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Adult Grade III Lymphomatoid GranulomatosisPhase 1NCT01158274

RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors

A Phase 1 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, capecitabine and laboratory biomarker analysis in people with Adult Grade III Lymphomatoid Granulomatosis and Adult Nasal Type Extranodal NK/T-cell Lymphoma, run by National Cancer Institute (NCI) at 2 sites in 2 countries.

Completed

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

Official record
Search all trials

Trial summary

This phase I clinical trial is studying the side effects and best dose of RO4929097 when given together with capecitabine in treating patients with refractory solid tumors. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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, capecitabine and laboratory biomarker analysis
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
2 sitesin 2 countries
Study dates
Jun 2010to Aug 2012
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

  • Patients must have histologically or cytologically confirmed advanced or metastatic solid tumor; patients with lymphoma will be eligible
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan
  • Patients must be at least 4 weeks since prior chemotherapy, 6 weeks if the last regimen included BCNU or mitomycin C; prior radiation is allowed as long as the radiation was completed 4 weeks prior to study treatment and no more than 35% of marrow irradiated
  • Life expectancy of greater than 3 months
  • ECOG performance status =< 2 (Karnofsky >= 60%)
  • Hemoglobin >= 9 g/dL
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  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • AST (SGOT)/ALT (SGPT) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal; a 24 hour urine collection and creatinine clearance can be measured if indicated
  • Treated, stable brain metastases are allowed; patients must be four weeks from radiation with stable brain imaging and off any medications used to treat brain metastases, excepting those anti-epileptics not metabolized by cytochrome P450
  • Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks 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
  • 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 and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; 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 teratogenic potential of RO4929097
  • 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 NOT to 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
  • Pre-pubertal females. The parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun. If a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward
  • Patients must demonstrate an ability to understand and the willingness to sign a written informed consent document
  • Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
  • PART 2A (MTD EXPANSION COLORECTAL CANCER):
  • For this cohort patients must have histologically or cytologically documented advanced or metastatic colorectal cancer; patients must have had at least one prior chemotherapy regimen for their disease but no more than 2
  • All 5 patients in this cohort must be willing and able to have tumor biopsies performed as part of the correlative studies associated with this trial
  • PART 2B (MTD EXPANSION BREAST CANCER):
  • For this cohort, patients must have histologically or cytologically documented advanced or metastatic breast cancer
  • Patient must be HER2/neu negative; HER2 negative will be defined as HER2 neither over-expressed or amplified; HER2 will be considered NOT over-expressed if the tumor stains as 0 or 1+ for HER2 by immunohistochemistry (IHC); if the IHC for HER2 is 2+, fluorescence in-site hybridization (FISH) ratio must be less than 2 to be considered NOT amplified; any tumor for which only FISH was performed must have a ratio of less than 2 to be considered NOT amplified
  • All 5 patients in this breast cancer cohort must be willing and able to have tumor biopsies performed as part of the correlative studies associated with this trial

Who cannot join

  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or capecitabine
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • Patients who are serologically positive for Hepatitis A, B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
  • Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study; note: it is acceptable to use corrected calcium when interpreting calcium levels
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  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, and a history of torsades de pointes or other significant cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued
  • HIV-positive patients, who are not on anti-retroviral therapy but have CD4 cells less than 200, should be excluded; HIV-positive patients are eligible if they are on HAART (highly active anti-retroviral therapy) which are not CYP3A4 substrates, inducers and/or inhibitors and meet all other criteria
  • Cardiovascular: baseline QTcF > 450 msec
  • Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency enzyme are excluded
  • Patients who have not recovered to < CTCAE grade 2 toxicities related to prior therapy are not eligible to participate in this study
  • A requirement for antiarrhythmics or other medications known to prolong QTc
  • PART2B (MTD EXPANSION BREAST CANCER):
  • Patients may not have had more than 1 prior cytotoxic chemotherapy for metastatic disease; prior endocrine or immunotherapy regimens for metastatic disease will not be counted as cytotoxic

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

United States1 site

  • University of Wisconsin Hospital and Clinics

    Madison, Wisconsin, 53792

Other trials in United States

Canada1 site

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: A Phase 1 Study of RO4929097 (NSC749225) in Combination With Capecitabine in Refractory Solid Tumors

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

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of RO4929097 and capecitabine administered in subjects with advanced solid tumors. (Part 1) II. To describe the dose-limiting toxicities (DLTs) of combined RO492097 and capecitabine. (Part 1) III. To determine the safety of RO4929097 and capecitabine administered in combination. (Part 1) IV. To determine the safety of RO4929097 and capecitabine in subjects with metastatic CRC. (Part 2a) V. To evaluate the safety of RO4929097 and capecitabine in combination for subjects with HER2/neu negative MBC. (Part 2b)

SECONDARY OBJECTIVES:

