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A Study of Pharmacokinetic Drug Interaction Study of the Hedgehog Pathway Inhibitor GDC-0449 in Combination With Rosiglitazone or Combined Oral Contraceptive in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists

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ClinicalTrials.gov Identifier: NCT01209143
Recruitment Status : Completed
First Posted : September 27, 2010
Results First Posted : June 29, 2015
Last Update Posted : June 29, 2015
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Description
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Brief Summary:
This is a single-arm, multicenter, Phase Ib study designed to describe the effect of GDC-0449 on the pharmacokinetics of rosiglitazone and oral contraceptives in patients with advanced solid tumors who are refractory to treatment or for whom no standard therapy exists.

Condition or disease Intervention/treatment Phase
Solid Cancers Drug: Vismodegib Drug: Rosiglitazone Drug: Norethindrone/ethinyl estradiol Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib, Open-Label, Pharmacokinetic Drug Interaction Study of the Hedgehog Pathway Inhibitor GDC-0449 in Combination With Rosiglitazone or Combined Oral Contraceptive in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists
Study Start Date : November 2010
Actual Primary Completion Date : March 2012
Actual Study Completion Date : March 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Arms and Interventions
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Arm Intervention/treatment
Experimental: Vismodegib + rosiglitazone
Participants received rosiglitazone 4 mg orally on Days 1 and 8 of the study. Participants also received vismodegib 150 mg orally once a day beginning on Day 2 until one of the following occurred; disease progression, intolerable toxicity, most probably attributable to vismodegib, or patient withdrawal of consent.
 Drug: Vismodegib
Vismodegib was supplied in hard gelatin capsules.
Other Name: GDC-0449

Drug: Rosiglitazone
Rosiglitazone was supplied in tablets.
Experimental: Vismodegib + oral contraceptive
Participants received the oral contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) orally on Days 1 and 8 of the study. Participants also received vismodegib 150 mg orally once a day beginning on Day 2 until one of the following occurred; disease progression, intolerable toxicity, most probably attributable to vismodegib, or patient withdrawal of consent.
 Drug: Vismodegib
Vismodegib was supplied in hard gelatin capsules.
Other Name: GDC-0449

Drug: Norethindrone/ethinyl estradiol
Norethindrone/ethinyl estradiol was supplied in tablets.


Outcome Measures
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Primary Outcome Measures :
  1. Geometric Mean Ratio of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-inf]) of Rosiglitazone [ Time Frame: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose ]
    On Days 1 and 8, blood samples were taken prior to the administration of rosiglitazone and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of rosiglitazone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma rosiglitazone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratio of AUC(0-inf) of rosiglitazone was defined as the AUC(0-inf) of rosiglitazone on Day 8/AUC(0-inf) of rosiglitazone on Day 1.

  2. Geometric Mean Ratio of the Maximum Plasma Concentration (Cmax) of Rosiglitazone [ Time Frame: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose ]
    On Days 1 and 8, blood samples were taken prior to the administration of rosiglitazone and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of rosiglitazone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma rosiglitazone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratio of Cmax of rosiglitazone was defined as the Cmax of rosiglitazone on Day 8/ Cmax of rosiglitazone on Day 1.

  3. Geometric Mean Ratio of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-inf]) of Ethinyl Estradiol and Norethindrone [ Time Frame: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose ]
    On Days 1 and 8, blood samples were taken prior to the administration of the contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of ethinyl estradiol and norethindrone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma ethinyl estradiol and norethindrone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratios of AUC(0-inf) of ethinyl estradiol and norethindrone were defined as the ratios of AUC(0-inf) of ethinyl estradiol and norethindrone on Day 8 divided by AUC(0-inf) of ethinyl estradiol and norethindrone on Day 1, respectively.

  4. Geometric Mean Ratio of the Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone [ Time Frame: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose ]
    On Days 1 and 8, blood samples were taken prior to the administration of the contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of ethinyl estradiol and norethindrone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma ethinyl estradiol and norethindrone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratios of Cmax of ethinyl estradiol and norethindrone were defined as the ratios of Cmax of ethinyl estradiol and norethindrone on Day 8 divided by Cmax of ethinyl estradiol and norethindrone on Day 1, respectively.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologic documentation of incurable, locally advanced, or metastatic solid malignancy that has failed to respond to at least one prior regimen or for which there is no standard therapy
  • Documented negative serum pregnancy test for women of childbearing potential and use of two forms of contraception. Contraception must be used while the patient is enrolled in the study and for 12 months after the patient discontinues from the study.
  • For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 3 months after their last dose of GDC-0449.
  • Agreement not to donate blood or blood products during the study and for at least 12 months after their last dose of GDC-0449
  • For male patients, agreement not to donate sperm during the study and for at least 3 months after their last dose of GDC-0449
  • Adequate hematopoietic capacity
  • Adequate renal function
  • Adequate hepatic function
  • At least 3 weeks since the patient's last chemotherapy, investigational agent, radiation therapy, or major surgical procedure and recovery to pre-treatment baseline or stabilization of all treatment-related toxicities

Exclusion Criteria:

  • Active infection requiring intravenous (IV) antibiotics
  • Clinically important history of liver disease significantly impairing hepatic function, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
  • Any medical condition or diagnosis that would likely impair absorption of an orally administered drug
  • Pregnant or lactating
  • Treatment with excluded medications, including strong CYP450 inhibitors and inducers, within 2 weeks of study entry
  • Male patients already receiving rosiglitazone
  • Male patients with a known contraindication to rosiglitazone
  • Female patients already receiving oral contraception < 14 days prior to Day 1
  • Female patients with known contraindication to oral contraceptions
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01209143


Locations
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United States, California
Stanford, California, United States, 94305
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Texas
Houston, Texas, United States, 77030
Sponsors and Collaborators
Genentech, Inc.
Investigators
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Study Director: Dawn Colburn, Pharm.D. Genentech, Inc.
More Information
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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01209143    
Other Study ID Numbers: SHH4593g
GO01353 ( Other Identifier: Hoffmann-La Roche )
First Posted: September 27, 2010    Key Record Dates
Results First Posted: June 29, 2015
Last Update Posted: June 29, 2015
Last Verified: June 2015
Additional relevant MeSH terms:
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Rosiglitazone
Ethinyl Estradiol
Norethindrone
Norethindrone Acetate
Estradiol
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
 Contraceptive Agents, Hormonal
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Hypoglycemic Agents
Contraceptives, Oral, Hormonal
Contraceptives, Oral
Contraceptives, Oral, Synthetic