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Temozolomide

Poly(ADP-ribose) Polymerase Inhibitors

Veliparib

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Alkylating Agents

Enzyme Inhibitors

ABT-888

Katherine E Warren, M.D.

Background:

- An experimental drug called ABT-888 has been studied in combination with temozolomide (a type of chemotherapy) in adults who have certain kinds of cancer. ABT-88 has been shown to increase tumor sensitivity to temozolomide and improve treatment outcomes in people who have cancer. More research is needed to determine if this combination of drugs will work well as an effective treatment for children who have brain tumors. This will be the first time this combination has been studied in pediatric patients.

Objectives:

* To determine the maximum doses of ABT-888 and temozolomide when given in combination in children with brain tumors.
* To learn how children metabolize and clear ABT-888 from their bodies so that appropriate doses of this medication can be recommended for future clinical trials of this drug.
* To learn what side effects may occur when ABT-888 and temozolomide are given together.
* To learn how certain tumors respond to this combination of drugs by studying the characteristics of these tumors in a laboratory.

Eligibility:

- Individuals less than 21 years of age who have been diagnosed with a cancer of the nervous system (including brain and brain stem tumors) that has not responded to standard therapy.

Design:

* Before beginning the study, participants will have a full medical history and physical examination, and may also be required to have scans of the brain and spine or provide samples of cerebrospinal fluid.
* Treatment will consist of up to 13 28-day cycles of therapy, for a total of 52 weeks (1 year). Participants will receive a dose of ABT-888 twice daily for 5 days, and will receive a dose of temozolomide once daily for 5 days, every 28 days. The morning dose of ABT-888 will be given 60-90 minutes before the dose of temozolomide.
* Participants will have routine blood tests at least once a week throughout the treatment cycles, and will have scans of the brain and spine performed as required by the researchers.

Background

* A subset of patients with pediatric CNS tumors continue to have a poor prognosis despite advances in surgery and radiation. Novel strategies are required for improving outcome for these patients.
* Temozolomide, an oral alkylating agent, has shown modest activity in recurrent pediatric CNS tumors, including high-grade gliomas, medulloblastoma/PNET, and low-grade gliomas.
* Temozolomide induces single-stranded DNA breaks, the majority of which are repaired by the base excision repair (BER) pathway. Poly(ADP-ribose) polymerase, or PARP, is a critical nuclear enzyme that binds to DNA breaks, recruits and activates key proteins in the BER and other DNA repair pathways, halts DNA replication, and facilitates repair of damaged DNA.
* ABT-888 is a potent and orally bioavailable PARP inhibitor that has been shown to enhance cytotoxicity of temozolomide and other chemotherapy agents in several pre-clinical models of human tumors.

Objectives

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

Eligibility

* Patient must be less than or equal to 21 years of age at registration.
* 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 Progression and recurrence will be documented by review of MRI scans. If time permits we will have the diagnosis confirmed by the NCI Laboratory of Pathology. Patients with intrinsic brain stem tumors must have radiographic evidence of progression.
* Karnofsky Performance Scale (KPS for greater than 16 yrs of age) or Lansky Performance Score (LPS for less than or equal to 16 years of age) greater than or equal to 50 assessed within two weeks of study enrollment.
* Patients must have recovered from the toxic effects of all prior therapy.
* Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.

Design

-ABT-888 will be given twice daily on day 1-5, and temozolomide will be given once daily on day 1-5, every 28 days. The morning dose of ABT-888 will be given 60-90 minutes prior to temozolomide.

