Clinical trial NCT01514201: Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
Official title: A Phase I/II Study of ABT-888, An Oral Poly(ADP-ribose) Polymerase Inhibitor, and Concurrent Radiation Therapy, Followed by ABT-888 and Temozolomide, in Children With Newly Diagnosed Diffuse Pontine Gliomas (DIPG)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Anaplastic Astrocytoma
Brain Stem Glioma
Childhood Mixed Glioma
Fibrillary Astrocytoma
Giant Cell Glioblastoma
Glioblastoma
Gliosarcoma
Untreated Childhood Anaplastic Astrocytoma
Untreated Childhood Brain Stem Glioma
Untreated Childhood Fibrillary Astrocytoma
Untreated Childhood Giant Cell Glioblastoma
Untreated Childhood Glioblastoma
Untreated Childhood Gliosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2012-01-23
Enrollment: 66
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial studies the side effects and the best dose of veliparib when given together with radiation therapy and temozolomide and to see how well they work in treating younger patients newly diagnosed with diffuse pontine gliomas. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x rays to kill tumor cells. 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 veliparib with radiation therapy and temozolomide may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. To identify the maximum-tolerated dose or recommended Phase II dose of ABT-888 (veliparib) which can be safely administered concurrently with radiation therapy, followed by maintenance therapy with ABT-888 and temozolomide (TMZ), in patients with newly diagnosed diffuse pontine gliomas (DIPG). (Phase I) II. To study the plasma pharmacokinetics (PK) of ABT-888 during ABT-888 and radiation therapy. (Phase I) III. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase I) IV. To describe the toxicities associated with administering ABT-888 and radiation therapy, followed by ABT-888 and TMZ, in patients with newly diagnosed DIPG. (Phase I) V. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase I) VI. To estimate the overall survival distribution for newly diagnosed patients with DIPG treated with the combination of ABT-888 and radiation therapy, followed by ABT-888 and TMZ, and compare to Pediatric Brain Tumor Consortium (PBTC) historical controls. (Phase II) VII. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase II) VIII. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) distribution and to summarize the best tumor responses observed prior to progression or recurrence.

II. To explore the plasma PK of ABT-888 during ABT-888 and radiation therapy. III. To explore peripheral blood mononuclear cell (PBMC) poly (ADP-ribose) polymerase 1(PARP) activity before and after treatment with ABT-888.

IV. To explore quantifying non-homologous end-joining (NHEJ) activity or gamma-H2A histone family, member X (H2AX) levels (as surrogate markers of unrepaired double-strand breaks (DSBs)) in PBMC before and after treatment with ABT-888.

V. To explore quantifying PARP activity and deoxyribonucleic acid (DNA)-repair protein levels in biopsied atypical pontine gliomas, if available.

VI. To explore associations of molecular parameters from secondary aims III, IV, and V with PFS and overall survival (OS) after conclusion of clinical trial.

VII. To explore the quantitative magnetic resonance (MR) measures of relative cerebral blood volume (rCBV), vascular permeability (Ktrans, fractional plasma volume \[vp\], and extravascular extracellular space volume fraction \[ve\] values), and apparent diffusion coefficient (ADC) within the first six months of initiating protocol treatment to correlate with disease outcome and determine whether such metrics differentiate patients with pseudo progression from those with true early progressive disease.

VIII. To explore the potential utility of urine biomarkers as a novel, non-invasive method of detecting and tracking changes in the status of pediatric brain stem gliomas.

OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.

DOSE-ESCALATION: Patients receive veliparib orally (PO) twice daily (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) once daily (QD) 5 days a week for 6-7 weeks.

MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 3 years.

Eligibility criteria: Inclusion Criteria:

* Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are eligible without histologic confirmation; patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma, or fibrillary astrocytoma

  * Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible;
  * Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician
* Patient must be able to swallow oral medications to be eligible for study enrollment
* Karnofsky \>= 50% for patients \> 16 years of age or Lansky \>= 50% 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 performance score
* Patients must have not received any prior therapy other than surgery and/or steroids
* Absolute neutrophil count \>= 1,000/mm\^3
* Platelets \>= 100,000/mm\^3 (unsupported)
* Hemoglobin \>= 10 g/dL (unsupported)
* Total bilirubin =\< 1.5 times upper limit of normal (ULN) for age
* Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =\< 5 x institutional upper limit of normal for age
* Albumin \>= 2 g/dL
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/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)
* Female patients of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test
* Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
* Signed informed consent according to institutional guidelines must be obtained; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

* 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 inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
* Patients with active seizures or a history of seizure are not eligible for study entry, with the exception of patients with documented febrile seizure

Primary outcomes:
measure: Maximum-tolerated Dose of Veliparib Defined as Highest Dose Level With Fewer Than 2 Dose Limiting Toxicities in 6 Patients as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phase I)
timeFrame: 10 weeks
measure: Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population)
timeFrame: 28 days per treatment cycle
measure: Overall Survival
timeFrame: Time from initiation of therapy to the date of death from any cause or to the date patient was known to be alive for surviving patients, assessed to up to 3 years
measure: Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs)
timeFrame: 10 weeks
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy), assessed up to 3 years
measure: Percentage of Patients With Pseudo Progression
timeFrame: Up to 6 months
measure: Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter]
timeFrame: Up to day 4
measure: Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter]
timeFrame: Up to day 4
measure: Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter]
timeFrame: Day 1
measure: Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter]
timeFrame: Up to day 4
measure: Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter]
timeFrame: Up to day 4
measure: Trough for Veliparib [Pharmacokinetic Parameter]
timeFrame: Up to day 4
Other outcomes:
measure: Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs)
timeFrame: Baseline and up to 11 weeks
measure: Change in Non-homologous End-joining (NHEJ) Activity as Measured in Peripheral Blood Monocytes (PBMCs)
timeFrame: Baseline to up to 3 years
measure: Change in Level of Gamma-H2A Histone Family, Member X (H2AX) Measured in PBMCs
timeFrame: Baseline to up to 3 years
measure: Levels of Urinary Biomarkers
timeFrame: Baseline to up to 3 years
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Pediatric Brain Tumor Consortium
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: Patricia Baxter
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sesen J, Driscoll J, Shah N, Moses-Gardner A, Luiselli G, Alexandrescu S, Zurakowski D, Baxter PA, Su JM, Pricola Fehnel K, Smith ER. Neogenin is highly expressed in diffuse intrinsic pontine glioma and influences tumor invasion. Brain Res. 2021 Jul 1;1762:147348. doi: 10.1016/j.brainres.2021.147348. Epub 2021 Feb 9. No abstract available.
citation: Baxter PA, Su JM, Onar-Thomas A, Billups CA, Li XN, Poussaint TY, Smith ER, Thompson P, Adesina A, Ansell P, Giranda V, Paulino A, Kilburn L, Quaddoumi I, Broniscer A, Blaney SM, Dunkel IJ, Fouladi M. A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2020 Jun 9;22(6):875-885. doi: 10.1093/neuonc/noaa016.