A Phase 1 Study of Temsirolimus in Combination With Irinotecan and Temozolomide in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors

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