Adult Solid NeoplasmPhase 1NCT01218620
Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced Solid Tumors
A Phase 1 study testing Gamma-Secretase Inhibitor RO4929097, Ketoconazole and Rifampin in people with Adult Solid Neoplasm, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This randomized phase I trial studies the side effects and best dose of RO4929097 in treating patients with advanced 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
- Conditions the study is for
- Adult Solid Neoplasm
- What is being tested?
- Gamma-Secretase Inhibitor RO4929097, Ketoconazole and Rifampin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2010to Dec 2014
- 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 confirmed malignancy that is metastatic or unresectable and for which there is no standard therapy
- Patients must not have received radiation to > 25% of bone marrow
- ECOG performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 12 weeks
- Hemoglobin >= 9 g/dL
- Leukocytes >= 3,000/mcL
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- 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
- 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
- Caution should be exercised when dosing ketoconazole, rifampin, omeprazole, midazolam, tolbutamide, and dextromethorphan 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
- The effects of RO4929097on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because Notch signal pathway inhibitors are known to be teratogenic, 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 randomized to Regimen I (Arm B) and Regimen II (Arm B), and receiving rifampin will need to use an additional, non-hormonal birth control during cycle 2; rifampin induces enzymes responsible for hormone metabolism, making hormonal birth control ineffective; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Patients must have measurable disease, or radiographically evaluable metastatic disease (e.g. osseous metastases) with evidence of disease progression (e.g. new lesions or rising tumor markers)
- 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
Who cannot join
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered (=< grade 1) from clinically significant adverse events due to agents administered more than 4 weeks earlier; prior palliative radiotherapy is allowed if greater than 2 weeks have elapsed and patient has also recovered to baseline or grade < 1 from any treatment adverse effects
- 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 other agents used in study
- 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 because RO4929097 is a gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with RO4929097, breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study
- HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with RO4929097; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
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- 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
- Patients must not be taking omeprazole or dextromethorphan, or be willing to take only the study dose and formulation on the PK days; patients who require or are likely to require therapeutic doses of these drugs are excluded
- Patients must not be taking rifampin, ketoconazole, tolbutamide, or midazolam; patients who require or are likely to require therapeutic doses of these drugs are excluded
- Patients must not be taking monoamine oxidase inhibitors, such as Clorgyline, Iproniazid, Isocarboxazid, Moclobemide, Nialamide, Pargyline, Phenelzine, Procarbazine, Rasagiline, Selegiline, Teloxantrone, or Tranylcypromine because of drug interactions with dextromethorphan
- Patients must not have acute narrow-angle glaucoma or untreated open-angle glaucoma, as midazolam is contraindicated
- Baseline QTcF > 450 msec
- 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 malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
- Because opioid containing pain medications may be metabolized by the CYP3A4 pathway, patients should be monitored carefully to avoid toxicity and doses adjusted if necessary; subjects who would not tolerate adjustments in their opioid pain medications are excluded
- Subjects with a history of hypoglycemia, diabetes mellitus, or abnormal glucagon regulation are excluded; subjects with a current diagnosis of diabetes mellitus who are receiving treatment (i.e. insulin or other medication) are not eligible; a diagnosis of diabetes mellitus that is managed by diet is allowable
- Subjects with mild to severe skin exanthems are excluded
- A requirement for antiarrhythmics or other medications known to prolong QTc
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
About this study
Official title: Randomized Drug Interaction Study of RO4929097 for Advanced Solid Tumors
This randomized phase I trial studies the side effects and best dose of RO4929097 in treating patients with advanced solid tumors. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate the extent that RO4929097 induces its own metabolism using a 20mg dose on Regimen I and a 50mg dose on Regimen II by comparing Cycle 1 Day 1 and Day 10 plasma pharmacokinetic parameters.
SECONDARY OBJECTIVES:
- To evaluate the effect of the strong inhibitor of CYP3A4, ketoconazole, on RO4929097 plasma pharmacokinetics.
