Imetelstat for Children With Refractory or Recurrent Solid Tumors and Lymphoma

BACKGROUND:

- Telomerase is an enzyme that plays a critical role in maintaining telomeres, the
specialized structures at the end of chromosomes involved in the replication and
stability of the chromosome. Inhibition of telomeres causes the length of the telomere
to shorten, and the cell becomes either senescent or undergoes apoptosis.

- In vitro and in vivo studies have demonstrated that imetelstat, a telomerase inhibitor,
inhibits primary tumor growth and prevents metastases; while six Phase 1 studies in
adults have demonstrated reasonable toxicity profiles with hematologic toxicity the
primary cause of dose limiting toxicity.

- Objective responses have been observed with repeated dosing when imetelstat was
administered in combination with bortezomib to patients with multiple myeloma, with
paclitaxel and bevacizumab to patients with advanced breast cancer, and with paclitaxel
plus carboplatin in patients with advanced NSCLC.

OBJECTIVES:

Primary Objectives:

- To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of
imetelstat administered as a 2-hour intravenous infusion, weekly X 2, every 21 days, to
children with refractory or recurrent solid tumors.

- To define and describe the toxicities of imetelstat administered on this schedule.

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

Secondary Objectives:

- To preliminarily define antitumor effects of imetelstat and to assess the biological
activity by assessing telomerase activity, telomere length, hTERT protein, hTERT mRNA and
hTR levels in patient PBMNC samples pretreatment and while on treatment, and assess
telomerase activity, hTERT expression and hTERT protein, telomere length, hTERT mRNA and hTR
levels in patient's pretreatment tumor samples.

ELIGIBILITY:

- Patients > 12 months and less than or equal to 21 years of age with recurrent or
refractory solid tumors, including lymphomas, without CNS tumors or known CNS metastases,
and with adequate hematologic, hepatic, renal and cardiac status. Must meet safety
laboratory testing levels.

DESIGN:

- In this phase I study, the maximum tolerated dose of imetelstat will be determined
using a rolling 6 design where a minimum of 2 evaluable patients will be entered at
each of 4 dose levels, where imetelstat is administered intravenously over two hours on
Day 1 and 8 of a 21-day cycle in children with recurrent or refractory solid tumors,
for up to 17 cycles, up to a total duration of therapy of 18 cycles (approximately 12
months).

- Premedication with acetaminophen and diphenhydramine will be administered prior to each
dose; anaphylactic precautions should be adhered to, and steroids may be used for
symptom control or as premedication after the first dose. Doses subsequent to the first
dose may be delayed or withheld for toxicity.

This study will include a required pharmacokinetic component, and one optional PK draw at 48
hours after the first dose (Day 1, Cycle 1). Patients will be asked to participate in
optional blood and tissue correlative biology studies. Radiology studies will undergo
central radiology review.

- Once MTD has been defined, up to 12 additional patients with relapsed/refractory solid
tumors, including

CNS tumors and lymphomas, may be enrolled to acquire additional PK data at the recommended
phase 2 dose, attempting to enroll at least 6 patients < 12 years of age. With a maximum
number of patients of

45, this study is anticipated to be completed within 22 to 25 months. Up to 5 patients will
be enrolled at NCI.

- INCLUSION CRITERIA:

- Age: Patients must be > than 12 months and less than or equal to 21 years of age at
the time of study enrollment.

- Diagnosis: Patients with refractory or recurrent solid tumors, including lymphomas,
without CNS tumors or known CNS metastases are eligible for the initial dose
escalation phase (Part A). Once the MTD or recommended phase 2 dose has been defined,
patients with CNS tumors or known CNS metastases may enroll in the expanded cohort
(Part B). All patients must have had histologic verification of malignancy at
original diagnosis or relapse except patients with intrinsic brain stem tumors, optic
pathway gliomas, or patients with pineal tumors and elevations of CSF or serum tumor
markers including alphafetoprotein or beta-HCG.

