This trial is a multi-center, non-randomized, open-label Phase II study evaluating the
feasibility and efficacy of vincristine, irinotecan, temozolomide, and atezolizumab. The
trial will enroll patients with pediatric relapsed/refractory solid tumors.
Inclusion Criteria:
1. Signed informed consent
2. Relapsed or refractory solid tumor after at least one prior course of therapy. Hodgkin
lymphoma or non-Hodgkin lymphoma are not permitted. Patients with CNS malignancy or
asymptomatic CNS metastases may be enrolled, provided all of the following criteria
are met. No metastatic or primary disease affecting the brainstem, midbrain, pons, or
cerebellum, or within 10 mm of optic nerve. No history of leptomeningeal disease No
history of intracranial or spinal cord hemorrhage. No evidence of progression of
neurologic deficit, in the investigator's judgment, within 7 days prior to initiation
of study medications.
3. Age ≥ 6 months and ≤ 30 years
4. Lansky Performance Status (patients < 16 years old) or Karnofsky Performance Status
(patients ≥ 16 years old) ≥ 50
5. Ability to comply with the study protocol, in the investigator's judgment
6. For efficacy cohort, disease must be measurable as defined by RECIST v1.1, mINRC, or
RANO criteria (as appropriate). For the feasibility cohort, disease must be evaluable,
but patients enrolled on the feasibility cohort will be prospectively assessed for
measurable disease. If they are deemed to have measurable disease and PD-L1(+)
staining, they will also be included in the efficacy cohort. Previously irradiated
lesions can be considered as measurable disease only if progressive disease has been
unequivocally documented at that site since radiation.
7. For the efficacy cohort, PD-L1(+) tumor is required. Staining may be performed in the
central site CAP/CLIA -certified laboratory using the 22c3 antibody for
immunohistochemical analysis. PD-L1(+) status will be defined as staining on ≥1% of
tumor cells or ≥1% of stroma. For the feasibility cohort, PD-L1 positivity is not
required but will be performed centrally in all cases for exploratory biomarker
studies.
8. Availability of a tumor specimen suitable for determination of PD-L1 status, either
from initial diagnosis or from a recurrence. For PD-L1 staining to be performed at the
central site, a formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin
block (preferred) or at least 15 slides containing unstained, freshly cut, serial
sections must be available along with an associated pathology report prior to study
enrollment. Patients for whom the required number of slides are not available may
still be eligible to enroll on study with PI approval
9. Adequate organ and marrow function as defined by the following laboratory values
obtained within 21 days prior to initiation of study medication.
1. For patients without known bone marrow involvement: (1) Absolute neutrophil count
≥ 1.0 x 10^9 / L (1000/µL) without granulocyte colony-stimulating factor support
(≥14 days after the last dose of a long-acting growth factor such as
pegfilgrastim, or 7 days after short-acting growth factor), (2) Absolute
lymphocyte count ≥ 0.5 x 10^9 / L (500/µL), (3) Platelet count ≥ 75 x 10^9 / L
(75,000/µL) without transfusion in the last 7 days.
2. Patients with known bone marrow metastatic disease will be eligible for the study
if they meet the following criteria: (1) Absolute neutrophil count (ANC) ≥
750/mm3, (2) Absolute lymphocyte count ≥ 0.4 x 10^9 / L (400/µL), (3) Platelet
count ≥ 50,000/mm3 (may receive transfusions provided they are not known to be
refractory to red cell or platelet transfusions).
3. Total bilirubin ≤1.5 x upper limit of normal (ULN) for age
4. AST (SGOT) and ALT (SPGT) ≤ 2.5 x ULN for age
5. Creatinine ≤ 1.5 x ULN for age or creatinine clearance (or radioisotope
glomerular filtration rate) ≥ 70 mL/min/1.73 m2 f Left ventricular ejection
fraction ≥ 50% or shortening fraction ≥ 30%
10. Negative HIV and hepatitis B surface antigen (HBsAg) tests at screening
11. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from
donating eggs, as defined below:
1. Women must remain abstinent or use contraceptive methods with a failure rate of
less than 1% per year during the treatment period and for 5 months after the
final doses of atezolizumab, vincristine, and temozolomide. Women must refrain
from donating eggs during this same period.
2. A woman is considered to be of childbearing potential if she is postmenarchal,
has not reached a postmenopausal state (12 or more continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus), regardless of sexual
orientation or marital status.
12. For men who are not surgically sterile: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
donating sperm, as defined below:
1. With a female partner of childbearing potential who is not pregnant, men must
remain abstinent or use a condom plus an additional contraceptive method that
together result in a failure rate of less 1% per year during the treatment period
and for 5 months after the final doses of atezolizumab, irinotecan, and
temozolomide. Men must refrain from donating sperm during this same period.
2. The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of contraception
Exclusion Criteria:
1. Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or
within 5 months after the final dose of study treatment. Women of childbearing
potential must have a negative serum pregnancy test result within 21 days prior to
initiation of study treatment.
