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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (gamma-secretase inhibitor RO4929097)<br>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<br>* Given PO<br>* Other names: RO4929097;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Group B (gamma-secretase inhibitor RO4929097, surgery)<br>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<br>* Given PO<br>* Other names: RO4929097;Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B) | RANO: Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): >/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Up to 6 months after completion of treatment | 
| Number of Participants With Toxicities Associated With Study Drug (Group A and Group B) | assessed by the National Cancer Institute CTCAE version 4.0 assessed if patient received at least one dose of study drug Grade 3-5 toxicities grade 3 -severe grade 4 - life threatening grade 5 - death | Up to 30 days after completion of study treatment | 
| Overall Survival | time to event endpoints for Group A will be measured from date of first dose. All patients who receive at least one dose will be included in 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). | 2 years | 
| Expression Levels of Notch Pathway Components and Downstream (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 the time of surgery | 
| Tumor Propagation (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 the time of surgery | 
| Progression Free Survival | 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. | 2 years |