  1. To determine the clinical activity of RO4929097 and capecitabine administered in combination to subjects with advanced solid tumors. (Parts 1, 2a, and 2b) II. To evaluate the changes in the expression of Notch1 signaling pathway members and downstream targets of Notch by PCR including HEs1, 3 and 5; Hey 1 and 2 after treatment with RO4929097 at the MTD expansion cohorts. (Parts 1, 2a, and 2b) III. To determine the pharmacokinetic and pharmacogenomic profiles of the combination of RO4929097 and capecitabine. (Parts 1, 2a, and 2b) IV. To determine the progression-free survival (PFS) of RO4929097 and capecitabine when administered at the MTD level in patients with metastatic colorectal cancer (CRC) and a history of 1 or 2 prior therapies. (Part 2a) V. To determine the response and overall survival (OS) rates following RO4929097 and capecitabine administration at the MTD level in subjects with metastatic CRC. (Part 2a) VI. To determine the overall response rate (ORR) of RO4929097 and capecitabine when administered at the MTD level to subjects when administered first or second line for HER2/neu negative metastatic breast cancer (MBC). (Part 2b) V. To determine the progression-free and overall survival rates following RO4929097 and capecitabine administration at the MTD level in subjects with HER2/neu negative MBC. (Part 2b)

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, and 15-17 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo tumor biopsy before and after treatment for biomarker analysis and blood sample collection periodically for pharmacokinetic and pharmacogenomic studies.

After completion of study treatment, patients are followed up for 30 days (Part 1) or every 3 months (Parts 2a and 2b).

Being tested
gamma-secretase/Notch signalling pathway inhibitor RO4929097, capecitabine, laboratory biomarker analysis
Medical subject headings
Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Intraocular Lymphoma, Breast Neoplasms, Male, Lymphoma, B-Cell, Marginal Zone, Burkitt Lymphoma, Lymphoma, Large B-Cell, Diffuse

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

  • capecitabineDrug

    Also called CAPE, Ro 09-1978/000, Xeloda

    Given orally

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT01158274
Study groupRoleWhat they receive
TreatmentExperimentalPatients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Drug: capecitabine; Other: laboratory biomarker analysis

What is being measured

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

  1. MTD of RO4929097 and capecitabine, defined as that dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) graded according to NCI CTCAE version 4.0 (Part 1)

    Measured: Up to 21 days

  2. Incidence of adverse events graded according to NCI CTCAE version 4.0 (Part 1)

    Possible adverse events will be reported in tabular format. To determine the severity of the reaction for adverse event reporting, the NCI CTCAE version 4.0 will be used.

    Measured: Up to 30 days after completion of study treatment

  3. Incidence of adverse events graded according to NCI CTCAE version 4.0 (Parts 2a and 2b)

    Possible adverse events will be reported in tabular format. To determine the severity of the reaction for adverse event reporting, the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used.

    Measured: Up to 24 months

Secondary outcomes (6)

  1. Confirmed anti-tumor response rate validated by the RECIST (Part 1)

    Responses will be summarized using descriptive statistics presented in tabular format. Furthermore, two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed, while adjusting for multiplicity.

    Measured: Up to 30 days after completion of study treatment

  2. Changes in the expression of Notch1 signaling pathway members (Part 1)

    Relative and absolute changes will be calculated for each patient and results will be summarized by means and standard deviations. Paired t-tests will be used to compare baseline and post-study values in expression levels.

    Measured: From baseline to 30 days after completion of study treatment

  3. Pharmacokinetics of the combination of RO4929097 and capecitabine, including Cmax, Tmax, AUC, t1/2, and CL (Part 1)

    PK parameters will be summarized by using means, standard deviations and ranges. PK parameters between patients with a response (partial or complete) will be compared to PK parameters of patients with no response using a nonparametric Wilcoxon Rank Sum test.

    Measured: Baseline on day 1 of course 1; baseline and 1, 2, 3, 4, 8, 12, 16, and 24 hours on days 3 and 10 of course 1; and baseline on day 1 of all subsequent courses

  4. PFS (Parts 2a and 2b)

    Presented in a tabular format.

    Measured: Up to 24 months

  5. OS (Part 2a and 2b)

    Presented in a tabular format.

    Measured: Number of days from the day of first RO4929097 and capecitabine administration to the patient's death, assessed up to 24 months

  6. Overall response rate (Parts 2a and 2b)

    Confirmed anti-tumor response rate will be validated by RECIST. Responses will be summarized using descriptive statistics presented in tabular format.

    Measured: Up to 24 months

Timeline

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

  1. First posted8 Jul 2010 (estimated)
  2. Study startJun 2010
  3. Primary completionAug 2012

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
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01158274
Sponsor's protocol ID
NCI-2012-02918
Other IDs
NCI-2012-02918, CDR0000680610, CO09907, 8515, U01CA062491, U01CA132123, P30CA014520
Status last verified
Jun 2014
First submitted
7 Jul 2010
Last updated
7 Nov 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, capecitabine and laboratory biomarker analysis in people with Adult Grade III Lymphomatoid Granulomatosis and Adult Nasal Type Extranodal NK/T-cell Lymphoma, run by National Cancer Institute (NCI) at 2 sites in 2 countries.

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 32 inclusion and 15 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 7 Nov 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 United States, 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?

MTD of RO4929097 and capecitabine, defined as that dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) graded according to NCI CTCAE version 4.0 (Part 1) (time frame: Up to 21 days). The study lists 3 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 NCT01158274.

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 7 Nov 2014.

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