Temsirolimus, Irinotecan Hydrochloride, and Temozolomide in Treating Younger Patients With Relapsed or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommended Phase 2 dose and schedule of
temsirolimus administered in combination with irinotecan and temozolomide every three weeks
to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of this regimen in these patients.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of this regimen in these patients.

II. To collect preliminary data regarding the biologic effects of temsirolimus on proteins
involved in signaling pathways of interest in these patients. (Exploratory)

OUTLINE: This is a multicenter study, dose-escalation study of temsirolimus.

Patients receive temsirolimus IV over 30 minutes on days 1 and 8 or on days 1, 8, and 15 and
irinotecan hydrochloride and oral temozolomide on days 1-5. Courses repeat every 21 days for
up to 12 months in the absence of disease progression or unacceptable toxicity.

Some patients undergo bone marrow collection at baseline and during study for
temsirolimus-induced changes in mTOR pathway proteins by flow cytometric analysis and
immunoblotting.

After completion of study therapy, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically confirmed solid tumor at original diagnosis or relapse except for the
following, which do not require biopsies:

- Intrinsic brain stem tumors

- Optic pathway gliomas

- Pineal tumors with elevations of serum, CSF alpha-fetoprotein, or beta-HCG

- Recurrent or refractory disease

- Measurable or evaluable disease

- Disease for which there is no known curative therapy or therapy proven to prolong
survival with an acceptable quality of life

- Patients with CNS tumors must have been relatively stable for ≥ 1 week

- Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS
50-100% (patients ≤ 16 years of age)

- ANC ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3 (transfusion independent)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on
age and/or gender as follows:

- ≤ 0.6 mg/dL (1 to < 2 years of age)

- ≤ 0.8 mg/dL (2 to < 6 years of age)

- ≤ 1.0 mg/dL (6 to < 10 years of age)

- ≤ 1.2 mg/dL (10 to < 13 years of age)

- ≤ 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- ≤ 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 110 U/L

- Serum albumin > 2 g/dL

- PT < 1.2 times ULN

- Serum triglycerides ≤ 300 mg/dL

- Serum cholesterol ≤ 300 mg/dL

- Random or fasting blood glucose normal

- Normal pulmonary function tests, including DLCO, if clinically indicated (e.g.,
dyspnea at rest, known requirement for supplemental oxygen)

- Patients with seizure disorder allowed provided it is well controlled with
non-enzyme-inducing anticonvulsants

- Nervous system disorders resulting from prior therapy ≤ grade 2

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infection

- No patients who, in the opinion of the investigator, may not be able to comply with
the safety monitoring requirements of the study

- No history of allergic reactions attributed to compounds of similar composition to
irinotecan hydrochloride, temozolomide, or temsirolimus

- No evidence of graft-vs-host disease

- Fully recovered from all prior anticancer therapy

- More than 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea)

- At least 14 days since prior long-acting growth factor (e.g., Neulasta) OR 7 days for
short-acting growth factor

- At least 7 days since prior biologic agent that is not a monoclonal antibody (e.g.,
platelet infusions)

- At least 6 weeks since prior immunotherapies (e.g., tumor vaccines)

- At least 3 half-lives since prior monoclonal antibody therapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 24 weeks since prior total-body irradiation, craniospinal radiotherapy
(RT), or RT to ≥ 50% to the pelvis

- At least 6 weeks since prior substantial bone marrow RT

- At least 12 weeks since prior stem cell transplantation or stem cell infusion without
RT

- Prior irinotecan hydrochloride, temozolomide, and temsirolimus as single agents or a
combination of 2 of the 3 drugs, including irinotecan hydrochloride and temozolomide,
allowed

- No prior combination of the 3 agents

- Concurrent corticosteroids allowed provided dose has been stable or decreasing for 7
days

- Intermittent use of corticosteroids to manage infusional reactions is allowed

- More than 6 weeks since prior major surgery

- Recent minor surgical procedures (e.g., vascular catheter placement, bone marrow
evaluation, or laparoscopic surgery) allowed

- No other concurrent investigational drugs

- No other concurrent anticancer agents, including chemotherapy, RT, immunotherapy, or
biologic therapy

- No concurrent enzyme-inducing anticonvulsants

- No concurrent CYP3A4 inducers or inhibitors including any of the following:

- Erythromycin

- Clarithromycin

- Ketoconazole

- Azithromycin

- Itraconazole

- Grapefruit juice

- St. John wort

- No concurrent therapeutic anticoagulants, including aspirin or low molecular weight
heparin

- No concurrent angiotensin-converting enzyme (ACE) inhibitors

- No concurrent cyclosporine, tacrolimus, or other agents to prevent either
graft-versus-host disease post-bone marrow transplant or organ rejection
post-transplant