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

NCT01218620 | Completed Phase 1

• 6 other identifiers: NCI-2012-02916CDR0000685426CO099088516P30CA014520U01CA062491
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Adult Solid Neoplasm

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 1 to 10

Secondary Outcomes (5)

• Changes in AUC in plasma pharmacokinetics for the stronger inhibitor of CYP3A4, ketoconazole evaluated by dose

  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

  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

  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

  Up to 30 days

• Evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors using RECIST criteria

  Up to 30 days after completion of study treatment

Study Arms (4)

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.

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.

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.

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.

Drug: Gamma-Secretase Inhibitor RO4929097; Drug: Rifampin; Drug: Midazolam Hydrochloride; Drug: Omeprazole; Drug: Tolbutamide; Drug: Dextromethorphan Hydrobromide; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis

Interventions

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Ketoconazole DRUG

Given PO

Also known as: Fungarest, Fungoral, KCZ, R-41400

Regimen I (Arm I); Regimen II (Arm I)

Rifampin DRUG

Given PO

Also known as: L-5103, RIF, Rifadin, Rimactane

Regimen I (Arm II); Regimen II (Arm II)

Midazolam Hydrochloride DRUG

Given IV

Also known as: midazolam, Versed

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Omeprazole DRUG

Given PO

Also known as: H168/68, Losec, OMEP, Prilosec

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Tolbutamide DRUG

Given PO

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Dextromethorphan Hydrobromide DRUG

Given PO

Also known as: DXM

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Pharmacological Study OTHER

Correlative studies

Also known as: pharmacological studies

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Laboratory Biomarker Analysis OTHER

Correlative studies

Regimen I (Arm I); Regimen I (Arm II); Regimen II (Arm I); Regimen II (Arm II)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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, 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Interventions

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Ketoconazole; Rifampin; Midazolam; Omeprazole; Tolbutamide; Dextromethorphan

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Benzimidazoles; Benzenesulfonamides; Sulfonamides; Amides; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons

Study Officials

• George Wilding

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2010
• First Posted: October 11, 2010
• Study Start: September 1, 2010
• Primary Completion: July 1, 2012
• Study Completion: December 1, 2014
• Last Updated: December 23, 2014

Record last verified: 2014-12

Locations

US (1)