PRIMARY OBJECTIVE:
I. To determine progression free survival and maintenance of quality of life at 12 months as based on physical function and compared to historical controls.
SECONDARY OBJECTIVES:
I. To identify proportion of participants with visual deficits at 1-year, 2-year, and 3-year follow-up.
II. To identify proportion of participants with neuroendocrine deficits at 1-year, 2-year, and 3-year follow-up.
EXPLORATORY OBJECTIVES:
I. To assess Quality of Life (QOL) and cognitive measures in children and young adults with newly diagnosed or recurrent craniopharyngioma.
II. To perform Immunohistochemistry (IHC)/Multiplexed ion beam imaging on pre-and post-treatment tumor tissue (as available), including at time of progression, to assess for patterns of protein density and spatial relationship in intact tumor tissue and elucidate changes in tumor tissue over the course of therapy and disease evolution.
III. To perform single-cell (scRNA) and single-nucleus (snRNA) RNA sequencing on pre- and post-treatment tumor tissue (as available), including at time of progression, to identify and characterize distinct cell subsets that make up the components of craniopharyngioma and elucidate changes in cell subsets over the course of therapy and disease evolution.
IV. To perform proteomic analysis on pre- and post-treatment tumor tissue, including at time of progression, to characterize distinct proteins and transcriptome pathways that are active in different tumor compartments and elucidate changes in proteomic profiles over the course of therapy and disease evolution.
V. To perform ELISA array/multiplex analysis on pre- and post-treatment cyst fluid, including at time of progression, to characterize distinct cytokine profiles and elucidate changes in cytokine profile over the course of therapy and disease evolution.
VI. Microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistic.
TREATMENT GROUPS:
Participants will be divided into 2 Groups (Newly diagnosed craniopharyngioma, Recurrent craniopharyngioma) with 3 treatment arms within each group (Neoadjuvant nivolumab, Neoadjuvant DAY101, Neoadjuvant combination nivolumab plus DAY101). There will also be a separate Non-biopsy/resection arm within the Recurrent Craniopharyngioma group.
Participants will be randomized in a 1:1:1 and will receive one dose of assigned drug prior to planned biopsy or resection. Participants with measurable disease will then continue on combination maintenance therapy. Participants may continue treatment for up to 24 months total and will be followed up 3 years after enrollment into the study.
Inclusion Criteria:
Newly Diagnosed Participants:
- Newly diagnosed craniopharyngioma diagnosis based on imaging characteristics and
central radiology review. Participants will initially be screened within confines of a
screening consent and only those participants with findings consistent with
craniopharyngioma and without findings suggesting an indeterminate lesion or lesion of
an alternative diagnosis (including abnormal tumor markers found in blood or cerebral
spinal fluid (CSF), if completed as part of standard of care (SOC) work-up or if
lesion concerning for alternate diagnosis) will move ahead with enrollment on the
treatment protocol. Additionally, for patients that have undergone initial biopsy to
confirm diagnosis, are within 4 weeks of radiographic diagnosis, and are planned to
undergo follow up second surgery for additional tumor resection as per standard of
care recommendations, these patients will also be considered eligible.
- Participants must be surgical candidates for biopsy or resection and planned for
standard of care biopsy or resection.
Recurrent Participants:
- Recurrent craniopharyngioma, as based on histologic confirmation at time of initial
diagnosis (participants will be eligible regardless of craniopharyngioma subtype; if
papillary subtype, clinical trial assignment will be to the exploratory cohort).
- Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffin
embedded unstained slides OR 1 block with tumor content of 40% or greater is required.
Participants who do not meet this criteria may be discussed on a case-by-case basis
with the Study Chairs."
- Participants should be surgical candidates for biopsy or resection. If participants
are not surgical candidates, but have available archival tumor tissue, participants
will be enrolled into the exploratory cohort.
- Participants can have been previously treated with surgical resection alone, radiation
therapy, other systemic therapies, or any combination thereof.
- Prior Therapy:
- Had their last dose of myelosuppressive chemotherapy >= 21 days prior to study
registration (>=42 days if nitrosourea therapy).
- Had their last dose of hematopoietic growth factor >=14 days (long-acting growth
factor) or >=7 days (short-acting growth factor) prior to study registration, or
beyond the time during which adverse events (AEs) are known to occur.
- Had their last dose of biologic (anti-neoplastic agent) >=7 days prior to study
registration, or beyond the time during which AEs are known to occur.
- Had their last dose of monoclonal antibodies >=21 days prior to study
registration.
Radiation:
- Had their last fraction of local irradiation to primary tumor ≥12 weeks prior to
registration; investigators are reminded to review potentially eligible cases to avoid
confusion with pseudo-progression.
- At least 14 days after local palliative radiation (small-port).
All Participants:
- Age 1 to 39 years.
- Participants continuing on maintenance therapy after standard of care biopsy/resection
must have measurable disease, as defined as lesions that can be accurately measured in
two dimensions (longest diameter to be recorded) with a minimum size of no less than
double the slice thickness. Previously irradiated lesions are considered
non-measurable except in cases of documented progression of the lesion since the
completion of radiation therapy. Participants without measurable disease may continue
on study and will be followed for study endpoints, but will not be included as part of
target accrual.
- Performance Score: Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50
for participants <= 16 years of age. Participants who are unable to walk because of
paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score.
- Corticosteroids: Participants who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to registration. The patient steroid dose
should be no more than a steroid-equivalent of dexamethasone 0.1 mg/kg/day (or maximum
4mg/day; whichever is the lower dose) at time of enrollment. Participants receiving
hormone replacement for hypopituitarism should be discussed with study chairs.
