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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


Phase 1
N/A
21 Years
Open (Enrolling)
Both
Childhood Atypical Teratoid/Rhabdoid Tumor, Childhood Central Nervous System Germ Cell Tumor, Childhood Choroid Plexus Tumor, Childhood Craniopharyngioma, Childhood Ependymoblastoma, Childhood Grade I Meningioma, Childhood Grade II Meningioma, Childhood Grade III Meningioma, Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Infratentorial Ependymoma, Childhood Low-grade Cerebellar Astrocytoma, Childhood Low-grade Cerebral Astrocytoma, Childhood Medulloepithelioma, Childhood Mixed Glioma, Childhood Oligodendroglioma, Childhood Supratentorial Ependymoma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Brain Tumor, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Pineoblastoma, Recurrent Childhood Spinal Cord Neoplasm, Recurrent Childhood Subependymal Giant Cell Astrocytoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor, Recurrent Childhood Visual Pathway and Hypothalamic Glioma

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Trial Information

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


PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of ABT-888 in combination with temozolomide
in children with recurrent or refractory CNS tumors.

II. To study the plasma pharmacokinetics (PK) of ABT-888 and PARP inhibition in peripheral
blood mononuclear cells (PBMC) in order to recommend a Phase 2 dose of ABT-888 in
combination with temozolomide in children with recurrent or refractory CNS tumors.

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

SECONDARY OBJECTIVES:

I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear
cells (PBMC) prior to and following ABT-888 administration.

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

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

IV. To document, within the confines of this phase 1 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.


Inclusion Criteria:



- Patients with a diagnosis of a primary CNS malignancy (including low-grade glioma)
that is recurrent or refractory to standard therapy and for which there is no known
curative therapy; all patients must have had histological verification of malignancy
at initial diagnosis or relapse, excluding patients with diffuse intrinsic brain stem
tumors, optic pathway tumors or CNS germ cell tumors with elevations of reliable
serum or CSF tumor markers (alpha-fetoprotein or beta-HCG); patients with intrinsic
pontine gliomas or optic pathway tumors do not require histological confirmation of
disease but should have clinical and/or radiographic evidence of progression

- Patients must have Karnofsky Performance Score (for patients > 16 years of age) or
Lansky Performance Score (for patients =< 16 years of age) >= 50% assessed within two
weeks of study enrollment

- Patients must be able to take oral medications (either capsules or liquid); patients
with neurologic deficits must have been stable for a minimum of 1 week prior to study
entry; 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

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study; recovery
is defined as all AE‟s, attributable to prior therapy, having improved to grade 2 or
better or as outlined below

- Myelosuppressive chemotherapy:

- Patients must have received their last dose of known myelosuppressive anticancer
chemotherapy at least three (3) weeks prior to study registration

- Patients must have received their last dose of nitrosourea (including Gliadel)
at least six (6) weeks prior to study registration

- Biologic agent (anti-neoplastic): Patient must have received their last dose of other
biologic agent ≥ 7 days prior to study registration

- 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

- Monoclonal antibody treatment: Patient must have received their last dose of
monoclonal antibody ≥ 4 weeks prior to registration

- Radiation - Patients who have had prior radiation must have had their last fraction
of:

- Craniospinal irradiation or total body irradiation > 3 months prior to
registration

- Local irradiation to the primary tumors or other sites (cumulative dose ≥ 40Gy)
> 3 months prior to registration

- Palliative irradiation delivered to symptomatic metastatic sites > 4 weeks prior
to registration

- Stem Cell Transplant: Patient must be:

- ≥ 6 months since allogeneic stem cell transplant prior to registration

- ≥ 3 months since autologous stem cell transplant prior to registration

- Corticosteroids: Patients who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to registration

- Growth factors:

- Off all colony forming growth factor(s) that support platelet or white blood
cell count, number or function for at least 1 week prior to registration
(filgrastim, sargramostim, erythropoietin)

- Off Pegylated G-CSF and/or Erythropoiesis Stimulating Protein for at least 14
days prior to registration

- Temozolomide: Patients who have received temozolomide previously are eligible for
this study if they meet all other inclusion and exclusion criteria

- Organ Function: Documented within 14 days of registration and within 7 days of
starting treatment

