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

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of nanoparticle albumin-bound rapamycin when given together with temozolomide and irinotecan hydrochloride in treating pediatric patients with solid tumors that have come back after treatment and a period of time during which the tumor could not be detected or has not responded to treatment. Nanoparticle albumin-bound rapamycin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nanoparticle albumin-bound rapamycin, temozolomide, and irinotecan hydrochloride may cause the cancer to stop growing or shrink for a period of time and may lessen the symptoms that are caused by the cancer.

Detailed Description
-----------------
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 OBJECTIVE: I. To preliminarily define the antitumor activity of ABI-009 in combination with temozolomide and irinotecan within the confines of a phase 1 study. EXPLORATORY OBJECTIVE: 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 cycle 1. Patients also receive temozolomide orally (PO) and irinotecan hydrochloride PO on days 1-5 beginning on cycle 2. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
-----------------
A Phase 1 Study of ABI-009 (NAB-RAPAMYCIN) in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors as a Single Agent and in Combination With Temozolomide and Irinotecan

Conditions
-----------------
Childhood Solid Neoplasm, Recurrent Malignant Solid Neoplasm, Recurrent Primary Central Nervous System Neoplasm, Refractory Malignant Solid Neoplasm, Refractory Primary Central Nervous System Neoplasm

Intervention / Treatment
-----------------
* Drug: Irinotecan Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Sirolimus Albumin-bound Nanoparticles
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Adequate Bone Marrow Function Defined as: For patients with solid tumors without known bone marrow involvement (no older than 7 days at the start of therapy): 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) 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 (no older than 7 days at the start of therapy): 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 (no older than 7 days at the start of therapy) 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 (no older than 7 days at the start of therapy) Serum albumin >= 2 g/dL (no older than 7 days at the start of therapy) 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 (no older than 7 days at the start of therapy) Serum total cholesterol level =< 300 mg/dL (no older than 7 days at the start of therapy) 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 (no older than 7 days at the start of therapy) International normalized ratio (INR) =< 1.5 (no older than 7 days at the start of therapy) 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 due to risks of fetal and teratogenic adverse events as seen in animal/human studies; 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 have known bone marrow involvement 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

Ages Eligible for Study
-----------------
Minimum Age: 12 Months
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nab-rapamycin, temozolomide, irinotecan)<br>Patients receive nanoparticle albumin-bound rapamycin IV over 30 minutes on days 1 and 8 beginning on cycle 1. Patients also receive temozolomide PO and irinotecan hydrochloride PO on days 1-5 beginning on cycle 2. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Irinotecan Hydrochloride<br>* Given PO<br>* Other names: U-101440E;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Sirolimus Albumin-bound Nanoparticles<br>* Given IV<br>* Other names: Sirolimus Protein-bound Particles;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Cycle 1 and 2 Dose Limiting Toxicities Attributable to Nanoparticle Albumin-bound Rapamycin | Number of patients with cycle 1 and 2 dose limiting toxicities possibly, probably, or definitely attributable with nanoparticle albumin-bound rapamycin stratified by dose level. | Up to 42 days | 
| Number of Patients With Adverse Events | The number of patients with adverse events that are at least possibly attributable to nanoparticle albumin-bound rapamycin stratified by dose level. | Up to 24 months | 
| Area Under the Serum of Nanoparticle Albumin-bound Rapamycin Concentration Curve | Median with minimum and maximum values of the area under the drug concentration over time curve stratified by dose level. | Days 1, 2, 3, 4, and 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Antitumor Activity of Nanoparticle Albumin-bound Rapamycin | The number of response-evaluable patients with best overall response of complete response (CR), disappearance of all target lesions; or partial response (PR), >=50% decrease in the sum of the products of the two perpendicular diameters of all target lesions (up to 5), while on study therapy stratified by dose level; Overall response (OR)=CR+PR. | Up to 24 months |