Know Cancer

or
forgot password

Randomized Drug Interaction Study of RO4929097 for Advanced Solid Tumors


N/A
18 Years
N/A
Open (Enrolling)
Both
Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

Randomized Drug Interaction Study of RO4929097 for Advanced Solid Tumors


PRIMARY OBJECTIVES:

I. 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:

I. 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 oral gamma-secretase inhibitor RO4929097 [RO4929097]): 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.

Arm I: 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.

Arm II: 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 (high-dose of RO4929097): 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.

Arm I: 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 II: 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.


Inclusion Criteria:



- 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

- 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

Exclusion Criteria:

- 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

- 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, Toloxatone, 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Metabolism induction measured by a change of 50% or more in the AUC

Outcome Description:

Compared using a paired t-test. Evaluated using a non-parametric Wilcoxon Signed Rank test.

Outcome Time Frame:

Day 1 to 10

Safety Issue:

No

Principal Investigator

George Wilding

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02916

NCT ID:

NCT01218620

Start Date:

September 2010

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001