Nanoparticle Albumin-Bound Rapamycin, Temozolomide, and Irinotecan Hydrochloride in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of
nanoparticle albumin-bound rapamycin (ABI-009) administered as an intravenous infusion over
30 minutes on days 1 and 8 of a 21-day cycle, in combination with temozolomide and irinotecan
hydrochloride (irinotecan) (administered on days 1-5) in pediatric patients with recurrent or
refractory solid tumors, including central nervous system (CNS) tumors.

II. To define and describe the toxicities of single-agent ABI-009 administered as an
intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle in pediatric patients
with recurrent or refractory solid tumors, including CNS tumors.

III. To define and describe the toxicities of ABI-009 administered as an intravenous infusion
over 30 minutes on days 1 and 8 of a 21-day cycle in combination with temozolomide and
irinotecan (administered on days 1-5) in pediatric patients with recurrent or refractory
solid tumors, including CNS tumors.

IV. To characterize the pharmacokinetics of ABI-009 in pediatric patients with recurrent or
refractory solid tumors, including CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of ABI-009 in combination with temozolomide
and irinotecan within the confines of a phase 1 study.

TERTIARY OBJECTIVES:

I. To assess the biologic activity of ABI-009 by examining S6K1 and 4E-BP1 expression status
in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.

OUTLINE: This is a dose-escalation study of nanoparticle albumin-bound rapamycin.

Patients receive nanoparticle albumin-bound rapamycin intravenously (IV) over 30 minutes on
days 1 and 8 beginning on course 1. Patients also receive temozolomide orally (PO) and
irinotecan hydrochloride PO on days 1-5 beginning on course 2. Treatment repeats every 21
days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have a body surface area (BSA) of >= 0.2 m^2 at the time of study
enrollment

- Patients with recurrent or refractory solid tumors, including CNS tumors, are
eligible; patients must have had histologic verification of malignancy at original
diagnosis or relapse except in patients with intrinsic brain stem tumors, optic
pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid
(CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic
gonadotropin (HCG)

- Patients must have either measurable or evaluable disease

- Patient?s current disease state must be one for which there is no known curative
therapy

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age

- Note: Neurologic deficits in patients with CNS tumors must have been relatively
stable for at least 7 days prior to study enrollment; patients 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

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment; if after the required timeframe, the
numerical eligibility criteria are met, e.g. blood count criteria, the patient is
considered to have recovered adequately

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; the
duration of this interval must be discussed with the study chair and the
study-assigned research coordinator prior to enrollment

- >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42
days if prior nitrosourea)

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced
platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
agent; the duration of this interval must be discussed with the study chair and the
study-assigned research coordinator prior to enrollment

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
toxicity related to prior antibody therapy must be recovered to grade =< 1

- Corticosteroids: If used to modify immune adverse events related to prior therapy, >=
14 days must have elapsed since last dose of corticosteroid

- Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth
factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; 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; the
duration of this interval must be discussed with the study chair and the
study-assigned research coordinator

- Interleukins, interferons and cytokines (other than hematopoietic growth factors): >=
21 days after the completion of interleukins, interferon or cytokines (other than
hematopoietic growth factors)

- Stem cell infusions (with or without total body irradiation [TBI]):

- Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell
infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days
after infusion, and no evidence of graft-versus-host disease (GVHD)

- Autologous stem cell infusion including boost infusion: >= 42 days

- Cellular therapy: >= 42 days after the completion of any type of cellular therapy
(e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)

- X ray (XRT)/external beam irradiation including protons: >= 14 days after local XRT;
>= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42
days if other substantial bone marrow (BM) radiation

- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine
metaiodobenzylguanidine [131I-MIBG]): >= 42 days after systemically administered
radiopharmaceutical therapy

- Irinotecan, temozolomide and mammalian target of rapamycin (mTOR) inhibitor exposure:

- Patients who have received prior single agent therapy with irinotecan,
temozolomide, or an mTOR inhibitor, excluding ABI-009, are eligible

- Patients who have received prior therapy with ABI-009 are not eligible

- Patients who have previously received irinotecan and temozolomide in combination
without progressive disease while on therapy are eligible

- Patients who have previously received irinotecan and temozolomide in combination
and had significant toxicity with these two drugs are not eligible

