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

Adult Glioblastoma Clinical Trial

Official title:

A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01122901
• Other study ID #: NCI-2012-02931
• Secondary ID: NCI-2012-02931CD
• Status: Active, not recruiting
• Phase: Phase 2
• First received: May 11, 2010
• Last updated: September 20, 2016
• Start date: December 2010

Study information

• Verified date: September 2016
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

PRIMARY OBJECTIVES:

I. 6-month progression-free survival (PFS6). (Group A) II. Efficiency of neurosphere generation after pretreatment with RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097). (Group B)

SECONDARY OBJECTIVES:

I. Radiographic response rate. (Group A) II. Toxicities associated with this regimen. (Group A) III. Overall survival. (Group A) IV. Expression levels of Notch pathway components and downstream targets. (Group B) V. Tumor propagation. An extension of lifespan by 50% in tumor bearing mice (mice bearing fresh tumor tissue). (Group B) VI. Patient event-free survival in correlation with expression levels of Notch pathway components and downstream targets.

VII. 6-month progression-free survival (PFS6). VIII. Toxicities associated with this regimen. IX. Overall survival.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

GROUP A: Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) once daily (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.

GROUP B (surgical resection indicated): 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/Notch signalling pathway inhibitor RO4929097 as in Group A.

After completion of study treatment, patients are followed up every 2 months.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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:

• 3 months from the completion of radiation

• 6 weeks from a nitrosourea chemotherapy

• 3 weeks from a non-nitrosourea chemotherapy

• 4 weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents

• 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., small molecule targeted therapy, thalidomide, bevacizumab, etc.)

• Patients may not be on an enzyme-inducing anti-epileptic drug (EIAED); if previously on an EIAED, patient must be off for at least 14 days prior to the first dose of RO4929097

• Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)

• Hemoglobin >= 9 g/dL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< institutional upper limit of normal

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 4.0 x institutional upper limit of normal

• Creatinine within institutional upper limit of normal OR

• Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Electrolytes - calcium, chloride, magnesium, potassium, phosphorus, sodium within institutional normal limits

• Patients must be able to provide written informed consent

• Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) starting prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately

• PREGNANCY TESTING: Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days prior to treatment start and be required to agree to have the test repeated within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will also be administered every 4 weeks (within 24 hours prior to starting every cycle) if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the potential of RO4929097 to cause serious or life-threatening birth defects

• Female patients of childbearing potential are defined as follows:

• Patients with regular menses

• Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding

• Women who have had tubal ligation

• Female patients may be considered to NOT be of childbearing potential for the following reasons:

• The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy

• The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months

• Patients may not be breast-feeding

• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years

• Patients must have a Mini Mental State Exam score of >= 15

Exclusion Criteria:

• 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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Brain Neoplasms
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Tumor

Intervention

Drug:
• gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given PO

Procedure:
• therapeutic conventional surgery
Undergo surgery

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) (Group A)	Actual estimate of the success rate, including confidence intervals, will be provided to allow direct assessment of the strength of the evidence for efficacy. Additional analyses will include Kaplan Meier estimates of time-to-event.	At 6 months	No
Primary	Efficiency of neurosphere generation after pretreatment with RO4929097 (Group B)		At time of surgery	No
Secondary	Radiographic response rate according to the Radiographic Assessment in Neuro-Oncology criteria (Group A)		Up to 6 months after completion of treatment	No
Secondary	Toxicity as assessed by the National Cancer Institute CTCAE version 4.0		Up to 30 days after completion of study treatment	Yes
Secondary	Overall survival	Overall survival between the 2 groups will be estimated.	Up to 6 months	No
Secondary	Expression levels of Notch pathway components and downstream (Group B)	The comparator arm will be the control arm from the Hedgehog antagonist trial (ABTC 0904) using Fisher's exact test.	At the time of surgery	No
Secondary	Tumor propagation (Group B)		At the time of surgery	No
Secondary	Patient event-free survival (Group B)	Patient event-free survival correlated with expression levels of Notch pathway components and downstream targets.	Up to 6 months	No
Secondary	PFS	PFS between the 2 groups will be estimated.	At 6 months	No