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Endometrial Papillary Serous CarcinomaPhase 1NCT01198184

Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 and Temsirolimus in Treating Patients With Advanced Solid Tumors

A Phase 1 study testing temsirolimus, gamma-secretase/Notch signalling pathway inhibitor RO4929097 and laboratory biomarker analysis in people with Endometrial Papillary Serous Carcinoma and Recurrent Endometrial Carcinoma, 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 giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus together 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?
temsirolimus, gamma-secretase/Notch signalling pathway inhibitor RO4929097 and laboratory biomarker analysis
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
2 sitesCanada
Study dates
Aug 2010to Oct 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:
  • Dose-escalation group:
  • 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
  • Expansion group:
Show all 62Show fewer
  • Histologically and/or cytologically confirmed endometrial (endometrioid, uterine papillary serious carcinoma, or carcinosarcoma) or renal cell cancer
  • Metastatic or unresectable disease
  • Disease for which standard curative or palliative measures do not exist or are no longer effective
  • Measurable or non-measurable disease
  • Measurable disease is 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 70-100%)
  • Life expectancy > 12 weeks
  • Leukocytes ≥ 3,000/mm^3
  • ANC ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 90 g/L (or ≥ 9 g/dL)
  • Total bilirubin normal
  • AST/ALT ≤ 2.5 times upper limit of normal
  • Serum creatinine normal OR creatine clearance ≥ 60 mL/min
  • Fasting cholesterol ≤ 350 mg/dL (9.0 mmol/L)
  • Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)
  • No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
  • Note: it is acceptable to use corrected calcium when interpreting calcium levels
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use two effective forms of contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study therapy
  • Able to swallow medication
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • No diarrhea ≥ grade 2 that is not under control with standard anti-diarrhea medications
  • No uncontrolled concurrent illness including, but not limited to, any of the following:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable anginal pectoris
  • Cardiac arrhythmia other than chronic, stable atrial fibrillation
  • Psychiatric illness or social situations that would limit compliance with study medications
  • QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females, as measured by ECG using Bazett formula
  • 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
  • Torsades de pointes
  • Recurrent syncope without known etiology
  • Sudden unexpected death
  • No pre-existing significant pulmonary infiltrates of unknown origin
  • No serologic positivity for hepatitis A, B, or C or history of liver disease or other forms of hepatitis or cirrhosis
  • No HIV-positive patients on combination antiretroviral therapy
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or temsirolimus
  • Female patients may not donate ova during or after 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
  • Any number of prior therapies allowed
  • Recovered from side effects of previous systemic anticancer therapy to < CTCAE grade 2 toxicity (except alopecia)
  • Concurrent leuteinizing hormone-releasing hormone agonist allowed in patients with castration-resistant prostate cancer
  • No prior gamma-secretase inhibitor or any inhibitor of the PI3K/Akt/mTOR pathway
  • At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for carmustine, nitrosoureas, or mitomycin C)
  • Exceptions may be made for low-dose, non-myelosuppressive radiotherapy for symptomatic palliation
  • No other concurrent investigational agents
  • No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
  • No concurrent medications that are strong inducers, inhibitors, or substrates of CYP3A4
  • No antiarrhythmics or other concurrent medications with known potential to prolong QT interval
  • No concurrent food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including grapefruit or grapefruit juice
  • No other concurrent anticancer agents or therapies

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: Safety and Efficacy of RO4929097 in Combination With Temsirolimus: A Pharmacokinetic and Pharmacodynamic Phase I Study in Patients With Advanced Solid Tumours With an Expansion of Cohort With Patients With Recurrent/Metastatic Endometrial and Renal Cell Cancers

This phase I trial is studying the side effects and best dose of giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus together in treating patients with advanced solid tumors. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the recommended phase II dose (RP2D) and safety profile of temsirolimus in combination with RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

  1. To obtain pharmacokinetic (PK) profiles for both drugs when administered in combination in order to quantify the expected interactive effects in PK between these two agents.

II. To evaluate pharmacodynamic (PD) effects of both drugs when administered in combination, with the goal of identifying potential predictive and PD markers that need further exploration and validation in future trials.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or orally (PO) on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples may be collected periodically for pharmacokinetic and correlative analyses.

After completion of study treatment, patients are followed up for 4 weeks.

Being tested
temsirolimus, gamma-secretase/Notch signalling pathway inhibitor RO4929097, laboratory biomarker analysis, pharmacological study
Medical subject headings
Endometrial Neoplasms, Carcinoma, Renal Cell

What participants receive

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

  • temsirolimusDrug

    Also called CCI-779, cell cycle inhibitor 779, Torisel

    Given IV or PO

  • gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug

    Also called R4733, RO4929097

    Given PO

  • laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

Study groups in NCT01198184
Study groupRoleWhat they receive
Treatment (temsirolimus and RO4929097)ExperimentalPatients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: temsirolimus; Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other: laboratory biomarker analysis; Other: pharmacological study

What is being measured

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

  1. Recommended phase II dose defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0

    Measured: 21 days

  2. Safety profile assessed using NCI CTCAE version 4.0

    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics, however, logistic regression may be used if warranted.

    Measured: Up to 4 weeks post-treatment

Secondary outcomes (3)

  1. Objective response to treatment assessed using the RECIST criteria 1.1

    All analyses will be considered exploratory and inference will be performed with appropriate caution. For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests. A p-value of 0.05 or less will be considered statistically significant.

    Measured: Up to 4 weeks post-treatment

  2. Pharmacokinetic profiles

    All analyses will be considered exploratory and inference will be performed with appropriate caution. For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests. A p-value of 0.05 or less will be considered statistically significant.

    Measured: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours

  3. Pharmacodynamic effects

    All analyses will be considered exploratory and inference will be performed with appropriate caution. For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests. A p-value of 0.05 or less will be considered statistically significant.

    Measured: Up to 4 weeks post-treatment

Timeline

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

  1. First posted9 Sep 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionJul 2013
  4. Study completionOct 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
NCT01198184
Sponsor's protocol ID
NCI-2011-02529
Other IDs
NCI-2011-02529, 8500, CDR0000684714, PJC-005, 8500, U01CA132123
Status last verified
Oct 2013
First submitted
8 Sep 2010
Last updated
30 May 2014
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing temsirolimus, gamma-secretase/Notch signalling pathway inhibitor RO4929097 and laboratory biomarker analysis in people with Endometrial Papillary Serous Carcinoma and Recurrent Endometrial Carcinoma, 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 62 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 30 May 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 defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0 (time frame: 21 days). The study lists 2 primary outcomes in all. 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 NCT01198184.

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 30 May 2014.

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