2. Medical conditions that are excluded:
1. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Guillain-Barré syndrome, multiple sclerosis, or Kawasaki
syndrome with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis
are excluded) are eligible for the study provided all of following
conditions are met at study initiation: (1) Rash must cover less 10% of body
surface area, (2) Disease is well controlled at baseline and requires only
low-potency topical corticosteroids, (3) No occurrence of acute
exacerbations of the underlying condition requiring psoralen plus
ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high-potency or oral corticosteroids within the
previous 12 months
2. Uncontrolled or symptomatic hypercalcemia (ionized calcium less than 1.5 mmol/L,
calcium less than 12 mg/dL or corrected serum calcium less than ULN)
3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures (once monthly or more frequently). Patients with
indwelling catheters (e.g., PleurX) are allowed.
4. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a
stable regimen at study entry for at least 2 weeks. Intermittent use of as needed
medication is allowed during this period.
5. Clinically significant gastrointestinal disorder that may interfere with
absorption of orally administered drugs (at the discretion of the treating
physician)
6. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,
or evidence of active pneumonitis on screening chest computed tomography (CT)
scan. History of radiation pneumonitis in the radiation field (fibrosis) is
permitted.
7. Significant cardiovascular disease (such as New York Heart Association Class II
or greater cardiac disease, myocardial infarction, or cerebrovascular accident)
within 3 months prior to initiation of study treatment, unstable arrhythmia, or
unstable angina
8. History of severe asthma or uncontrolled asthma i Dyspnea at rest or requirement
for supplemental oxygen
j. Uncontrolled seizures. Patients taking a stable dose of anticonvulsants (for 2
weeks) are permitted, as long as they are not strong inducers or inhibitors of CYP3A4.
k. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from
treatment complications in the opinion of the treating investigator
3. Washout periods from prior therapies:
1. Myelosuppressive chemotherapy or radiotherapy within 21 days prior to starting
study treatment. Subjects must have recovered from all acute prior
treatment-related toxicities to grade 1 or baseline (excluding alopecia and
clinically stable toxicities requiring ongoing medical management, such as
hypothyroidism).
2. Non-myelosuppressive cancer therapy, such as kinase inhibitors, within 7 days
prior to study treatment.
3. Treatment with monoclonal antibodies with long half-lives, within 3 half-lives
prior to study treatment.
4. Treatment with targeted cellular therapies within 28 days prior to starting study
treatment.
5. Major surgical procedure, other than for diagnosis, within 30 days prior to
initiation of study treatment, or anticipation of need for a major surgical
procedure during the first four cycles of the study.
- Biopsy tissue collection or placement of a vascular access device is
permitted if the site has healed prior to initiation of study medications.
- For patients with CNS disease, no neurosurgical resection, brain biopsy, or
stereotactic/whole-brain radiation within 30 days prior to Cycle 1, Day 1
6. Treatment with a live, attenuated vaccine within 30 days prior to initiation of
study treatment, or anticipation of need for such a vaccine during atezolizumab
treatment or within 5 months after the final dose of atezolizumab
7. Treatment with investigational therapy within 21 days prior to initiation of
study treatment or concurrent participation with another investigational agent
8. Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment
9. Treatment with systemic immunosuppressive medication (including, but not limited
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide,
and anti-TNF-agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48
hours of corticosteroids for a contrast allergy) are eligible for the study
after Principal Investigator confirmation has been obtained.
- Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma,
or low-dose corticosteroids for orthostatic hypotension or adrenal
insufficiency are eligible for the study.
- Patients with CNS disease can be receiving concurrent treatment with
corticosteroids with approval from the Principal Investigator. Patients must
be receiving a stable or decreasing dose for ≥ 5 days prior to the baseline
MRI scan and at the time of drug initiation. The Principal Investigator
should be informed when steroid doses are increased because of declining
patient status.
10. Use of strong CYP3A4 inhibitors or inducers or strong UGT1A1 inhibitors within 12
days of Cycle 1, Day 1.
11. Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3
months prior to initiation of study drug
12. Treatment with herbal cancer therapy within 1 week prior to initiation of study
medications.
13. Treatment with a long-acting hematopoietic growth factor (such as pegfilgrastim)
within 2 weeks prior to initiation of study medications, or a short-acting
hematopoietic growth factor (such as G-CSF) within 1 week prior to initiation of
study medications.
4. Prior treatments:
1. Prior allogeneic stem cell or solid organ transplantation
2. Prior treatment with CD137 agonists or immune checkpoint blockade therapies to
include all anti-PD-1, and anti-PD-L1 therapeutic antibodies
3. Subjects must not have previously progressed while receiving regimens that
include irinotecan or temozolomide. Patients who have received irinotecan or
temozolomide and did not progress while on these medications are eligible.
5. Known ongoing or untreated infection, including, but not limited to bacteremia, active
tuberculosis, severe pneumonia, current treatment with anti-viral therapy for HBV,
active hepatitis C
a. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible for the
study.
6. Known allergy or hypersensitivity to any component of the study medications
1. History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
2. Known hypersensitivity to Chinese hamster ovary cell products or to any component
of the atezolizumab formulation