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

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

National Cancer Institute (NCI)

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Neoplasm Metastasis

Breast Neoplasms

Thyroid Neoplasms

Thyroid Diseases

Sarcoma

Wilms Tumor

Thyroid Cancer, Papillary

Neuroblastoma

Fibrosarcoma

Nephroma, Mesoblastic

Nervous System Neoplasms

Soft Tissue Sarcoma

Wilms' Tumor

Papillary Thyroid Carcinoma

Ewing Sarcoma

Congenital Mesoblastic Nephroma

Amino Acids

Entrectinib

Protein Kinase Inhibitors

Tyrosine

Arm closed for further enrollment

ROS1, ALK non-gene fusion molecular alterations

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

molecular alterations, including gene fusions

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

harboring - NTRK1/2/3, ROS1, ALK gene fusions

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

Any participant who otherwise meet all other eligibility criteria

Oral entrectinib (RXDX-101)

gene fusions

Oral entrectinib (RXDX-101)

NTRK 1,2,3 and ROS1 fusions

Oral entrectinib (RXDX-101)

Clinical Trials

This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)

AE, ECG and Labs assessed by NCI CTCAE v4.03

Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Assessed by RECIST v1.1 per the BICR and investigator

Assessed by RANO per the BICR and investigator

Assessed by the Curie scale per the BICR and investigator

Assessed by RECIST v1.1 per the investigator

Hoffmann-La Roche

Vismodegib will be dosed at 150mg-300mg orally (max dose: 300mg) once a day on days 1 to 28 of a 28-day cycle. In the absence of unacceptable toxicity or disease progression, treatment may continue for as long as tolerated.

Vismodegib

Giselle Sholler, MD

Albert Cornelius, MD

The purpose of this research study is to evaluate an investigational drug (Vismodegib) for Pontine Glioma that is growing or has come back (reoccurred). This study will look at the tumors response to the study drug, Vismodegib, and will also look at the safety and tolerability of Vismodegib.

Vismodegib has been tested in multiple adult clinical trials and one pediatric trial. Laboratory testing in pontine gliomas suggests that this drug may be effective in treating this disease.

Erivedge (Vismodegib) in the Treatment of Pediatric Patients With Refractory Pontine Glioma

A Phase II, Open-label, Multi-center Study of Erivedge (Vismodegib) in the Treatment of Pediatric Patients With Refractory Pontine Glioma.

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.

To determine the safety and tolerability of Vismodegib as a single agent in pediatric and young adult patients with refractory or recurrent pontine glioma

Overall Survival (OS) and clinical benefit (ORR + stable disease, SD)

Evaluate the impact of Quality of Life of children receiving Vismodegib using PedsQL questionnaires

To determine the objective response rates (partial and complete response) for patients without and with evidence of activation of Hedgehog signaling pathway in their tumors

Phoenix Children's Hospital

Giselle Sholler

Beat Childhood Cancer Chair

Vismodegib will be dosed at 150mg-300mg orally (max dose: 300mg) once a day on days 1 to 28 of a 28-day cycle. In the absence of unacceptable toxicity or disease progression, treatment may continue for as long as tolerated.

Vismodegib

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Number of Days Participants Experienced Progression Free Survival (PFS)

Number of Participants With Adverse Events as a Measure of Safety and Tolerability

Not evaluated due to early closure. Study data does not exist.

Determine the Median Overall Survival (OS) of Participants

QOL's not collected due to early closure of study. Data not collected or analyzed threfore no data exists.

Evaluate the Impact of Quality of Life of Children Receiving Vismodegib Using PedsQL Questionnaires

No samples collected for hedgehog pathway. No data exists.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors	NCT00994071	Medulloblastoma Pontine Glioma Ependymoma Astrocytoma PNET	Temozolomide ABT-888	- 21 Years	National Institutes of Health Clinical Center (CC)
Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options	NCT02650401	Solid Tumors CNS Tumors	Entrectinib	0 Years - 18 Years	Hoffmann-La Roche
Erivedge (Vismodegib) in the Treatment of Pediatric Patients With Refractory Pontine Glioma	NCT01774253	Pontine Glioma	Vismodegib	3 Years - 18 Years	Milton S. Hershey Medical Center
A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors	NCT00994071	Medulloblastoma Pontine Glioma Ependymoma Astrocytoma PNET	Temozolomide ABT-888	- 21 Years	National Institutes of Health Clinical Center (CC)
Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options	NCT02650401	Solid Tumors CNS Tumors	Entrectinib	0 Years - 18 Years	Hoffmann-La Roche

Spots Global Cancer Trial Database for pontine glioma