- Hgb > 8 gm/dL (transfusion independent)

- Platelet count > 100,000/mm^3 (transfusion independent)

- Absolute neutrophil count (ANC) > 1, 500/mm^3

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

- SGPT (ALT) ≤ 2.5 times institutional ULN for age

- Serum albumin ≥ 2 g/dL

- Creatinine clearance or radioisotope GFR ≥ 70 ml/min/1.73m^2 or a serum creatinine
based on age as follows:

- ≤ 5 years - 0.8 mg/dL maximum serum creatinine

- > 5 to ≤ 10 years - 1 mg/dL maximum serum creatinine

- > 10 to ≤ 15 years - 1.2 mg/dL maximum serum creatinine

- > 15 years - 1.5 maximum serum creatinine

- Patients must not be pregnant or breast-feeding; females of reproductive potential
must have a negative serum or urine pregnancy test (within 72 hours prior to
enrollment); males or females of reproductive potential may not participate unless
they have agreed to use an effective contraceptive method, which includes abstinence

- Signed informed consent which includes consent to participate in the REQUIRED
pharmacokinetic and pharmacodynamic studies prior to registration

Exclusion Criteria:

- Patients receiving any of the following medications are not eligible for study entry:

- Anti-cancer therapy

- Investigational agents

- Patients with any clinically significant, unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
that would compromise the patient's ability to tolerate protocol therapy or would
likely interfere with the study procedures or results

- Patients with uncontrolled seizures are not eligible for study entry

- Patients with inadequately controlled systemic hypertension (SBP and/or DBP > 95th
percentile for age and height

- Patients with a prior history of hypertensive crisis and/or hypertensive
encephalopathy

- If a BP measurement prior to registration is > 95th percentile for age and height, it
must be rechecked and documented to be < 95th percentile for age and height prior to
registration; if a patient falls between the height or weight percentiles, site
should average the value as appropriate; for patients ≥ 18 years the normal blood
pressure should be < 140/90 mm of Hg; patients with hypertension are eligible if
their blood pressures become < 95th percentile for age and height after
anti-hypertensive medications

- Patients with documented CNS ischemia and/or infarction, whether symptomatic or
discovered incidentally without clinical symptoms, will be excluded from study
participation

- Patients with an inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD or recommended phase II dose of veliparib

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Jack Su

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03177

NCT ID:

NCT00946335

Start Date:

July 2009

Completion Date:

Related Keywords:

  • Childhood Atypical Teratoid/Rhabdoid Tumor
  • Childhood Central Nervous System Germ Cell Tumor
  • Childhood Choroid Plexus Tumor
  • Childhood Craniopharyngioma
  • Childhood Ependymoblastoma
  • Childhood Grade I Meningioma
  • Childhood Grade II Meningioma
  • Childhood Grade III Meningioma
  • Childhood High-grade Cerebellar Astrocytoma
  • Childhood High-grade Cerebral Astrocytoma
  • Childhood Infratentorial Ependymoma
  • Childhood Low-grade Cerebellar Astrocytoma
  • Childhood Low-grade Cerebral Astrocytoma
  • Childhood Medulloepithelioma
  • Childhood Mixed Glioma
  • Childhood Oligodendroglioma
  • Childhood Supratentorial Ependymoma
  • Recurrent Childhood Brain Stem Glioma
  • Recurrent Childhood Brain Tumor
  • Recurrent Childhood Cerebellar Astrocytoma
  • Recurrent Childhood Cerebral Astrocytoma
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Pineoblastoma
  • Recurrent Childhood Spinal Cord Neoplasm
  • Recurrent Childhood Subependymal Giant Cell Astrocytoma
  • Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Recurrent Childhood Visual Pathway and Hypothalamic Glioma
  • Astrocytoma
  • Brain Neoplasms
  • Neoplasms
  • Craniopharyngioma
  • Adamantinoma
  • Ependymoma
  • Glioma
  • Medulloblastoma
  • Meningioma
  • Oligodendroglioma
  • Spinal Cord Neoplasms
  • Central Nervous System Neoplasms
  • Choroid Plexus Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Pinealoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Rhabdoid Tumor
  • Optic Nerve Glioma

Name

Location

Pediatric Brain Tumor ConsortiumMemphis, Tennessee  38105