RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

NCT01189240 | Terminated Phase 1 Results DMC

• 4 other identifiers: NCI-2011-02509CDR0000683099ABTC-1002U01CA137443
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I/II trial is studying the side effects and the best dose of RO4929097 to see how well it works when given together with bevacizumab compared to bevacizumab alone in treating patients with progressive or recurrent malignant glioma. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving RO4929097 together with bevacizumab may kill more tumor cells.

Conditions

Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Outcome Measures

Primary Outcomes (1)

• Maximum-tolerated Dose and the Recommended Phase II Dose of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab Determined by Dose-limiting Toxicity Rate (Phase I)

  Pts were treated at escalating dose levels of RO4929097 (Dose levels: 5, 10 or 20 mg) for an observed evaluation at the end of a 4week period. 3 pts treated at each cohort if less than or equal to 33% dose will be escalated. Pts must receive one dose of treatment to be evaluated for toxicity. A standard 3+3 dose escalation method will be used

  28 days

Secondary Outcomes (5)

• Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab

  28 days - 1 cycle

• Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1

  24 hrs

• Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15

  24hr

• Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1

  24hrs

• Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15

  24hr

Study Arms (7)

Phase I Dose Finding

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study

Phase II Stage I

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.Other: laboratory biomarker analysis: correlative studies. Phase 2 - not implemented due to drug supply from company

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis

Phase II Stage II Arm 1

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: laboratory biomarker analysis: correlative studies. Phase 2 - not implemented due to drug supply from company

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis

Phase II Stage II Arm 2

ACTIVE COMPARATOR

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15. Other: laboratory biomarker analysis: correlative studies. Phase 2 - not implemented due to drug supply from company

Biological: bevacizumab; Other: laboratory biomarker analysis

Phase I Dose Finding - Level 1 5mg

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 5mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study

Phase I Dose Finding - Level 2 10mg

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 10mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study

Phase I Dose Finding - Level 3 20mg

EXPERIMENTAL

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 20mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study

Interventions

gamma-secretase/Notch signalling pathway inhibitor RO4929097 DRUG

Given orally

Also known as: R4733, RO4929097

Phase I Dose Finding; Phase I Dose Finding - Level 1 5mg; Phase I Dose Finding - Level 2 10mg; Phase I Dose Finding - Level 3 20mg; Phase II Stage I; Phase II Stage II Arm 1

bevacizumab BIOLOGICAL

Given IV

Also known as: anti-VEGF humanized monoclonal antibody, anti-VEGF monoclonal antibody, Avastin, rhuMAb VEGF

Phase I Dose Finding; Phase I Dose Finding - Level 1 5mg; Phase I Dose Finding - Level 2 10mg; Phase I Dose Finding - Level 3 20mg; Phase II Stage I; Phase II Stage II Arm 1; Phase II Stage II Arm 2

laboratory biomarker analysis OTHER

Correlative studies

Phase I Dose Finding; Phase I Dose Finding - Level 1 5mg; Phase I Dose Finding - Level 2 10mg; Phase I Dose Finding - Level 3 20mg; Phase II Stage I; Phase II Stage II Arm 1; Phase II Stage II Arm 2

pharmacological study OTHER

Correlative studies

Phase I Dose Finding; Phase I Dose Finding - Level 1 5mg; Phase I Dose Finding - Level 2 10mg; Phase I Dose Finding - Level 3 20mg

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed malignant glioma (phase I)
• Glioblastoma
• Anaplastic astrocytoma
• Anaplastic oligodendroglioma
• Mixed anaplastic oligoastrocytoma
• Histologically confirmed glioblastoma following radiotherapy and temozolomide (phase II)
• Progressive or recurrent disease after conformal external-beam radiation therapy and concurrent temozolomide, followed by ≥ 1 adjuvant course of temozolomide
• Measurable disease by MRI within the past 2 weeks
• Tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of malignant glioma completed and signed by a pathologist
• Karnofsky performance status 60-100%
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Total bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal

You may not qualify if:

• No serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive the treatment outline in this protocol with reasonable safety
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to gamma-secretase inhibitor RO4929097 or bevacizumab
• Must be able to swallow capsules
• No malabsorption syndrome or other condition that would interfere with intestinal absorption
• No baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
• Not history of being serologically positive for hepatitis A, B, or C
• No history of cirrhosis
• No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia despite adequate electrolyte supplementation
• No uncontrolled intercurrent illness including, but not limited to, any of the following:
• 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
• Psychiatric illness and/or social situations that would limit compliance with study requirements
• No serious or non-healing wound, ulcer, or bone fracture

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

University of California at Los Angeles (UCLA )

Los Angeles, California, 90095, United States

Location

University of California San Francisco Medical Center-Parnassus

San Francisco, California, 94143, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Astrocytoma; Oligodendroglioma; 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; Bevacizumab

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; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

This is Phase 1/Phase 2 Study. It closed prematurely by Roche, study still in Phase 1. Roche halted pt enrollment in ALL clinical trials w/ RO4929097 \& cease production of drug \& development. Phase 2 of this study was never activated.

Results Point of Contact

• Title: Dr. Edward Pan
• Organization: Adult Brain Tumor Consortium (ABTC)

Edward.Pan@UTSouthwestern.edu

Study Officials

• Edward Pan, MD

  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 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2010
• First Posted: August 26, 2010
• Study Start: December 1, 2010
• Primary Completion: January 1, 2013
• Study Completion: February 1, 2015
• Last Updated: December 14, 2015
• Results First Posted: July 14, 2015

Record last verified: 2015-10

Locations

US (4)