Gamma-Secretase Inhibitor RO4929097 And Gemcitabine Hydrochloride In Treating Patients With Advanced Solid Tumors

Study Overview

Gamma-Secretase Inhibitor RO4929097 and Gemcitabine Hydrochloride in Treating Patients With Advanced Solid Tumors

This phase I trial is studying the side effects and best dose of gamma-secretase inhibitor RO4929097 when given together with gemcitabine hydrochloride in treating patients with advanced solid tumors. Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gamma-secretase inhibitor RO4929097 together with gemcitabine hydrochloride may kill more tumor cells.

PRIMARY OBJECTIVES: I. To determine the safety profile and establish the maximum-tolerated dose and recommended phase II dose of gamma-secretase inhibitor RO4929097 in combination with gemcitabine hydrochloride in patients with advanced solid tumors. SECONDARY OBJECTIVES: I. To determine the pharmacokinetic profile of gamma-secretase inhibitor RO4929097 when given in combination with gemcitabine hydrochloride and to correlate the pharmacokinetic profile with toxicity and biological activity. II. To assess the antitumor activity of gamma-secretase inhibitor RO4929097 and gemcitabine hydrochloride in patients with advanced solid tumors. III. To correlate the expression of biomarkers of Notch signaling in archival tumor tissue with antitumor activity of gamma-secretase inhibitor RO4929097 in combination with gemcitabine hydrochloride. OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097. Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Plasma and blood samples may be collected periodically for pharmacokinetic studies and biomarker analysis. After completion of study treatment, patients are followed up every 1 month for up to 1 year.

Adenocarcinoma of the Pancreas
Recurrent Pancreatic Cancer
Stage III Pancreatic Cancer
Stage IV Pancreatic Cancer
Unspecified Adult Solid Tumor, Protocol Specific

DRUG: gamma-secretase/Notch signalling pathway inhibitor RO4929097
DRUG: gemcitabine hydrochloride
OTHER: pharmacological study
OTHER: laboratory biomarker analysis

NCI-2011-01433
NCI-2011-01433 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
CDR0000674950
PHL-078 (OTHER Identifier) (OTHER: University Health Network-Princess Margaret Hospital)
8575 (OTHER Identifier) (OTHER: CTEP)
U01CA132123 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2010-06-15	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2014-02-21
First Submitted that Met QC Criteria 2010-06-15	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2014-02-24
First Posted (ESTIMATED) 2010-06-16	Results First Posted N/A	Last Verified 2013-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (RO4929097 and gemcitabine hydrochloride) Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unaccepta	DRUG: gamma-secretase/Notch signalling pathway inhibitor RO4929097 Given orally DRUG: gemcitabine hydrochloride Given IV OTHER: pharmacological study Correlative studies OTHER: laboratory biomarker analysis Correlative studies

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (RO4929097 and gemcitabine hydrochloride)

Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unaccepta

DRUG: gamma-secretase/Notch signalling pathway inhibitor RO4929097

Given orally

DRUG: gemcitabine hydrochloride

Given IV

OTHER: pharmacological study

Correlative studies

OTHER: laboratory biomarker analysis

Correlative studies

Primary Outcome Measures	Measure Description	Time Frame
Recommended phase II dose of RO4929097 in combination with gemcitabine hydrochloride, defined as the dose level in which no more than 1 of 6 patients or 0/3 experience DLT, graded according to NCI CTCAE version 4.0		28 days

Secondary Outcome Measures	Measure Description	Time Frame
Cmax, Tmax, t 1/2, AUC0-24, and clearance of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and gemcitabine hydrochloride when given together		Before dosing and at 1, 2, 4, 6, 8, and 24 hours after dosing on days 1 and 10; before dosing on days 3, 9, and 15; before dosing and 1 and 2 hours after dosing on day 8; and any time on day 22 of course 1 and before drug dosing on day 1 of course 2
Objective response according to RECIST criteria 1.1		Up to 1 year

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Meets one of the following sets of criteria:

Histologically and/or cytologically confirmed solid malignancy

Metastatic or unresectable disease
Disease for which standard curative or palliative measures do not exist or are no longer effective
Histologically and/or cytologically confirmed adenocarcinoma of the pancreas (for patients in the expansion cohort)

Locally advanced or metastatic disease
No prior chemotherapy for advanced disease
Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
No known brain metastases
ECOG performance status (PS) 0-1 (Karnofsky PS 60-100%)
Life expectancy > 12 weeks
Hemoglobin ≥ 90 g/L (or ≥ 9 g/dL)
Leukocytes ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Total bilirubin ≤ 1.25 times upper limit of normal (ULN)
AST/ALT ≤ 1.5 times ULN
Serum creatinine =< ULN OR creatinine clearance ≥ 60 mL/min
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two forms of adequate contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
Able to swallow medication
No malabsorption syndrome or other condition that would interfere with intestinal absorption
No uncontrolled concurrent illness including, but not limited to, any of the following:

Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia other than chronic, stable atrial fibrillation
Psychiatric illness or social situations that would limit compliance with study requirements
No baseline QTc > 450 msec (for male patients) or > 470 msec (for female patients)
No history of risk factors for QT interval prolongation including, but not limited to, a family or personal history of any of the following:

Long QT syndrome
Recurrent syncope without known etiology
Sudden unexpected death
No history of torsade de pointes or other significant cardiac arrhythmias or the need for concomitant meds with known potential to prolong QT interval or antiarrhythmics
No diarrhea ≥ grade 2 not under control with standard anti-diarrhea medications
No serologic positivity for hepatitis A, B, or C
No history of liver disease or other forms of hepatitis or cirrhosis
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or to gemcitabine hydrochloride
Female patients may not donate ova during or after completion of study treatment
Male patients may not donate sperm during and for ≥ 12 months after completion of study treatment
Patients may not donate blood during and for ≥ 12 months after completion of study treatment
No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
Any number of prior therapies allowed
No prior therapy with a Notch inhibitor
At least 4 weeks since prior radiotherapy, chemotherapy, or systemic therapy (6 weeks if the last regimen included nitrosourea or mitomycin C) and recovered

Exceptions may be made for low-dose, non-myelosuppressive radiotherapy for symptomatic palliation
Patients in the expansion cohort must meet the following criteria:

No prior chemotherapy for advanced disease except for fluorouracil (with or without folinic acid) or gemcitabine hydrochloride given concurrently with radiotherapy as a "radiosensitizer"
At least 6 months since prior adjuvant gemcitabine hydrochloride
Prior radiotherapy for the management of local disease allowed provided > 4 weeks have elapsed since the last radiation treatment and all toxicities have resolved
Patients who have had radiotherapy to their sole site of disease are eligible provided they have documented progression of that lesion before study registration
Recovered from side effects of previous systemic anticancer therapy to ≤ CTCAE grade 2
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
No concurrent medications with known potential to prolong QT interval
No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit or grapefruit juice
No other concurrent investigational agents

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Philippe Bedard, University Health Network-Princess Margaret Hospital

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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