Imetelstat Sodium in Treating Young Patients With Refractory or Recurrent Solid Tumors or Lymphoma

OBJECTIVES:

Primary

- To estimate the maximum-tolerated dose (MTD) and/or recommended phase II dose of
imetelstat sodium in children with refractory or recurrent solid tumors or lymphoma.

- To define and describe the toxicities of imetelstat sodium.

- To characterize the pharmacokinetics of imetelstat sodium in children with refractory
or recurrent solid tumors or lymphoma.

Secondary

- To determine, in a preliminary manner, the antitumor effects of imetelstat sodium in
children with refractory or recurrent solid tumors or lymphoma. (exploratory)

- To provide preliminary assessment of the biological activity of imetelstat sodium in
children with recurrent or refractory malignancies by assessing telomerase activity,
telomere length, hTERT protein, hTERT mRNA, and hTR levels in patient peripheral blood
mononuclear cells (PBMNC) samples pretreatment and on treatment. (Exploratory)

- To assess telomerase activity, hTERT expression, telomere length, hTERT protein, hTERT
mRNA, and hTR levels in patients' pretreatment tumor samples. (Exploratory)

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

Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every
21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic and correlative studies. Tumor tissue samples from diagnosis and/or
subsequent tumor resections or biopsies may also be collected for correlative studies.

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

DISEASE CHARACTERISTICS:

- Diagnosis of refractory or recurrent solid tumors, including lymphoma

- No CNS tumors or known CNS metastases (Part A, dose escalation)

- CNS tumors or known CNS metastases allowed (Part B, maximum-tolerated dose or
recommended phase II dose)

- No prior or concurrent CNS hemorrhage on a baseline MRI within the past 14
days

- All patients must have histologic verification of malignancy at original
diagnosis or relapse except for:

- Intrinsic brain stem tumors

- Optic pathway gliomas

- Pineal tumors and elevations of CSF or serum tumor markers including
alpha-fetoprotein or beta-HCG

- 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 known bone marrow metastatic disease will be eligible for study
provided they meet the blood count criteria and they are not known to be refractory
to red cell or platelet transfusions

PATIENT CHARACTERISTICS:

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

- ANC ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³ (transfusion-independent, defined as not receiving
platelet transfusion within the past 7 days prior to enrollment)

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

- ALT ≤ 110 U/L (ULN for ALT is 45 U/L)

- Serum albumin ≥ 2 g/dL

- aPTT < 1.2 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use an effective contraception method

- 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

PRIOR CONCURRENT THERAPY:

- Recovered from acute toxic effects of all prior anti-cancer chemotherapy,
immunotherapy, or radiotherapy

- At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)

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

- At least 7 days since prior biologic or anti-neoplastic agent

- At least 6 weeks since any type of prior immunotherapy (e.g., tumor vaccines)

- At least 3 half-lives since last dose of a monoclonal antibody

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

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

- At least 6 weeks since prior substantial bone marrow radiation

- At least 12 weeks since prior transplantation or stem cell infusion with no evidence
of active graft vs host disease

- Prior and concurrent stable or decreasing dose of corticosteroids within the past 7
days allowed

- No prior allogeneic transplant

- No other concurrent investigational drug

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

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