BN Brachyury and Radiation in Chordoma

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to determine if the combination of BN-Brachyury plus radiation therapy can induce objective radiographic response rate (ORR) in patients, using a Simon 2-stage optimal design. In stage 1, a minimum of threshold of activity is needed to proceed to stage 2.

Official Title
-----------------
A Phase 2 Trial of BN-Brachyury and Radiation Therapy in Patients With Advanced Chordoma

Conditions
-----------------
Chordoma

Intervention / Treatment
-----------------
* Biological: BN-Brachyury plus radiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically confirmed chordoma Patients must have measurable disease by RECIST 1.1 Patients must be scheduled to have radiation therapy to at least 1 target lesion. Age ≥12 years Patients must have normal organ and marrow function Must have recovered completely from any reversible toxicity associated with recent therapy. There should be a minimum of 2 weeks from any chemotherapy, small molecule/targeted therapy, immunotherapy and/or radiation prior to enrolment Females of childbearing potential and male partners of Females of childbearing potential must agree to use effective birth control or abstinence from screening to after the last vaccination therapy Exclusion Criteria: Concurrent treatment for cancer, with specific exceptions noted in the inclusion criteria Chronic hepatitis B or C infection. Any significant disease, that in the opinion of the investigator may impair the patient's tolerance of trial treatment. Significant dementia, altered mental status, or any psychiatric condition that would prohibit the understanding, or rendering of informed consent. 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. Concurrent use of systemic steroids, except for physiological doses of systemic steroid replacement or local steroid use. Patients who are receiving any other investigational agents within 28 days before start of trial treatment. History of allergic reactions attributed to compounds of similar chemical or biological composition to MVA-BN/FPV-Brachyury or other agents used in trial. History of allergic reactions to aminoglycoside antibiotic or egg products. Serious or uncontrolled intercurrent illness, included but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with trial requirements. Pregnant women are excluded from this trial due to the unknown effects of the BN-Brachyury on the fetus or infant. HIV-positive patients are ineligible because of the potential for decreased immune response to the vaccine. Significant cardiovascular disease, which includes but is not limited to New York Heart Association Heart Failure Class II or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BN-Brachyury plus radiation<br>BN-Brachyury as both MVA and FPV are given before radiation, and followed by FPV-Brachyury | Biological: BN-Brachyury plus radiation<br>* MVA-BN-Brachyury injections will be given on day 0 and 14. FPV-Brachyury injection will be given on day 28, followed by radiation on days 42 through approximately day 70. FPV-Brachyury will then be given two weeks after radiation then every 6-12 weeks through 110 weeks after radiation is complete.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Rate of subjects achieving a best response of either Complete Response or Partial Response per modified RECIST v1.1. A modified RECIST v1.1 assessment is based on targeted radiated lesion(s). Progression of a non-target lesion does not result in disease progression by the modified RECIST evaluation for this trial. Assessment for targeted radiated lesion(s): Complete Response (CR)=Disappearance of all target radiated lesions; Partial Response (PR)= >=30% decrease in the sum of the longest diameter of target radiated lesions; Progressive Disease (PD) = >=20% increase in the sum of the longest diameter of target radiated lesions, Stable Disease (SD)=-30%<sum of the longest diameter of target radiated lesions<20%. | Within 12 months post-completion of radiation on target lesion(s) based on modified RECIST v1.1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Kaplan-Meier of the time interval from first treatment to objective tumor progression based on modified RECIST v1.1 or death. A modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) based on targeted radiated lesion(s) will be used. Progression will be defined as a 20% increase in the sum of the longest diameter of target radiated lesions in this trial, and a progression of a non-target lesion does not result in disease progression by the modified RECIST evaluation used for this trial. | Time from the day of first treatment to the start of disease progression or death, whichever occurs first up to 30 days after last tumor assessment visit. Data were collected up to 29 months. | 
| Baseline and Overall Treatment Period Change From Baseline Brief Pain Improvement-Short Form Best Observed Scores | Pain intensity and pain interference scores are summarized. Pain intensity scores includes pain items Worst Pain in the Last Week, Least Pain in the Last Week, and Average Pain in the Last Week and Pain Right Now. Composite pain severity score (a mean severity score of the four pain items listed before). Composite pain interference score (a mean of the seven interference items). This will be calculated if at least four of the seven interference items have been completed on a given administration. Pain scores range from 0 to 10 with a score of 10 is the worst pain imaginable and a score of 0 is no pain. Best observed scores is the lowest score value observed. | Overall Treatment Period: The time from the day of first treatment to the last scheduled trial visit, approximately 30 days after the last treatment visit. Data were collected up to 29 months. | 
| Baseline and Overall Treatment Period Change From Baseline Brief Pain Improvement-Short Form Worst Observed Scores | Pain intensity and pain interference scores are summarized. Pain intensity scores includes pain items Worst Pain in the Last Week, Least Pain in the Last Week, and Average Pain in the Last Week and Pain Right Now. Composite pain severity score (a mean severity score of the four pain items listed before). Composite pain interference score (a mean of the seven interference items). This will be calculated if at least four of the seven interference items have been completed on a given administration. Pain scores range from 0 to 10 with a score of 10 is the worst pain imaginable and a score of 0 is no pain. Worst observed scores is the highest score value observed. | Overall Treatment Period: The time from the day of first treatment to the last scheduled trial visit, approximately 30 days after the last treatment visit. Data were collected up to 29 months. |