Yeast-Brachyury Vaccine in Treating Patients with Locally Advanced Chordoma That Cannot Be Removed by Surgery

Status: Temporarily Closed to Accrual

Description

This randomized phase II trial studies how well vaccine therapy with brachyury-expressing yeast vaccine GI-6301 works in treating patients with chordoma, a type of bone cancer that usually starts in the lower spinal column or at the base of the skull, that has spread from where it started to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery. The vaccine is made with baker's yeast. The gene for brachyury is inserted into the yeast, and the yeast is grown so that it expresses brachyury protein. Brachyury is found on the surface of chordoma cells. The yeast is then killed with heat. Because the yeast is a foreign substance, the immune system should recognize it and try to identify it. By making the yeast also create the brachyury protein, it is hoped that the immune system will also identify the brachyury as a target and track down and kill cells with brachyury on their surfaces, which includes the chordoma cells. This vaccine therapy may be an effective treatment in patients with chordoma.

Eligibility Criteria

Inclusion Criteria

  • Patients should have histologically confirmed chordoma by the Laboratory of Pathology, National Cancer Institute (NCI), which is advanced and not considered resectable; if the original tissue cannot be retrieved, diagnostic documentation at an outside institution will be acceptable; 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 met
  • Patients must have disease that is measurable by RECIST version 1.1
  • Fresh or archived tumor specimen should be available for correlative studies as required
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study entry (Karnofsky >= 70)
  • Patients must have fully recovered from prior surgery before enrollment; prior radiation therapy is allowed provided the radiation field can safely be irradiated within the guidelines in the opinion of the treating radiation oncologist
  • Serum creatinine =< 1.5 X upper limit of normal OR creatinine clearance on a 24-hour (h) urine collection of >= 60 mL/min
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 X the upper limits of normal
  • Total bilirubin =< 1.5 X upper limit of normal OR in patients with Gilbert’s syndrome, a total bilirubin =< 3.0
  • Granulocyte count >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • 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 known 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 (note, patients may not be on tricyclic antidepressants at the time of yeast skin test)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients should have no evidence of immune dysfunction as listed below
  • Human immunodeficiency virus (HIV) positivity
  • Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment; 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
  • 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
  • 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 magnetic resonance imaging (MRI) and/or computed tomography (CT) in the case of subjects with known contrast dye allergies

Locations & Contacts

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Temporarily closed to accrual
Contact: Deric M Park
Phone: 240-760-6024
Email: deric.park@nih.gov

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine if there is a difference in overall response rate (ORR) defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST )1.1 in the irradiated tumor site after up to 24 months among patients with chordoma who are treated with radiation plus vaccine versus (vs.) radiation plus placebo.

SECONDARY OBJECTIVES:

I. To evaluate improvement in progression-free survival (PFS) in the combination arm as compared with the standard radiotherapy arm.

II. To evaluate improvement in overall survival in the combination arm as compared with the standard radiotherapy arm.

III. To longitudinally evaluate patient reported outcome measures using self-reported symptom severity and interference with daily activities using the MD Anderson Symptom Inventory (MDASI) instrument.

TERTIARY OBJECTIVES:

I. To identify clinically meaningful endpoints that might be used for a definitive trial to demonstrate clinical benefit in this rare disease, including: overall response rate by other criteria (Choi, immune-related [ir]RECIST, volumetric growth rate kinetics), PFS by other criteria (Choi, irRECIST, volumetric, growth rate kinetics).

II. To evaluate brachyury-specific T cell response pre-, during, and post-treatment.

III. To evaluate other parameters of general immune activation detailed in the protocol.

IV. To evaluate the quantity and quality of tumor infiltrating lymphocytes and other markers of local immune response and inflammation pre- and post-treatment in both groups.

V. To objectively evaluate daily physical activity using actigraphy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive brachyury-expressing yeast vaccine GI-6301 subcutaneously (SC) once every 2 weeks for 3 doses, and then undergo definitive radiotherapy per standard of care on days 43-100. Within 14-28 days following radiotherapy or upon resolution of complications, patients resume vaccine treatment every 2 weeks for 6 weeks, once monthly for 4 months, every 3 months for 2 years, and then every 6-12 months based upon vaccine supply and patient preference.

ARM II: Patients receive placebo SC once every 2 weeks for 3 doses, and then undergo definitive radiotherapy per standard of care on days 43-100. Within 14-28 days following radiotherapy, patients resume placebo vaccine treatment every 2 weeks for 6 weeks, once monthly for 4 months, every 3 months for 2 years, and then every 6-12 months based upon vaccine supply and patient preference. Patients may cross-over to Arm I. Patients for whom radiation therapy is not an option may proceed directly to vaccine doses.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Deric M Park

Trial IDs

Primary ID 15-C-0118
Secondary IDs NCI-2015-02206, 1407-1336, GI-6301-02, RD-15-III-13, P142114
Clinicaltrials.gov ID NCT02383498