Screening
Inclusion Criteria:
- - • DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNS
tumor that is progressive or recurrent defined as radiographic progression in any
known residual tumor, or the appearance of one or more new lesions, leptomeningeal
disease, or new cerebrospinal fluid (CSF) positivity for malignant cells, after most
recent treatment modality.
At the time of diagnosis or recurrence, all tumors must
have histologic verification of one of the following:
- - Glioblastoma multiforme (GBM)
- Anaplastic astrocytoma.
- - High-grade astrocytoma, NOS.
- - Anaplastic oligodendroglioma.
- - Anaplastic ependymoma (WHO Grade III)
- Ependymoma (WHO Grade II)
Diffuse Intrinsic Pontine Gliomas (DIPG) Patients:
Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as
tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are
eligible without histologic confirmation and will proceed directly to enrollment without
screening.
• TUMOR TISSUE- Patients must provide tumor tissue (3 unstained slides or paraffin block)
to determine their survivin expression status.
Demonstration of survivin expression of at least 1% on tumor tissue by
immunohistochemistry is required and must be performed in the central laboratory at
Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility.
- - Age: Patients must be ≥ 1 year of age and ≤ 21 years of age at the time of
screening.
- - Screening Consent: Participant is willing to sign a screening consent.
The screening
consent is to be obtained according to institutional guidelines. Assent, when
appropriate, will be obtained according to institutional guidelines.
- - Potential Eligibility for Study Enrollment: Patients screened for this trial should
be expected to meet the criteria for treatment.
Enrollment
Inclusion Criteria:
• DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNS tumor
that is progressive or recurrent defined as progression in any known residual tumor, or
the appearance of one or more new lesions, or new cerebrospinal fluid (CSF) positivity
for malignant cells, after having failed standard therapy. At the time of diagnosis or
recurrence, all tumors must have histologic verification of one of the following:
- - Glioblastoma multiforme (GBM)
- Anaplastic astrocytoma.
- - High-grade astrocytoma, NOS.
- - Anaplastic oligodendroglioma.
- - Anaplastic ependymoma (WHO Grade III)
- Ependymoma (WHO Grade II)
Patients with newly diagnosed DIPG: Patients with diffuse intrinsic pontine gliomas
(DIPGs) will be eligible 14 to 56 days post-completion of radiation therapy if they do
not have any evidence of progression.
- - Patients with a typical DIPG on MR imaging, defined as a tumor with a pontine
epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without
histologic confirmation.
o Note: Patients with typical DIPG who undergo a biopsy are eligible provided the
tumor is a diffuse glioma WHO Grade II-IV with OR without H3 K27M mutation.
- - Patients with pontine lesions that do not meet these MR imaging criteria will be
eligible if there is histologic confirmation of diffuse glioma WHO Grade II-IV with
H3 K27M mutation.
- - DEMONSTRATION OF SURVIVIN EXPRESSION: For patients with relapsed or progressive
medulloblastoma, HGG, or ependymoma, demonstration of survivin expression as
assessed after screening consent/assent of at least 1% on tumor tissue by
immunohistochemistry (ICH) is required and must have been performed in the central
laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm
eligibility.
For patients with DIPG, diagnostic biopsy for histologic confirmation
is not required, and tumor expression of survivin is therefore not required for
eligibility for these patients.
- - DISEASE STATUS: Patients must have evaluable disease within the central nervous
system to be eligible.
Evaluable disease includes either measurable OR
non-measurable disease, defined as follows:
Measurable disease: bi-dimensionally measurable disease; at least one lesion that can be
accurately measured in at least two dimensions (per protocol guidelines).
- - Non-measurable disease:
- A lesion that does not meet the criteria for measurable disease as defined
above; or.
- - diffuse leptomeningeal disease, or.
- - no tumor visible on imaging but presence of malignant cells on cytologic
examination of CSF.
- - AGE:
- Stratum 1 (progressive or recurrent) patients must be ≥10 years of age and ≤ 21
years of age at the time of study screening.
- - Stratum 2 (progressive or recurrent) patients must be ≥1 year of age and < 10
years of age at the time of study screening.
- - Stratum 3 (newly diagnosed DIPG) patients must be ≥1 year of age and ≤ 21 years
of age at the time of study enrollment.
- - Patients with recurrent or progressive disease must have received prior
chemotherapy, and/or radiotherapy.
- - Patients must have recovered from the acute treatment related toxicities
(defined as ≤ Grade 1 if not defined in eligibility criteria; excludes
alopecia) prior to entering this study.
