Trial Outcomes & Findings for A Study of Hedgehog Pathway Inhibitor GDC-0449 in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists (NCT NCT00968981)

NCT ID: NCT00968981

Last Updated: 2017-07-11

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

67 participants

Primary outcome timeframe

Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Results posted on

2017-07-11

Participant Flow

Participant milestones

Participant milestones
Measure	GDC-0449 150 mg QD Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule once daily (QD) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule three times weekly (TIW) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule once weekly (QW) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Overall Study STARTED	23	22	22
Overall Study Pharmacokinetic(PK) Evaluable Population	20	21	22
Overall Study COMPLETED	1	0	0
Overall Study NOT COMPLETED	22	22	22

Reasons for withdrawal

Reasons for withdrawal
Measure	GDC-0449 150 mg QD Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule once daily (QD) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule three times weekly (TIW) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule once weekly (QW) orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Overall Study Adverse Event	2	0	0
Overall Study Disease Progression	14	16	13
Overall Study Lost to Follow-up	0	0	1
Overall Study Physician Decision	5	3	5
Overall Study Withdrawal by Subject	1	3	3

Baseline Characteristics

A Study of Hedgehog Pathway Inhibitor GDC-0449 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	GDC-0449 150 mg QD n=23 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=22 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=22 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).	Total n=67 Participants Total of all reporting groups
Age, Continuous	62.1 years STANDARD_DEVIATION 10.4 • n=5 Participants	64.0 years STANDARD_DEVIATION 12.3 • n=7 Participants	62.9 years STANDARD_DEVIATION 10.3 • n=5 Participants	63.0 years STANDARD_DEVIATION 10.9 • n=4 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	9 Participants n=7 Participants	10 Participants n=5 Participants	29 Participants n=4 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	13 Participants n=7 Participants	12 Participants n=5 Participants	38 Participants n=4 Participants

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: The PK Evaluable Population. Number of participants analyzed (N) is equal to (=) participants with baseline and at least one post-baseline assessment for this outcome; n = participants evaluable at specified time-points.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=15 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=18 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=18 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 Unbound; Days 29-36 (n=15, 18, 18)	24 hours Interval 0.0 to 168.0	6 hours Interval 0.0 to 168.0	6 hours Interval 1.0 to 72.0
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 Total: Days 29-36 (n=15,18,18)	24 hours Interval 1.0 to 168.0	72 hours Interval 0.0 to 96.0	15 hours Interval 1.0 to 96.0
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 Total: Days 50-57 (n=11,13,10)	74 hours Interval 4.0 to 164.0	74 hours Interval 4.0 to 164.0	24 hours Interval 4.0 to 74.0
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449 Unbound: Days 50-57 (n=11,13,10)	104 hours Interval 4.0 to 164.0	94 hours Interval 4.0 to 104.0	4 hours Interval 4.0 to 74.0

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: PK Evaluable Population. Here number of participants analyzed (N) = participants with baseline and at least 1 post baseline assessment for this outcome.

Percent change = (\[trough concentration on Day 15 minus trough concentration on Day 57\] divided by trough concentration on Day 15) multiplied by 100.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=7 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=13 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=9 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) Total GDC-0449	0 participants	1 participants	4 participants
Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough) Unbound GDC-0449	0 participants	6 participants	9 participants

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: The PK Evaluable Population. N = participants who completed Day 57 of the study were included in this analysis.

Ratio = trough concentration on Day 57 divided by trough concentration on Day 15. If the ratio of total and unbound trough GDC-0449 concentration between Day 57 to Day 15 is less than 1, then it indicates reduction in total and unbound trough GDC-0449 concentration between Day 15 to Day 57.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=7 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=13 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=9 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 Css,trough for Total GDC-0449	1.23 ratio Interval 1.01 to 1.73	0.87 ratio Interval 0.49 to 1.27	0.54 ratio Interval 0.47 to 0.66
Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15 Css,trough for Unbound GDC-0449	1.34 ratio Interval 0.96 to 2.21	0.58 ratio Interval 0.28 to 1.49	0.20 ratio Interval 0.11 to 0.35

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: PK Evaluable Population. N = participants with baseline and post baseline data available for measurement of Css at steady state.

Plasma GDC-0449 concentrations were reported in nanogram per milliliter (ng/mL) units and converted to micromolar (mcM) units using the molecular weight (421.30 grams per mole \[g/mol\]) prior to PK analysis. Css was calculated for Days 28 to 56.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=15 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=18 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=18 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 Total GDC-0449	28 mcM Standard Deviation 11.4	26.1 mcM Standard Deviation 11.8	16.9 mcM Standard Deviation 5.89
Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449 Unbound GDC-0449	0.163 mcM Standard Deviation 0.056	0.088 mcM Standard Deviation 0.0408	0.0489 mcM Standard Deviation 0.0259

PRIMARY outcome

Timeframe: 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1, 15 and 57 post-dose

Population: PK Evaluable Population. 'n' signifies number of participants with data available at specified timepoint in each group.