- Disease Status: Patients must have either measurable or evaluable disease

- Therapeutic Options: Patient's current disease state must be one for which there is
no known curative therapy or therapy proven to prolong survival with anacceptable
quality of life.

- Performance Level: Karnofsky greater than or equal to 50% for patients > 16 years of
age and Lansky greater than or equal to 50 for patients less than 16 years of age.
Note: Neurologic deficits in patients with CNS tumors must have been relatively
stable for a minimum of 1 week 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.

Prior Therapy

- Patients must have fully recovered from the acute toxic effects of all prior anti-cancer
chemotherapy, immunotherapy, or radiotherapy.

1. Myelosuppressive chemotherapy: Must not have received

myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks
if prior nitrosourea).

2. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting
growth factor (e.g. Neulasta) 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.

3. Biologic (anti-neoplastic agent): At least 7 days after the last dose of 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.

4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy,
e.g. tumor vaccines.

5. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a
monoclonal antibody.

6. XRT: greater than or equal to 2 weeks for local palliative XRT (small port); :
greater than or equal to 24 weeks must have elapsed if prior TBI, craniospinal XRT or
if : greater than or equal to 50% radiation of pelvis; greater than or equal to 6
weeks must have elapsed if other substantial BM radiation.

7. Stem Cell Infusion without TBI: No evidence of active graft vs. host disease and :
greater than or equal to 12 weeks must have elapsed since transplant or stem cell
infusion. Patients with prior allogeneic transplants are not eligible.

Organ Function Requirements

- Adequate Bone Marrow Function Defined as:

1. For patients with solid tumors without known bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) : greater than or equal to 1000/mm(3)

- Platelet count : greater than or equal to 100,000/mm(3) (transfusion
independent, defined as not receiving platelet transfusions within a 7 day
period priorto enrollment)

2. Patients with known bone marrow metastatic disease will be eligible for study
provided they meet the blood counts in

-.a (may receive transfusions provided they are not known to be refractory to red
cell or platelet transfusions). These patients will not be evaluable for hematologic
toxicity. At least 5 of every cohort of 6 patients with a solid tumor must be
evaluable for hematologic toxicity. If dose-limiting hematologic toxicity is
observed, all subsequent patients enrolled must be evaluable for hematologic
toxicity.

- Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73
m(2) or

- A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL)

Male Female

1 to < 2 years 0.6 0.6

2 to < 6 years 0.8 0.8

6 to < 10 years 1 1

10 to < 13 years 1.2 1.2

13 to < 16 years 1.5 1.4

greater than or equal to 16 years1.7 1.4

- Adequate Liver Function Defined as:

- Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 x upper
limit of normal (ULN) for age

- SGPT (ALT) less than or equal to 110 U/L. For the purpose of this study, the ULN
for

SGPT is 45 U/L.

- Serum albumin greater than or equal to 2 g/dL

Adequate Coagulation Defined as:

- aPTT < 1.2 x ULN

Informed Consent: 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.

EXCLUSION CRITERIA:

- Pregnancy or Breast-Feeding

Pregnant or breast-feeding women will not be entered on this study, because there is
yet no available information regarding human fetal or teratogenic toxicities.
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.

Concomitant Medications

- Corticosteroids: Patients receiving corticosteroids who have not been on a stable
or decreasing dose of corticosteroid for the prior 7 days are not eligible.

- Investigational Drugs: Patients who are currently receiving another investigational
drug are not eligible.

- Anti-cancer Agents: Patients who are currently receiving other anticancer agents
are not eligible.

- Anti-GVHD or agents to prevent organ rejection post-transplant:

Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection post
transplant are not eligible for this trial.

- Infection: Patients who have an uncontrolled infection are not eligible.

- Prior or current CNS bleed (Part B): Patients with CNS tumors or known CNS
metastases who have imaging evidence of a prior or current CNS hemorrhage on the
baseline MRI obtained within 14 days prior to study enrollment are not eligible.
Note: The presence of small punctate areas consistent with hemorrhage on ECHO
gradient MRI sequences will not exclude patients from participation.

- Patients with prior allogeneic transplants 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.