QUILT-3.011 Phase 2 Yeast-Brachyury Vaccine Chordoma
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 100 |
| Updated: | 9/20/2018 |
| Start Date: | April 17, 2015 |
| End Date: | March 1, 2020 |
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...
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
- 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
- INCLUSION CRITERIA:
Participants must meet the following criteria for participation:
1. 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.
2. Patients must have disease that is measurable by RECIST version 1.1.
3. Fresh or archived tumor specimen must be available for correlative studies.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study entry
(Karnofsky greater than or equal to 70)
5. 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.
6. 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.
7. 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
8. 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.
9. 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.
10. 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.
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