Plasma GDC-0449 concentrations were reported in ng/mL units and converted to mcM units using the molecular weight (421.30 g/mol) prior to PK analysis.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=21 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=22 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Total GDC-0449: Single Dose (n=20,21,22)	7.09 mcM Standard Deviation 3.66	8.08 mcM Standard Deviation 3.48	7.29 mcM Standard Deviation 3.24
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Total GDC-0449: Day 29-36 (n=15,18,18)	30.4 mcM Standard Deviation 11.6	29.5 mcM Standard Deviation 12.6	21.2 mcM Standard Deviation 5.59
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Total GDC-0449: Day 50-57 (n=11,13,10)	33.9 mcM Standard Deviation 12.2	28.6 mcM Standard Deviation 13.8	18.2 mcM Standard Deviation 4.23
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Unbound GDC-0449: Single Dose (n=20,21,22)	0.02 mcM Standard Deviation 0.02	0.02 mcM Standard Deviation 0.02	0.02 mcM Standard Deviation 0.01
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Unbound GDC-0449:Day 29-36 (n=15,18,18)	0.215 mcM Standard Deviation 0.0797	0.122 mcM Standard Deviation 0.0602	0.0998 mcM Standard Deviation 0.0516
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449 Cmax,Unbound GDC-0449:Day 50-57 (n=11,13,10)	0.247 mcM Standard Deviation 0.0841	0.132 mcM Standard Deviation 0.0717	0.0688 mcM Standard Deviation 0.0312

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: PK Evaluable Population. n = number of participants with data available at specified timepoint in each group.

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). Below the limit of quantitation (BLQ) values at pre-dose were considered as zero for PK analysis.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=21 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=22 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Total GDC-0449: Day 29 (n=14,17,18)	696 mcM*hour Standard Deviation 258	595 mcM*hour Standard Deviation 241	455 mcM*hour Standard Deviation 116
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Unbound GDC-0449:Day 29 (n=14,17,17)	4.06 mcM*hour Standard Deviation 1.13	2.39 mcM*hour Standard Deviation 1.29	1.81 mcM*hour Standard Deviation 0.958
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Unbound GDC-0449:Day 50 (n=11,13,9)	4.8 mcM*hour Standard Deviation 1.75	2.44 mcM*hour Standard Deviation 1.19	1.51 mcM*hour Standard Deviation 0.615
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Total GDC-0449: Single Dose (n=20,21,22)	130.88 mcM*hour Standard Deviation 73.69	129.44 mcM*hour Standard Deviation 71.66	126.05 mcM*hour Standard Deviation 61.73
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Total GDC-0449: Day 50 (n=11,13,9)	729 mcM*hour Standard Deviation 251	587 mcM*hour Standard Deviation 274	387 mcM*hour Standard Deviation 86
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449 AUC0-24,Unbound GDC-0449: Single Dose (n=20,21,22)	0.38 mcM*hour Standard Deviation 0.31	0.30 mcM*hour Standard Deviation 0.27	0.32 mcM*hour Standard Deviation 0.20

PRIMARY outcome

Timeframe: Predose and 1, 2, 4, 6, 24, 48, and 72 on Days 1, 29, 50, and 54 and predose on Days 8, 10, 15, 22, 33, 36, 43, and 57

Population: PK Evaluable Population. n = number of participants with data available at specified time point in each group.

AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). BLQ values at pre-dose were considered as zero for PK analysis.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=21 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=22 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Total GDC-0449: Day 49-56 (n=9,13,9)	5235.09 mcM*hour Standard Deviation 2010.93	4074.88 mcM*hour Standard Deviation 1779.33	2656.65 mcM*hour Standard Deviation 666.09
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Unbound GDC-0449: Single Dose (n=20,21,22)	1.19 mcM*hour Standard Deviation 0.73	1.08 mcM*hour Standard Deviation 0.82	1.09 mcM*hour Standard Deviation 0.65
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Total GDC-0449: Single Dose (n=20,21,22)	431.20 mcM*hour Standard Deviation 201.18	478.38 mcM*hour Standard Deviation 212.88	453.14 mcM*hour Standard Deviation 209.48
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Total GDC-0449: Day 28-35 (n=14,14,18)	4834.06 mcM*hour Standard Deviation 1708.27	4302.84 mcM*hour Standard Deviation 1691.87	2935.33 mcM*hour Standard Deviation 926.74
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Unbound GDC-0449:Day 28-35 (n=14,17,17)	28.32 mcM*hour Standard Deviation 8.37	15.69 mcM*hour Standard Deviation 7.79	10.50 mcM*hour Standard Deviation 6.08
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449 AUClast,Unbound GDC-0449:Day 49-56 (n=8,13,9)	33.40 mcM*hour Standard Deviation 11.91	15.57 mcM*hour Standard Deviation 6.52	8.76 mcM*hour Standard Deviation 3.23

PRIMARY outcome

Timeframe: 0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1

Population: PK Evaluable Population.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=63 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449 Total GDC-0449	48 hours Interval 1.0 to 72.0	—	—
Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449 Unbound GDC-0449	48 hours Interval 1.0 to 72.0	—	—

SECONDARY outcome

Timeframe: Screening, Day 57, and every 8 weeks thereafter up to 52 weeks

Population: Efficacy Evaluable Population: all participants who had measurable disease at baseline and either had at least one follow-up tumor assessment or discontinued the study due to disease progression.

Disease progression (assessed by Response Evaluation Criteria in Solid Tumors \[RECIST\]) was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing non target lesions.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=17 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Percentage of Participants With Disease Progression or Death	52.9 percentage of participants	75.0 percentage of participants	40.0 percentage of participants

SECONDARY outcome

Timeframe: Screening Day 57, and every 8 weeks thereafter up to 52 weeks

Population: Efficacy Evaluable Population; only participants with measurable disease at baseline were included in the analysis.

BOR was defined as the best overall response observed during the treatment period according to RECIST. CR: disappearance of all TLs, with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in the sum of diameters of TLs, taking as reference the BL sum diameters. Progressive disease (PD): at least a 20% increase in the sum of diameters of TLs, taking as a reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase in 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Stable disease (SD) was defined as neither sufficient shrinkages to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=13 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=18 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=15 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Percentage of Participants With a Response by Best Overall Response (BOR) Complete Response	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With a Response by Best Overall Response (BOR) Partial Response	7.7 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With a Response by Best Overall Response (BOR) Stable Disease	30.8 percentage of participants	22.2 percentage of participants	53.3 percentage of participants
Percentage of Participants With a Response by Best Overall Response (BOR) Progressive Disease	61.5 percentage of participants	77.8 percentage of participants	40.0 percentage of participants
Percentage of Participants With a Response by Best Overall Response (BOR) Unevaluable (UE)	0.0 percentage of participants	0.0 percentage of participants	6.7 percentage of participants

SECONDARY outcome

Timeframe: Screening Day 57, and every 8 weeks thereafter up to 52 weeks

Population: Efficacy Evaluable Population.

PFS defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by the investigator review of tumor assessments using RECIST, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).

Outcome measures

Outcome measures
Measure	GDC-0449 150 mg QD n=17 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=20 Participants Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Progression-Free Survival (PFS) Time	1.9 months Interval 1.45 to 2.04	1.9 months Interval 1.84 to 1.97	2.2 months Interval 1.74 to 4.01

SECONDARY outcome

Timeframe: Screening Day 57, and every 8 weeks thereafter up to 52 weeks

DR during first line therapy is defined as the time from when response (complete response \[CR\] or partial response \[PR\]) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only be calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow up for progression of disease during first line therapy. CR: disappearance of all target lesions (TLs) with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 millimeters. PR: at least a 30% decrease in the sum of diameters of TLs, with reference to baseline sum diameters. DR was not calculated as only 1 responding participant reached their response at the last scheduled response assessment, hence follow-up data are not available.

Outcome measures

Outcome data not reported

Adverse Events

GDC-0449 150 mg QD

Serious events: 6 serious events

Other events: 19 other events

Deaths: 0 deaths

GDC-0449 150 mg TIW

Serious events: 8 serious events

Other events: 19 other events

Deaths: 0 deaths

GDC-0449 150 mg QW

Serious events: 8 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-LaRoche

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	GDC-0449 150 mg QD n=20 participants at risk Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QD orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QD orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg TIW n=21 participants at risk Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule TIW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule TIW orally from Day 15 to Day 57 (maintenance dose).	GDC-0449 150 mg QW n=22 participants at risk Single dose of GDC-0449 150 mg capsule orally on Day 1 and then one capsule QW orally from Day 4 to Day 14 (loading dose) followed by 150 mg capsule QW orally from Day 15 to Day 57 (maintenance dose).
Gastrointestinal disorders Intestinal obstruction	15.0% 3/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Small intestinal obstruction	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Constipation	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Jejunal ulcer	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Ileus paralytic	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Gastrointestinal haemorrhage	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
General disorders Gait disturbance	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
General disorders Pain	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Infections and infestations Urosepsis	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	9.5% 2/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Infections and infestations Abdominal wall abscess	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Infections and infestations Pneumonia	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Infections and infestations Cystitis	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Metabolism and nutrition disorders Dehydration	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.5% 1/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Nervous system disorders Headache	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Nervous system disorders Spinal cord compression	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Psychiatric disorders Mental status changes	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Renal and urinary disorders Renal failure acute	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	4.8% 1/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.
Vascular disorders Lymphoedema	5.0% 1/20 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/21 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.	0.00% 0/22 • From signature of informed consent up to 30 days after last dose of study medication (maximum 57 days on study medication). Safety Population included all participants who received at least 1 dose of study medication.