II. To evaluate the effect of the strong inducer of CYP3A4, 2D6 and 2C9, rifampin on RO4929097 plasma pharmacokinetics.
III. To evaluate the effect of RO4929097 on the plasma pharmacokinetics of CYP450 substrates; midazolam (CYP3A4), omeprazole (CYP2C19), tolbutamide (CYP2C9) and dextromethorphan (CYP2D6) after single dose and chronic administration.
IV. To assess the influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on RO4929097 plasma pharmacokinetics V. To assess any evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors.
OUTLINE: Patients are randomized to 1 of 2 treatment regimens.
Regimen I (low-dose of RO4929097): Patients receive low-dose RO4929097 orally (PO) once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV over 1 minute, omeprazole PO, tolbutamide PO, and dextromethorphan hydrobromide PO on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Arm A: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and ketoconazole PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Arm B: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and rifampin PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Regimen II (high-dose of RO4929097): Patients receive high-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Arm A: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.
Arm B: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only.
In all arms, treatment with RO4929097 repeats every 21 days for >= 3 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetics studies and evaluation of SNPs in CYP2D6, CYP2C9, ABCB1, and CYP3A4/5.
After completion of study therapy, patients are followed up for 30 days.
- Conditions
- Adult Solid Neoplasm
- Being tested
- Gamma-Secretase Inhibitor RO4929097, Ketoconazole, Rifampin, Midazolam Hydrochloride, Omeprazole
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gamma-Secretase Inhibitor RO4929097Drug
Also called RO4929097
Given PO
KetoconazoleDrug
Also called Fungarest, Fungoral, KCZ, R-41400
Given PO
RifampinDrug
Also called L-5103, RIF, Rifadin, Rimactane
Given PO
Midazolam HydrochlorideDrug
Also called midazolam, Versed
Given IV
OmeprazoleDrug
Also called H168/68, Losec, OMEP, Prilosec
Given PO
TolbutamideDrug
Given PO
Dextromethorphan HydrobromideDrug
Also called DXM
Given PO
Also called pharmacological studies
Correlative studies
Laboratory Biomarker AnalysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Regimen I (Arm I) | Experimental | Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only. Receives: Drug: Gamma-Secretase Inhibitor RO4929097; Drug: Ketoconazole; Drug: Midazolam Hydrochloride; Drug: Omeprazole; Drug: Tolbutamide; Drug: Dextromethorphan Hydrobromide; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis |
| Regimen I (Arm II) | Experimental | Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only. Receives: Drug: Gamma-Secretase Inhibitor RO4929097; Drug: Rifampin; Drug: Midazolam Hydrochloride; Drug: Omeprazole; Drug: Tolbutamide; Drug: Dextromethorphan Hydrobromide; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis |
| Regimen II (Arm I) | Experimental | Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only. Receives: Drug: Gamma-Secretase Inhibitor RO4929097; Drug: Ketoconazole; Drug: Midazolam Hydrochloride; Drug: Omeprazole; Drug: Tolbutamide; Drug: Dextromethorphan Hydrobromide; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis |
| Regimen II (Arm II) | Experimental | Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only. Receives: Drug: Gamma-Secretase Inhibitor RO4929097; Drug: Rifampin; Drug: Midazolam Hydrochloride; Drug: Omeprazole; Drug: Tolbutamide; Drug: Dextromethorphan Hydrobromide; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Metabolism induction measured by a change of 50% or more in the AUC
Compared using a paired t-test. Evaluated using a non-parametric Wilcoxon Signed Rank test.
Measured: Day 1 to 10
Secondary outcomes (5)
Changes in AUC in plasma pharmacokinetics for the stronger inhibitor of CYP3A4, ketoconazole evaluated by dose
Evaluated using a non-parametric Wilcoxon Signed Rank test. Analysis of variance will be used to evaluate changes between Regimen I and Regimen II.
