A PHASE 1/2 STUDY OF RO4929097, AN ORAL SMALL MOLECULE INHIBITOR OF GAMMA-SECRETASE, IN CHILDREN WITH RELAPSED/REFRACTORY SOLID OR CNS TUMORS, LYMPHOMA, OR T-CELL LEUKEMIA

Inclusion Criteria:

- Histologically confirmed malignancy (at diagnosis or relapse)

- Biopsy not required for intrinsic brain stem tumors or optic pathway gliomas

- No B-cell precursor acute lymphoblastic lymphoma (ALL) or acute myeloid leukemia

- No T-cell leukemia with CNS3 disease

- Measurable or evaluable disease

- Current disease state must be one for which there is no known curative therapy or
therapy proven to prolong survival with an acceptable quality of life

- Neurologic deficits in patients with CNS tumors must have been relatively stable for
1 week

- No active CNS leukemia

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

- 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 PS

- Patients with solid tumors without bone marrow involvement must meet the following
criteria:

- Peripheral ANC ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions within the past 7 days)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Patients with known bone marrow metastatic disease must meet the above criteria and
must not be known to be refractory to red cell or platelet transfusion

- Patients with leukemia must meet the following criteria:

- Platelet count ≥ 20,000/mm^3 (may receive platelet transfusions)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Must not be known to be refractory to RBC or platelet transfusions

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

- ≤ 0.6 mg/dL (patients 1 to < 2 years)

- ≤ 0.8 mg/dL (patients 2 to < 6 years)

- ≤ 1 mg/dL (patients 6 to < 10 years)

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

- ≤ 1.4 mg/dL (female patients ≥ 13 years)

- ≤ 1.5 mg/dL (male patients 13 to < 16 years)

- ≤ 1.7 mg/dL (male patients ≥ 16 years)

- Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal
(ULN) for age

- ALT ≤ 110 U/L (for the purpose of this study, the ULN for ALT is 45 U/L)

- Serum albumin ≥ 2 g/dL

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia defined as < lower limit of normal despite adequate electrolyte
supplementation

- Baseline QTc < 450 msec

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective double-method contraception (i.e., one highly
effective method and one additional effective method) for ≥ 4 weeks before, during,
and for ≥ 12 months after completion of study treatment

- Female patients may not donate ova during or after study treatment

- Able to comply with the safety monitoring requirements of the study, in the opinion
of the investigator

- Able to swallow tablets and capsules

- No known malabsorption syndrome or other condition that would interfere with
intestinal absorption

- No known serological positivity for hepatitis A, B, or C, no known history of liver
disease, and no other forms of hepatitis or cirrhosis

- No known HIV positivity

- No uncontrolled infection

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 or dexamethasone

- Patients may not donate blood during or for ≥ 12 months after completion of study
treatment

- No hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia that
is uncontrolled despite adequate electrolyte supplementation

- No prior gamma-secretase inhibitor RO4929097

- Fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy

- More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)
(for patients with solid tumors, CNS tumors, or lymphomas)

- Patients with T-cell leukemia must meet the following criteria:

- Patients who relapsed on standard ALL maintenance chemotherapy must not have
received maintenance chemotherapy within the past 3 days

- Patients who relapsed when they were not receiving standard ALL maintenance
therapy are eligible provided it has been ≥ 14 days since the completion of
cytotoxic chemotherapy with the exception of hydroxyurea

- Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours
before the start of study treatment

- At least 6 months since prior total-body irradiation (TBI), craniospinal
radiotherapy, or radiotherapy to ≥ 50% of the pelvis

- At least 6 weeks since other prior substantial bone marrow radiotherapy

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

- At least 3 months since prior stem cell transplantation or rescue without TBI and no
evidence of active graft-vs-host disease

- At least 7 days since the completion of therapy with a biologic agent

- 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)

- At least 7 days or 3 half-lives, whichever is longer, since prior treatment with a
monoclonal antibody

- More than 7 days since prior growth factors that support platelet or white cell
number or function

- At least 7 days since prior corticosteroids

- No other concurrent investigational drugs

- No other concurrent anticancer agents including chemotherapy (except for
hydroxyurea), radiotherapy, immunotherapy, or biologic therapy

- Patients with T-ALL who benefit from treatment with gamma-secretase inhibitor
RO4929097 in combination with dexamethasone may receive intrathecal methotrexate

- No concurrent warfarin sodium (Coumadin®)

- No concurrent medications that are strong inducers and/or inhibitors of CYP3A4

- No concurrent medications or food that may interfere with the metabolism or
gamma-secretase inhibitor RO4929097, including ketoconazole and fresh-squeezed
grapefruit juice