist if other requirements are not met. Patients must have disease that is measurable by RECIST version 1.1. Fresh or archived tumor specimen must be available for correlative studies. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study entry (Karnofsky greater than or equal to 70) Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of GI-6301 (Yeast Brachyury vaccine) in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Prior Therapy: Patients must have fully recovered from prior surgery before enrollment. Prior radiation therapy is allowed provided the radiation field can safely irridated in the opinion of the treating radiation oncologist. Patients must have normal organ and marrow function as defined below: Serum creatinine less than or equal to 1.5 X upper limit of normal OR creatinine clearance on a 24-h urine collection of greater than or equal to 60 mL/min. ALT and AST less than or equal to 3 X the upper limits of normal. Total bilirubin less than or equal to 1.5 X upper limit of normal OR in patients with Gilbert s syndrome, a total bilirubin less than or equal to 3.0. Hematological eligibility parameters (within16 days of starting therapy): Granulocyte count greater than or equal to 1,500/mm3 Platelet count greater than or equal to 100,000/mm3 Men and women of child-bearing potential must agree to use effective birth control or abstinence during and for a period of 4 months after the last vaccination therapy. Patients must not have a history of yeast allergy. If patient has a questionable history of allergy to yeast, a yeast skin test can be performed. Patients would be eligible if skin test is negative. Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Patients with any of the following will not be eligible for participation in this study: 1. Patients should have no evidence of immune dysfunction as listed below. Human immunodeficiency virus (HIV) positivity due to the potential for decreased immune response to the vaccine. Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment. This requirement is due to the potential risks of exacerbating autoimmunity. However, patients with vitiligo, diabetes mellitus, and Hashimoto thyroiditis on appropriate replacement therapy may be enrolled. History of allergy or untoward reaction to yeast-based products (any hypersensitivity to yeast-based products will be excluded). Pregnant or breast-feeding women, due to the unknown effects of the Yeast-brachyury vaccine on the fetus or infant. Serious intercurrent medical illness which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis. Chronic hepatitis infection, including B and C, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy. Any significant disease that, in the opinion of the investigator, may impair the patient s tolerance of study treatment. Significant dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. Patients may not be on systemic steroids within 4 weeks of enrolling on study with the exception of physiologic replacement doses (for instance in the case of adrenal insufficiency) or steroid premedication for baseline MRI and/or CT in the case of subjects with known contrast dye allergies.

Wedekind MF, Widemann BC, Cote G. Chordoma: Current status, problems, and future directions. Curr Probl Cancer. 2021 Aug;45(4):100771. doi: 10.1016/j.currproblcancer.2021.100771. Epub 2021 Jul 1.