- Organ Function Requirements:
- Adequate Bone Marrow Function defined as:
- Peripheral absolute neutrophil count (ANC) >=1000/mm3.
- Platelet count >= 100,000/mm3 (transfusion independent, defined as not
receiving platelet transfusions for at least 7 days prior to enrollment).
- Adequate Renal Function defined as Creatinine clearance or radioisotope
Glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2 or a serum creatinine based
on age/gender as follows:
- Age 1 - 2 years: Maximum Serum Creatinine (mg/dL) Male 0.6, Female 0.6.
- Age 2 < 6 years: Maximum Serum Creatinine (mg/dL) Male 0.8, Female 0.8.
- Age 6 < 10 years: Maximum Serum Creatinine (mg/dL) Male 1, Female 1.
- Age 10 < 13 years: Maximum Serum Creatinine (mg/dL) Male 1.2, Female 1.2.
- Age 13 < 16 years: Maximum Serum Creatinine (mg/dL) Male 1.5, Female 1.4.
- Age >=16 years: Maximum Serum Creatinine (mg/dL) Male 1.7, Female 1.4. NOTE:
The threshold creatinine values in this table were derived from the Schwartz
formula for estimating GFR utilizing child length and stature data published
by the Center for Disease Controls (CDC).
- Adequate Liver Function defined as-
- Bilirubin (sum of conjugated + unconjugated) <= 1.5 x upper limit of normal
(ULN) for age (except in patients with documented Gilbert syndrome).
- Serum glutamic-pyruvic transaminase (SGPT)((alanine aminotransferase (ALT))
<= 3 x ULN.
- Serum albumin >=2 g/dL (20g/L).
- Adequate Neurologic Function defined as participants with seizure disorder may be
enrolled if well controlled. Participants on non-enzyme inducing anticonvulsants
may be excluded pending interaction(s) with study drug.
- Adequate Pancreatic Function defined as serum lipase <= 1.5 x ULN at baseline.
- Adequate Pulmonary Function defined as no evidence of dyspnea at rest, no
exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of >
92% while breathing room air.
- The effects of DAY101 and nivolumab on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation and 6 months after completion of DAY101
and/or nivolumab administration, whichever is later. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.
- A legal parent/guardian or patient must be able to understand, and willing to sign, a
written informed consent and assent document, as appropriate.
Exclusion Criteria:
Newly Diagnosed Participants:
- Participants should not have undergone any previous tumor-directed therapy.
Recurrent Participants:
- Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from acute adverse events due to agents administered more than 4 weeks
earlier.
- Participants must be at least 1 week since the completion of therapy with a biologic
or small molecule agent. For any agent with known adverse events that can occur beyond
1 week after administration, the period prior to enrollment must be beyond the time
during which adverse events are known to occur. Such participants should also be
discussed with study chairs.
- Participants should not have previously received any RAS-pathway directed therapy
combined with PD-1 inhibition. However, individual therapy with either of these
individual agents will be allowed. Such subjects should be discussed with study
chairs.
All Participants:
- Rapidly progressive symptoms that require urgent surgery or radiation therapy, which
would prevent central review and or preclude participation with tumor-directed medical
management alone.
- Uncontrolled symptoms of neuroendocrine dysfunction such as diabetes insipidus,
hypothyroidism, panhypopituitarism (participants can be on supplemental medications
for hormonal repletion; however, should be on controlled doses for at least 2 weeks
prior to enrollment).
- Patients with a history or current evidence of central serous retinopathy (CSR),
retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be
considered a risk factor for CSR or RVO. Ophthalmological findings secondary to
long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or
strabismus) will NOT be considered a significant abnormality for the purposes of this
study.
- Clinically significant active cardiovascular disease, or history of myocardial
infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to
registration, ongoing cardiomyopathy, or current prolonged QT interval corrected for
heart rate by Fridericia's formula (QTcF) interval > 440 ms based on triplicate ECG
average.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to DAY101 or nivolumab or other agents used in study.
- History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome,
Stevens Johnsons syndrome (SJS), or hypersensitivity to the investigational medicinal
product or to any drug with similar chemical structure or to any other excipient
present in the pharmaceutical form of the investigational medicinal product.
- History of pneumonitis within the last 5 years or history of thoracic radiation,
including prior craniospinal irradiation (CSI) or have radiation fields that overlap
the lung.
- Nausea and vomiting >= Grade 2, malabsorption requiring supplementation, or
significant bowel or stomach resection that would preclude adequate absorption.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection.
- Participants who are receiving any other investigational agents.
- Participants who have received a live / attenuated vaccine within 30 days of
registration.
- Participants with a known disorder that affects their immune system, such as HIV or
Hepatitis B or C, an auto-immune disorder disease that has required systemic treatment
in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment. Note: Participants that are currently
using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are
not necessarily excluded from the study but need to be discussed with the study chair.
- Participants with a ≥ Grade 2 hypothyroidism due to history of autoimmunity are not
eligible. (Note: Hypothyroidism due to previous irradiation or thyroidectomy will not
impact eligibility).
- Participants who have received prior solid organ or bone marrow transplantation are
not eligible.
- Women of childbearing potential must not be pregnant or breast-feeding.
- Current treatment with a strong cytochrome P4502C8(CYP2C8) inhibitor or inducer other
than those allowed per Section 5.6.1. Medications that are substrates of CYP2C8 are
allowed but should be used with caution.
- Participants with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy.
