ABT-888 and Temozolomide in Treating Young Patients With Recurrent or Refractory CNS Tumors

Conditions:Brain Cancer
Therapuetic Areas:Oncology
Age Range:Any
Start Date:July 2009

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A Phase I Study of ABT-888, an Oral Inhibitor of Poly (ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors

RATIONALE: ABT-888 may stop the growth of tumor cells by blocking some of the enzymes needed
for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to
stop the growth of tumor cells, either by killing the cells or by stopping them from
dividing. Giving ABT-888 together with temozolomide may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of ABT-888 when given
in combination with temozolomide in treating young patients with recurrent or refractory CNS



- To estimate the maximum tolerated dose of ABT-888 in combination with temozolomide in
pediatric patients with recurrent or refractory CNS tumors.

- To study the pharmacokinetics of ABT-888 in order to recommend a phase II dose of
ABT-888 in combination with temozolomide in pediatric patients with recurrent or
refractory CNS tumors.

- To describe the toxicities of the combination of ABT-888 and temozolomide in pediatric
patients with recurrent or refractory CNS tumors.


- To measure non-homologous end-joining activity in peripheral blood mononuclear cells
before and after ABT-888 administration.

- To assess PARP expression and/or activity in tumor tissue obtained at either initial
diagnosis or relapse.

- To determine expression and/or activity of DNA repair pathways, including MGMT and
mismatch repair, in tumor tissues, when available.

- To document, within the confines of this phase I trial, radiographic tumor response to
ABT-888 and temozolomide.

OUTLINE: This is a dose-escalation study of ABT-888.

Patients receive oral ABT-888 twice daily and oral temozolomide once daily on days 1-5.
Treatment repeats every 28 days for 13-26 courses in the absence of disease progression or
unacceptable toxicity.

Blood samples are collected for pharmacokinetics and further laboratory analysis.


- Diagnosis of primary CNS malignancy (including low-grade glioma) that is recurrent or
refractory to standard therapy and for which there is no known curative therapy

- Histological verification of malignancy at initial diagnosis or relapse required

- Histological verification waived for brain stem or optic pathway gliomas
provided there is clinical and/or radiographic evidence of disease

- Histological verification waived for CNS germ cell tumors provided there
are elevated reliable serum or CSF tumor markers (alpha-fetoprotein or


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

- Hemoglobin > 8 g/dL (transfusion independent)

- Platelet count > 100,000/mm³ (transfusion independent)

- Absolute neutrophil count > 1,500/mm³

- Total bilirubin (conjugated + unconjugated) ≤ 1.5 times upper limit of normal (ULN)
for age

- SGPT ≤ 2.5 times ULN for age

- Serum albumin ≥ 2 g/dL

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum
creatinine based on age as follows:

- 0.8 mg/dL in patients < 5 years of age

- 1 mg/dL in patients 5 to 9 years of age

- 1.2 mg/dL in patients 10 to 14 years of age

- 1.5 mg/dL in patients ≥ 15 years of age

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to take oral medications (either capsules or liquid)

- Able to return for follow-up visits or obtain follow-up studies required to assess
toxicity to treatment

- Neurologic deficits allowed provided they have been stable for ≥ 1 week prior to
study entry

- No uncontrolled seizures

- None of the following:

- Inadequately controlled systemic hypertension (systolic BP and/or diastolic BP >
95th percentile for age and height*)

- History of hypertensive crisis and/or hypertensive encephalopathy

- NOTE: *If a BP measurement before registration is > 95th percentile for age and
height, it must be rechecked and documented to be < 95th percentile for age and
height before registration. If a patient falls between the height or weight
percentiles, the values should be averaged as appropriate. For patients ≥ 18 years of
age the BP should be < 140/90 mm Hg. Patients with hypertension are eligible provided
that their BP is < 95th percentile for age and height after antihypertensive

- No documented CNS ischemia and/or infarction, whether symptomatic or discovered
incidentally without clinical symptoms

- No clinically significant, unrelated systemic illness (e.g., serious infection or
significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would
compromise the patient's ability to tolerate study therapy or would likely interfere
with the study procedures or results


- Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

- At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for
nitrosoureas, including Gliadel wafer)

- At least 7 days since prior anticancer biologic agents

- At least 4 weeks since prior monoclonal antibody therapy

- More than 3 months since prior craniospinal irradiation, total-body irradiation, or
local irradiation to the primary tumor or other sites (cumulative dose ≥ 40 Gy)

- More than 4 weeks since prior palliative irradiation to symptomatic metastatic sites

- At least 6 months since prior allogeneic stem cell transplantation

- At least 3 months since prior autologous stem cell transplantation

- At least 1 week since prior colony-forming growth factor(s) that support platelet or
white blood cell count, number, or function (filgrastim [G-CSF], sargramostim
[GM-CSF], or erythropoietin)

- At least 14 days since prior pegylated G-CSF and/or erythropoiesis-stimulating

- Prior temozolomide allowed

- Concurrent dexamethasone allowed provided patient has been on a stable or decreasing
dose for ≥ 1 week prior to study registration

- No other concurrent anticancer therapy or investigational agents
We found this trial at
2515 N Clark St
Chicago, Illinois 60614
(312) 227-6060
Children's Memorial Hospital, Chicago Ann & Robert H. Lurie Children
Chicago, IL
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(901) 495-3300
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Bethesda, MD
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2301 Erwin Rd
Durham, North Carolina 27710
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