- Patients who have received prior therapy with all three agents in combination
(i.e. irinotecan, temozolomide, and an mTOR inhibitor) are not eligible

- For patients with solid tumors without known bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- Hemoglobin >= 8.0 g/dl at baseline (may receive red blood cell [RBC]
transfusions)

- Patients with known bone marrow metastatic disease will be eligible for the study if
they meet the following criteria:

- Peripheral absolute neutrophil count (ANC) >= 750/mm^3

- Platelet count >= 50,000/mm^3 (may receive transfusions provided they are not
known to be refractory to red cell or platelet transfusions)

- Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC]
transfusions, provided they are not known to be refractory to RBC transfusions);
these patients will not be evaluable for hematologic toxicity; at least 5 of
every cohort of 6 patients must be evaluable for hematologic toxicity for the
dose-escalation part of the study; if dose-limiting hematologic toxicity is
observed, all subsequent patients enrolled must be evaluable for hematologic
toxicity

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- Age: maximum serum creatinine (mg/dL)

- 1 to < 2 years: 0.6 (male and female)

- 2 to < 6 years: 0.8 (male and female)

- 6 to < 10 years: 1 (male and female)

- 10 to < 13 years: 1.2 (male and female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
ULN = 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Serum albumin >= 2 g/dL

- Pulse oximetry > 94% on room air if there is clinical indication for determination
(e.g. dyspnea at rest)

- Patients with seizure disorder may be enrolled if on non-enzyme inducing
anticonvulsants and well controlled

- Nervous system disorders (National Cancer Institute Common Terminology Criteria for
Adverse Events [NCI CTCAE] version 5.0) resulting from prior therapy must be =< grade
2 with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible

- Serum triglyceride level =< 300 mg/dL

- Serum total cholesterol level =< 300 mg/dL

- Random or fasting blood glucose =< the upper normal limits for age; if the initial
blood glucose is a random sample that is outside of the normal limits, then follow-up
fasting blood glucose can be obtained and must be =< the upper normal limits for age

- International normalized ratio (INR) =< 1.5

- Not currently receiving anticoagulation therapy

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

- Tissue blocks or slides must be sent for all patients; if tissue blocks or slides are
unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method both during and for 6 months after participation in this study;
abstinence is an acceptable method of contraception

- Patients receiving corticosteroids must have been on a stable or decreasing dose of
corticosteroid for at least 7 days prior to enrollment; if used to modify immune
adverse events related to prior therapy, >= 14 days must have elapsed since last dose
of corticosteroid

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anti-cancer agents are not eligible

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this trial

- Patients must not have received enzyme-inducing anticonvulsants for at least 7 days
prior to enrollment

- Patients who are currently receiving therapeutic anticoagulants (including aspirin,
low molecular weight heparin, and others) are not eligible

- Patients must not be receiving any strong CYP3A4 or P-glycoprotein (P-gp) inducers or
inhibitors within 7 days prior to enrollment; moderate inducers or inhibitors of
CYP3A4 and P-gp should also be avoided during ABI-009 treatment, if possible

- Patients with interstitial lung disease and/or pneumonitis are not eligible

- Patients with a history of allergic reactions attributed to compounds of similar
composition, including macrolide and ketolide antibiotics, temsirolimus/other mTOR
inhibitors, temozolomide or irinotecan are not eligible

- Patients with hypersensitivity to albumin are not eligible

- Patients who have had or are planning to have the following invasive procedures are
not eligible:

- Major surgical procedure, laparoscopic procedure, open biopsy or significant
traumatic injury within 28 days prior to enrollment

- Subcutaneous port placement or central line placement is not considered major
surgery; external central lines must be placed at least 3 days prior to
enrollment and subcutaneous ports must be placed at least 7 days prior to
enrollment

- Core biopsy within 7 days prior to enrollment

- Fine needle aspirate within 7 days prior to enrollment

- NOTE: For purposes of this study, bone marrow aspirate and biopsy are not
considered surgical procedures and therefore are permitted within 14 days prior
to start of protocol therapy

- Patients with current deep vein thrombosis or deep vein thrombosis within the past 6
months are not eligible

- Patients with a history of, or current grade 4 depression are not eligible

- Patients who have an uncontrolled infection are not eligible

- Patients who have received a prior solid organ transplantation are not eligible

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible