Trial Outcomes & Findings for 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 (NCT NCT01209143)

NCT ID: NCT01209143

Last Updated: 2015-06-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

52 participants

Primary outcome timeframe

Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose

Results posted on

2015-06-29

Participant Flow

Participant milestones

Participant milestones
Measure	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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.	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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Norethindrone/ethinyl estradiol: Norethindrone/ethinyl estradiol was supplied in tablets.
Overall Study STARTED	24	28
Overall Study COMPLETED	5	8
Overall Study NOT COMPLETED	19	20

Reasons for withdrawal

Reasons for withdrawal
Measure	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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.	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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Norethindrone/ethinyl estradiol: Norethindrone/ethinyl estradiol was supplied in tablets.
Overall Study Adverse Event	2	1
Overall Study Death	0	1
Overall Study Physician Decision	3	1
Overall Study Lost to Follow-up	1	0
Overall Study Withdrawal by Subject	2	1
Overall Study Disease progression	11	16

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vismodegib + Rosiglitazone n=24 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.	Vismodegib + Oral Contraceptive n=28 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Norethindrone/ethinyl estradiol: Norethindrone/ethinyl estradiol was supplied in tablets.	Total n=52 Participants Total of all reporting groups
Age, Continuous	62.1 years STANDARD_DEVIATION 14.4 • n=93 Participants	59.2 years STANDARD_DEVIATION 14.6 • n=4 Participants	60.5 years STANDARD_DEVIATION 14.4 • n=27 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	27 Participants n=4 Participants	27 Participants n=27 Participants
Sex: Female, Male Male	24 Participants n=93 Participants	1 Participants n=4 Participants	25 Participants n=27 Participants

PRIMARY outcome

Timeframe: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose

Population: Pharmacokinetic population: All participants with pharmacokinetic data on Day 1 and Day 8.

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.

Outcome measures

Outcome measures
Measure	Vismodegib + Rosiglitazone n=24 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.
Geometric Mean Ratio of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-inf]) of Rosiglitazone	92.0 ng/mL*hr Interval 87.4 to 96.8

PRIMARY outcome

Timeframe: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose

Population: Pharmacokinetic population: All participants with pharmacokinetic data on Day 1 and Day 8.

Outcome measures

Outcome measures
Measure	Vismodegib + Rosiglitazone n=24 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.
Geometric Mean Ratio of the Maximum Plasma Concentration (Cmax) of Rosiglitazone	93.1 ng/mL Interval 85.0 to 102.0

PRIMARY outcome

Timeframe: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose

Population: Pharmacokinetic population: All participants with pharmacokinetic data on Day 1 and Day 8.

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.

Outcome measures

Outcome measures
Measure	Vismodegib + Rosiglitazone n=27 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.
Geometric Mean Ratio of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-inf]) of Ethinyl Estradiol and Norethindrone Ethinyl estradiol	99.6 ng/mL*hr Interval 92.9 to 107.0
Geometric Mean Ratio of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-inf]) of Ethinyl Estradiol and Norethindrone Norethindrone	123 ng/mL*hr Interval 115.0 to 131.0

PRIMARY outcome

Timeframe: Pre-dose and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose

Population: Pharmacokinetic population: All participants with pharmacokinetic data on Day 1 and Day 8.

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.

Outcome measures

Outcome measures
Measure	Vismodegib + Rosiglitazone n=27 Participants 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.
Geometric Mean Ratio of the Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone Ethinyl estradiol	105 ng/mL Interval 94.4 to 116.0
Geometric Mean Ratio of the Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone Norethindrone	112 ng/mL Interval 101.0 to 124.0

Adverse Events

Vismodegib + Rosiglitazone

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Vismodegib + Oral Contraceptive

Serious events: 0 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical Communications

Genentech, Inc.

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Vismodegib + Rosiglitazone n=24 participants at risk 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Rosiglitazone: Rosiglitazone was supplied in tablets.	Vismodegib + Oral Contraceptive n=28 participants at risk 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. Vismodegib: Vismodegib was supplied in hard gelatin capsules. Norethindrone/ethinyl estradiol: Norethindrone/ethinyl estradiol was supplied in tablets.
Musculoskeletal and connective tissue disorders Muscle spasms	54.2% 13/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	35.7% 10/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Musculoskeletal and connective tissue disorders Back pain	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Musculoskeletal and connective tissue disorders Pain in extremity	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Constipation	29.2% 7/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	25.0% 7/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Nausea	16.7% 4/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	28.6% 8/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Vomiting	4.2% 1/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	14.3% 4/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Abdominal pain	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	7.1% 2/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Diarrhoea	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Abdominal tenderness	0.00% 0/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	7.1% 2/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Gastrointestinal disorders Dry mouth	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	0.00% 0/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Nervous system disorders Dysgeusia	37.5% 9/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	32.1% 9/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Nervous system disorders Headache	12.5% 3/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Nervous system disorders Hypogeusia	8.3% 2/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	0.00% 0/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
General disorders Fatigue	29.2% 7/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	17.9% 5/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Skin and subcutaneous tissue disorders Alopecia	12.5% 3/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	7.1% 2/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Skin and subcutaneous tissue disorders Night sweats	4.2% 1/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	10.7% 3/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Metabolism and nutrition disorders Decreased appetite	16.7% 4/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	14.3% 4/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Psychiatric disorders Insomnia	12.5% 3/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Psychiatric disorders Anxiety	4.2% 1/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	7.1% 2/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Investigations Weight decreased	12.5% 3/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	3.6% 1/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Blood and lymphatic system disorders Anaemia	4.2% 1/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	7.1% 2/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/24 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).	10.7% 3/28 Safety-evaluable population: All participants who received any amount of study drug (vismodegib or rosiglitazone or norethindrone/ethinyl estradiol).