Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma

NCT01122901 | Terminated Phase 2 Results DMC

• 4 other identifiers: NCI-2012-02931CDR0000672628ABTC-0906U01CA137443
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 5

Brief Summary

This phase II trial is studying how well gamma-secretase/Notch signalling pathway inhibitor RO4929097 works in treating patients with recurrent or progressive glioblastoma. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Outcome Measures

Primary Outcomes (2)

• Overall Median Progression-free Survival (6-month PFS)

  Time to event endpoints for Group A will be measured from the date of first dose. All patients who receive at least one dose of study drug will be included in the analysis. Time to event endpoints for Group B will be measured from the first post-surgical date (this will be considered start date of treatment). Progression defined as: \>25% increase sum of products of perpendicular diameters (bi-dimensional measurements) of enhancing lesions (over baseline (BL) if no decrease) on stable or increasing doses of corticosteroids. and/or b) Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared to BL scan or best response following initiation of therapy c) Any new lesion. d) Clear clinical deterioration not attributable to other causes apart from the tumor e) Failure to return for evaluation due to death or deteriorating condition.

  At 6 months

• Efficiency of Neurosphere Generation After Pretreatment With RO4929097 (Group B)

  This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug. All CTEP-sponsored trials using RO4929097 were closed to accrual and all patients had to be off treatment by 7/31/12.

  At time of surgery

Secondary Outcomes (6)

• Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)

  Up to 6 months after completion of treatment

• Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)

  Up to 30 days after completion of study treatment

• Overall Survival

  2 years

• Expression Levels of Notch Pathway Components and Downstream (Group B)

  At the time of surgery

• Tumor Propagation (Group B)

  At the time of surgery

Study Arms (2)

Group A (gamma-secretase inhibitor RO4929097)

EXPERIMENTAL

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other: pharmacological study

Group B (gamma-secretase inhibitor RO4929097, surgery)

EXPERIMENTAL

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Procedure: therapeutic conventional surgery; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

gamma-secretase/Notch signalling pathway inhibitor RO4929097 DRUG

Given PO

Also known as: R4733, RO4929097

Group A (gamma-secretase inhibitor RO4929097); Group B (gamma-secretase inhibitor RO4929097, surgery)

therapeutic conventional surgery PROCEDURE

Undergo surgery

Group B (gamma-secretase inhibitor RO4929097, surgery)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Group A (gamma-secretase inhibitor RO4929097); Group B (gamma-secretase inhibitor RO4929097, surgery)

laboratory biomarker analysis OTHER

Correlative studies

Group B (gamma-secretase inhibitor RO4929097, surgery)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically proven glioblastoma which is progressive or recurrent following radiation therapy +/- chemotherapy
• Patients must have measurable contrast-enhancing progressive or recurrent glioblastoma by magnetic resonance imaging (MRI) imaging within two weeks of starting treatment; patient must be able to tolerate MRIs
• GROUP B PATIENTS ONLY: Patients must be eligible for surgical resection according to the following criteria:
• Expectation that the surgeon can resect \>= 50% of the Gd-enhancing tumor with low risk of inducing neurological injury
• Absence of hematologic, cardiac or other medical contraindications to surgery
• Surgery must take place Monday-Thursday with the exception of patients being treated at Cleveland Clinic/University Hospitals: these patients may undergo surgery Monday-Friday
• Patients must have a tumor size \>= 2.5 cm in diameter in two perpendicular planes in order to enable correlative studies
• Paraffin embedded tissue must be available from initial surgical resection at diagnosis (prior to any treatment)
• Patients may have an unlimited number of prior therapy regimens but no prior gamma-secretase inhibitors
• Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
• months from the completion of radiation
• weeks from a nitrosourea chemotherapy
• weeks from a non-nitrosourea chemotherapy
• weeks from any investigational (not Food and Drug Administration \[FDA\]-approved) agents
• weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., small molecule targeted therapy, thalidomide, bevacizumab, etc.)

You may not qualify if:

• Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety, are ineligible
• Patients with prior treatment with gamma-secretase inhibitors are ineligible
• Patients may not be receiving any other investigational agents
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study are ineligible
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption are ineligible; patients must be able to swallow capsules
• Patients with the following cardiovascular abnormalities are ineligible: baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
• Patients with a requirement for antiarrhythmics or other medications known to prolong QTc are ineligible
• Patients with a history of being serologically positive for hepatitis B or C, or who have a history of cirrhosis are ineligible
• Patients with a history of uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, a history of torsades de pointes or other significant cardiac arrhythmias other than chronic stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
• Pregnant women or those who are breastfeeding are ineligible
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Patients who have not recovered to \< Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15232, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Limitations and Caveats

Study terminated prematurely by Company due to their decision to terminate drug supply for further development of this drug. All CTEP-sponsored trials using RO4929097 were closed to accrual and all patients had to be off treatment by 7/31/12.

Results Point of Contact

• Title: David Peereboom, MD
• Organization: Adult Brain Tumor Consortium

jfisher@jhmi.edu

410-955-8837

Study Officials

• David Peereboom

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2010
• First Posted: May 13, 2010
• Study Start: December 1, 2010
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: May 3, 2017
• Results First Posted: May 3, 2017

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)