Measured: Day 1 of course 1 to day 10 of course 2
Changes in AUC in RO4929097 plasma pharmacokinetics for the strong inducer of CYP3A4, 2D6 and 2C9, rifampin evaluated by dose
Evaluated using a non-parametric Wilcoxon Signed Rank test. Analysis of variance will be used to evaluate changes between Regimen I and Regimen II.
Measured: Day 1 of course 1 to day 10 of course 2
Changes in AUC in the plasma pharmacokinetics of CYP450 substrates; midazolam (CYP3A4), omeprazole (CYP2C19), tolbutamide (CYP2C9) and dextromethorphan (CYP2D6) evaluated by dose
Evaluated using a non-parametric Wilcoxon Signed Rank test. Analysis of variance will be used to evaluate changes between Regimen I and Regimen II.
Measured: Day 1 of course 1 to day 10 of course 2
Influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on RO4929097 plasma pharmacokinetics
Measured using lease-square regression models.
Measured: Up to 30 days
Evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors using RECIST criteria
Measured: Up to 30 days after completion of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2010 (estimated)
- Study startSep 2010
- Primary completionJul 2012
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Adult Solid NeoplasmStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- George Wilding, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01218620
- Sponsor's protocol ID
- NCI-2012-02916
- Other IDs
- NCI-2012-02916, CDR0000685426, CO09908, 8516, P30CA014520, U01CA062491
- Status last verified
- Dec 2014
- First submitted
- 8 Oct 2010
- Last updated
- 23 Dec 2014
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Dec 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Drug Interaction Study of RO4929097 for Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT01218620
- Acronym / sponsor ID
- NCI-2012-02916
- Conditions
- Adult Solid Neoplasm
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Sep 2010
- Primary completion
- Jul 2012 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 11 Oct 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This randomized phase I trial studies the side effects and best dose of RO4929097 in treating patients with advanced solid tumors. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES:
- To evaluate the extent that RO4929097 induces its own metabolism using a 20mg dose on Regimen I and a 50mg dose on Regimen II by comparing Cycle 1 Day 1 and Day 10 plasma pharmacokinetic parameters.
SECONDARY OBJECTIVES:
- To evaluate the effect of the strong inhibitor of CYP3A4, ketoconazole, on RO4929097 plasma pharmacokinetics.
II. To evaluate the effect of the strong inducer of CYP3A4, 2D6 and 2C9, rifampin on RO4929097 plasma pharmacokinetics.
III. To evaluate the effect of RO4929097 on the plasma pharmacokinetics of CYP450 substrates; midazolam (CYP3A4), omeprazole (CYP2C19), tolbutamide (CYP2C9) and dextromethorphan (CYP2D6) after single dose and chronic administration.
IV. To assess the influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on RO4929097 plasma pharmacokinetics V. To assess any evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors.
OUTLINE: Patients are randomized to 1 of 2 treatment regimens.
Regimen I (low-dose of RO4929097): Patients receive low-dose RO4929097 orally (PO) once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV over 1 minute, omeprazole PO, tolbutamide PO, and dextromethorphan hydrobromide PO on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Arm A: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and ketoconazole PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Arm B: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and rifampin PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Regimen II (high-dose of RO4929097): Patients receive high-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.
Arm A: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.
Arm B: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only.
In all arms, treatment with RO4929097 repeats every 21 days for >= 3 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetics studies and evaluation of SNPs in CYP2D6, CYP2C9, ABCB1, and CYP3A4/5.