- - Patients with newly diagnosed DIPG must have completed radiation therapy.
- - CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressive
anticancer therapy at least 21 days prior to enrollment or at least 42 days if
nitrosourea.
Patients must have received their last dose of non-myelosuppressive
chemotherapy at least 7 days prior to enrollment.
- - INVESTIGATIONAL/ BIOLOGIC AGENT:
- Biologic or investigational agent (anti-neoplastic): Patient must have
recovered from any acute toxicity potentially related to the agent and received
their last dose of the investigational or biologic agent ≥ 7 days prior to
study enrollment.
- - For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur.
- - Monoclonal antibody treatment and agents with known prolonged half-lives:
Patient must have recovered from any acute toxicity potentially related to the
agent and received their last dose of the agent ≥ 28 days prior to study
enrollment.
- - RADIATION:
- Recurrent or Progressive CNS tumor patients must have had their last fraction
of:
- Craniospinal irradiation, whole brain radiation, total body irradiation or
radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
- - Focal irradiation ≥ 14 days prior to enrollment.
- - DIPG Patients: Patients with DIPG are eligible after completion of initial
radiotherapy (with or without concurrent treatment) and in the absence of
progressive disease on post-radiation imaging.
- - Patients must have completed radiation therapy at least 14 days prior to
enrollment but no longer than 56 days and cannot have received any other
tumor-directed treatment except the following: Patient may have received
temozolomide or other non-investigational agents during irradiation at the
treating physician's discretion.
If the patient has received such agents
concurrently with radiation, then patient must have recovered from the acute
treatment related toxicities (defined as < Grade 1) prior to enrollment.
- - CELLULAR THERAPY: Patient must be:
- ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no
evidence of active graft vs. host disease.
- - ≥ 3 months since autologous stem cell transplant prior to enrollment.
- - > 42 days since completion of any other type of adoptive cellular therapy prior to
enrollment.
- - CRANIAL SURGERY: Patients who have had recent cranial surgery (VP shunt, ETV, tumor
resection) are eligible for inclusion, but the vaccine may not be administered prior
to post-operative Day 14.
- - NEUROLOGIC STATUS: Patients with neurological deficits should have deficits that are
stable for a minimum of 1 week prior to enrollment.
A baseline neurological exam
should clearly document the neurological status of the patient at the time of
enrollment on the study.
- - PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for > 16 years of age) or
Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks prior
to enrollment must be ≥ 60%.
Patients who are unable to walk because of neurologic
deficits, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score.
- - ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined
below:
- Absolute neutrophil count ≥ 0.75 x 109 cells/L.
- - Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion
within 7 days prior to enrollment)
- Hemoglobin ≥ 8 g/dl (may receive transfusions)
- PT/INR, PTT ≤ 1.5 x ULN.
- - Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)
- ALT(SGPT) ≤ 3 x institutional upper limit of normal.
- - Blood creatinine based on age/gender as noted below.
Patients that do not meet
the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope
or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for
age/gender:
- - Age 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)
- Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
- Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
- Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
- Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
- Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
- INFECTIOUS DISEASES.
- - Human Immunodeficiency Virus (HIV) Infected Individuals: Patients who are known
to be Human immunodeficiency virus (HIV)-infected must be on effective
anti-retroviral therapy with undetectable viral load for 6 months prior to
study enrollment.
- - Hepatitis B Chronically Infected Individuals: For patients with known evidence
of chronic hepatitis B virus (HBV) infection, the HBV viral load must be
undetectable on suppressive therapy, if indicated.
- - Hepatitis C (HCV) Infected Individuals: Patients with a known history of
hepatitis C virus (HCV) infection must have been treated and cured.
Patients
with known HCV infection who are currently on treatment are eligible if they
have an undetectable HCV viral load.
- - CORTICOSTEROIDS: Patients who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to enrollment.
A maximum dose of 0.1
mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) is
permitted at study entry. Effort should be made to reduce to lowest tolerated
steroid dose.
Patients must be willing to use brief courses (at least 72 hours) of steroids as directed
for potential inflammatory side effects of the therapy if recommended by their treating
physician.
- - GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at
least 14 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin).
Two
- (2) weeks must have elapsed if the patient received a long-acting formulation.
- - PREGNANCY - Pregnant women or nursing mothers are excluded from this study because
SurVaxM is an agent with the potential for teratogenic effects.
