Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

NCT01514201 | Completed Phase 1 Results

• 7 other identifiers: NCI-2012-00082PBTC-03312-C-0213CDR0000717423P12978U01CA081457UM1CA081457
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 12

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.

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

Outcome Measures

Primary Outcomes (4)

• 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)

  The traditional 3+3 dose finding algorithm was used to estimate the maximum-tolerated dose of veliparib given concurrently with radiation therapy. The dose-limiting toxicity observation period was the first 10 weeks of therapy. Dose-limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with a few exceptions (see section 5.2.1.2 of the protocol document), any grade 2 non-hematologic toxicity that persisted for \>7 days and considered medically significant that required treatment interruption; grade 3 or higher thrombocytopenia or grade 4 neutropenia; and any Veliparib related adverse event that led to a dose reduction or the permanent cessation of therapy.

  10 weeks

• Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population)

  Unacceptable toxicities during maintenance included events at least possibly attributable to Veliparib and temozolomide (TMZ) such as any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., grade 3 nausea/vomiting \<5 days, grade 3 fever or infection \<5 days), grade 3+ thrombocytopenia, grade 4 neutropenia, delay \>14 days in starting subsequent cycle due to neutrophil \<1,000/mm3 or platelet \<100,000/mm3. Maintenance therapy was initiated with 25 mg/m2 Veliparib and 135 mg/m2 of TMZ, with the possibility to escalate TMZ to 175 mg/m2 and 200 mg/m2 in courses 2 and 3, respectively, if no unacceptable toxicities occurred following one course of treatment at each of the dose levels to be tested. Intra-patient dose escalation to a given dose (135, 175, or 200 mg/m2) was halted based on rules employed in 3+3 designs. This dose escalation was intended for all patients but was halted early, during the phase I portion, as it was not well tolerated.

  28 days per treatment cycle

• Overall Survival

  Overall survival was defined as the interval from date on treatment to date of death from any cause or to date of last follow-up. Patients who had not failed (died) at the time of analyses were censored at their last date of contact. The method of Kaplan and Meier was used to estimate overall survival. The 3-year estimate with a 95% confidence interval is reported.

  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

• Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs)

  DLTs were defined as any of the following adverse events that were at least possibly attributable to Veliparib observed during the dose finding phase (the first 10 weeks of therapy). Hematologic dose limiting toxicities included grade 3 and higher thrombocytopenia or grade 4 neutropenia. Non-hematologic dose limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of \<5 days; fever or infection of \<5 days; hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral supplementation; elevation of transaminases that return to levels meeting eligibility criteria within 7 days), or any grade non-hematologic toxicity that persisted for \>7 days and considered medically significant or sufficiently intolerable by patients that required treatment interruption.

  10 weeks

Secondary Outcomes (8)

• Progression-free Survival (PFS)

  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

• Percentage of Patients With Pseudo Progression

  Up to 6 months

• Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter]

  Up to day 4

• Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter]

  Up to day 4

• Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter]

  Day 1

Other Outcomes (4)

• Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs)

  Baseline and up to 11 weeks

• Change in Non-homologous End-joining (NHEJ) Activity as Measured in Peripheral Blood Monocytes (PBMCs)

  Baseline to up to 3 years

• Change in Level of Gamma-H2A Histone Family, Member X (H2AX) Measured in PBMCs

  Baseline to up to 3 years

Study Arms (1)

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

EXPERIMENTAL

DOSE-ESCALATION: Patients receive veliparib PO BID 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D-CRT or IMRT 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.

Radiation: 3-Dimensional Conformal Radiation Therapy; Radiation: Intensity-Modulated Radiation Therapy; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Drug: Veliparib

Interventions

3-Dimensional Conformal Radiation Therapy RADIATION

Undergo 3D-CRT

Also known as: 3-dimensional radiation therapy, 3D CONFORMAL RADIATION THERAPY, 3D CRT, 3D-CRT, Conformal Therapy, Radiation Conformal Therapy

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Intensity-Modulated Radiation Therapy RADIATION

Undergo IMRT

Also known as: IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Laboratory Biomarker Analysis OTHER

Optional correlative studies

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Pharmacological Study OTHER

Correlative studies

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Veliparib DRUG

Given PO

Also known as: ABT-888, PARP-1 inhibitor ABT-888

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• mg/dL (1 to \< 2 years of age)
• mg/dL (2 to \< 6 years of age)

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Pediatric Brain Tumor Consortium

Memphis, Tennessee, 38105, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Publications (2)

• 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.

  PMID: 33571520 DERIVED

• 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.

  PMID: 32009149 DERIVED

MeSH Terms

Conditions

Astrocytoma; Glioblastoma; Gliosarcoma

Interventions

Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Temozolomide; veliparib

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Catherine Billups
• Organization: St. Jude Children's Research Hospital

catherine.billups@stjude.org

901-595-3709

Study Officials

• Patricia Baxter

  Pediatric Brain Tumor Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2012
• First Posted: January 23, 2012
• Study Start: February 1, 2012
• Primary Completion: March 28, 2018
• Study Completion: March 28, 2018
• Last Updated: August 13, 2019
• Results First Posted: August 13, 2019

Record last verified: 2019-07

Locations

US (12)