After completion of study therapy, patients are followed up for 30 days.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Regimen I (Arm I) | Experimental | Drug: Gamma-Secretase Inhibitor RO4929097, Drug: Ketoconazole, Drug: Midazolam Hydrochloride, Drug: Omeprazole, Drug: Tolbutamide, Drug: Dextromethorphan Hydrobromide, Other: Pharmacological Study, Other: Laboratory Biomarker AnalysisPatients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms. Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only. |
| Regimen I (Arm II) | Experimental | Drug: Gamma-Secretase Inhibitor RO4929097, Drug: Rifampin, Drug: Midazolam Hydrochloride, Drug: Omeprazole, Drug: Tolbutamide, Drug: Dextromethorphan Hydrobromide, Other: Pharmacological Study, Other: Laboratory Biomarker AnalysisPatients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms. Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only. |
| Regimen II (Arm I) | Experimental | Drug: Gamma-Secretase Inhibitor RO4929097, Drug: Ketoconazole, Drug: Midazolam Hydrochloride, Drug: Omeprazole, Drug: Tolbutamide, Drug: Dextromethorphan Hydrobromide, Other: Pharmacological Study, Other: Laboratory Biomarker AnalysisPatients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms. Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only. |
| Regimen II (Arm II) | Experimental | Drug: Gamma-Secretase Inhibitor RO4929097, Drug: Rifampin, Drug: Midazolam Hydrochloride, Drug: Omeprazole, Drug: Tolbutamide, Drug: Dextromethorphan Hydrobromide, Other: Pharmacological Study, Other: Laboratory Biomarker AnalysisPatients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms. Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which there is no standard therapy
- Patients must not have received radiation to > 25% of bone marrow
- ECOG performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 12 weeks
- Hemoglobin >= 9 g/dL
Key exclusion criteria (18 listed)
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered (=< grade 1) from clinically significant adverse events due to agents administered more than 4 weeks earlier; prior palliative radiotherapy is allowed if greater than 2 weeks have elapsed and patient has also recovered to baseline or grade < 1 from any treatment adverse effects
- 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 other agents used in study
- 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 because RO4929097 is a gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with RO4929097, breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gamma-Secretase Inhibitor RO4929097Also: RO4929097Given PO | Drug | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| KetoconazoleAlso: Fungarest, Fungoral, KCZ, R-41400Given PO | Drug | Regimen I (Arm I), Regimen II (Arm I) |
| RifampinAlso: L-5103, RIF, Rifadin, RimactaneGiven PO | Drug | Regimen I (Arm II), Regimen II (Arm II) |
| Midazolam HydrochlorideAlso: midazolam, VersedGiven IV | Drug | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| OmeprazoleAlso: H168/68, Losec, OMEP, PrilosecGiven PO | Drug | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| TolbutamideGiven PO | Drug | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| Dextromethorphan HydrobromideAlso: DXMGiven PO | Drug | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| Pharmacological StudyAlso: pharmacological studiesCorrelative studies | Other | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Regimen I (Arm I), Regimen I (Arm II), Regimen II (Arm I), Regimen II (Arm II) |
Primary outcome
Metabolism induction measured by a change of 50% or more in the AUC
Time frame: Day 1 to 10
Compared using a paired t-test. Evaluated using a non-parametric Wilcoxon Signed Rank test.
5 secondary outcomes
Changes in AUC in plasma pharmacokinetics for the stronger inhibitor of CYP3A4, ketoconazole evaluated by dose
Time frame: Day 1 of course 1 to day 10 of course 2
Changes in AUC in RO4929097 plasma pharmacokinetics for the strong inducer of CYP3A4, 2D6 and 2C9, rifampin evaluated by dose
Time frame: Day 1 of course 1 to day 10 of course 2
Changes in AUC in the plasma pharmacokinetics of CYP450 substrates; midazolam (CYP3A4), omeprazole (CYP2C19), tolbutamide (CYP2C9) and dextromethorphan (CYP2D6) evaluated by dose
Time frame: Day 1 of course 1 to day 10 of course 2
Influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on RO4929097 plasma pharmacokinetics
Time frame: Up to 30 days
Evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors using RECIST criteria
Time frame: Up to 30 days after completion of study treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Dec 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
George Wilding principal investigator
University of Wisconsin, Madison
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Gamma-Secretase Inhibitor RO4929097, Ketoconazole and Rifampin in people with Adult Solid Neoplasm, run by National Cancer Institute (NCI) at 1 site in United States.
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 18 inclusion and 18 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 23 Dec 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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?
Metabolism induction measured by a change of 50% or more in the AUC (time frame: Day 1 to 10). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 23 Dec 2014.