Female patients of
childbearing potential must have a negative serum or urine pregnancy test. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
- - PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must be
willing to use a medically acceptable form of birth control, which includes
abstinence, while being treated on this study.
- - INFORMED CONSENT - The patient or parent/guardian is able to understand the consent
and is willing to sign a written informed consent document according to
institutional guidelines.
Assent, when appropriate, will be obtained according to
institutional guidelines.
Exclusion Criteria:
- - • BREAST FEEDING WOMEN - Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with SurVaxM
breastfeeding should be discontinued if the mother is treated with SurVaxM.
Female
patients who are breastfeeding are not eligible for this study unless they agree not
to breastfeed.
Excluded Diagnoses:
- - Patients with spinal cord primary tumors.
- - Patients with relapsed or progressive DIPG.
- - Patients with metastatic disseminated DIPG are not eligible.
MRI of spine must be
performed if disseminated disease is suspected by the treating physician.
- - Patients with midline high grade gliomas including those with H3 K27M-altered
diffuse midline glioma (DMG) centered outside of the pons.
- - Patients with Grade II myxopapillary ependymoma.
- - Patients with WHO Grade I or II gliomas are not eligible unless tumor is defined as
DIPG as per above.
- - Patients with bone-only metastatic lesions that do not have otherwise evaluable CNS
disease.
Bulky Disease.Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as any of the
following:
- - Tumor with evidence of clinically significant tonsillar herniation.
- - Tumor with evidence of clinically significant uncal herniation causing midbrain
compression or midline shift greater than 5 mm.
- - Tumor with a diameter >4cm in one dimension on T2/FLAIR.
- - Tumor that in the opinion of the site investigator, shows significantly rapid
progression of mass effect in either the brain or spinal cord such that the priming
phase of vaccination (i.e., 6 weeks) cannot be completed before clinical
deterioration is likely to occur.
Treating physicians should contact the Study Chair to request a rapid central imaging
review to confirm fulfilment of these eligibility criteria, if they have concerns. If
clinically appropriate, surgical debulking of large tumors should be considered before
study entry.
Concurrent Illness:
- - Active, uncontrolled infection requiring treatment (including HIV infection)
- Patients with active autoimmune disease or documented history of autoimmune
disease/syndrome that requires ongoing systemic steroids or systemic
immunosuppressive agents, with the exception of:
- Patients with vitiligo or resolved asthma/atopy.
- - Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome.
- - History of or ongoing pneumonitis or significant interstitial lung disease.
- - Patients with any clinically significant unrelated systemic illness (significant
cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the
investigator would compromise the patient's ability to tolerate protocol therapy,
put them at additional risk for toxicity or would interfere with the study
procedures or results.
- - Patients with a prior or concurrent malignancy whose natural history or treatment
has the potential to interfere with the safety or efficacy assessment of the
investigational regimen for this trial.
- - Any medical condition that, in the opinion of the Principal Investigator, would
compromise the patient's ability to participate in the study.
• CONCOMITANT MEDICATIONS:
- - Patients who are receiving any other anti-cancer or investigational drug therapy are
ineligible.
- - Patients who are receiving any cannabidiol (CBD) or medical marijuana treatment are
ineligible.
- - Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to
enrollment are ineligible.
Examples of live vaccines include, but are not limited
to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG,
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
- - Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14
days of the start of protocol therapy are ineligible.
- - Patients may not be on immunosuppressive therapy, including corticosteroids (except
as defined in the corticosteroids inclusion criteria) at time of enrollment.
However, patients who require intermittent use of bronchodilators, local steroid
injections, or topical steroids will not be excluded from the study.
- - Patients may not be receiving concomitant chemotherapy, immunotherapy, radiotherapy,
radiosurgery, interferon, allergy desensitization injections, growth factors,
interleukins, or any investigational therapeutic medication at the time of
enrollment.
- - INABILITY TO PARTICIPATE: Patients who in the opinion of the investigator are
unwilling or unable to return for required follow-up visits or obtain follow-up
studies required to assess toxicity of therapy or to adhere to drug
administration plan, other study procedures, and study restrictions.
- - ALLERGY: Known allergy or hypersensitivity to Keyhole Limpet Hemocyanin (KLH),
granulocyte colony-macrophage stimulating factor (sargramostim) or MRI contrast
agent.
- - BLEEDING DISORDER: Patients with a known coagulopathy or bleeding diathesis or
requires the use of systemic, anticoagulant medication are not eligible.
