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Adenocarcinoma of the PancreasPhase 1NCT01145456

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

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, gemcitabine hydrochloride and pharmacological study in people with Adenocarcinoma of the Pancreas and Recurrent Pancreatic Cancer, run by National Cancer Institute (NCI) at 2 sites in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
gamma-secretase/Notch signalling pathway inhibitor RO4929097, gemcitabine hydrochloride and pharmacological study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
2 sitesCanada
Study dates
Jun 2010to Nov 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

None listed.

Trial locations and contacts

2 sites in 1 country.

Canada2 sites

  • Juravinski Cancer Centre at Hamilton Health Sciences

    Hamilton, Ontario, L8V 5C2

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: A Phase I Study of R04929097 in Combination With Gemcitabine in 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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Being tested
gamma-secretase/Notch signalling pathway inhibitor RO4929097, gemcitabine hydrochloride, pharmacological study, laboratory biomarker analysis
Medical subject headings
Pancreatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug

    Also called R4733, RO4929097

    Given orally

  • gemcitabine hydrochlorideDrug

    Also called dFdC, difluorodeoxycytidine hydrochloride, gemcitabine, Gemzar

    Given IV

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT01145456
Study groupRoleWhat they receive
Treatment (RO4929097 and gemcitabine hydrochloride)ExperimentalPatients 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.
Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Drug: gemcitabine hydrochloride; Other: pharmacological study; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 28 days

Secondary outcomes (2)

  1. Cmax, Tmax, t 1/2, AUC0-24, and clearance of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and gemcitabine hydrochloride when given together

    Measured: 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

  2. Objective response according to RECIST criteria 1.1

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jun 2010 (estimated)
  2. Study startJun 2010
  3. Primary completionNov 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01145456
Sponsor's protocol ID
NCI-2011-01433
Other IDs
NCI-2011-01433, CDR0000674950, PHL-078, 8575, U01CA132123
Status last verified
Dec 2013
First submitted
15 Jun 2010
Last updated
24 Feb 2014
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, gemcitabine hydrochloride and pharmacological study in people with Adenocarcinoma of the Pancreas and Recurrent Pancreatic Cancer, run by National Cancer Institute (NCI) at 2 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 60 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01145456.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2014.

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