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

A Phase Ib, Open-Label, Dose-Scheduling 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

This is a two stage, Phase Ib study designed to describe the pharmacokinetics of GDC-0449 in patients with advanced solid tumors that are refractory to treatment or for whom no standard therapy exists.

Study Overview

• Status: Completed
• Conditions: Solid Cancers
• Intervention / Treatment: Drug: GDC-0449; Drug: GDC-0449; Drug: GDC-0449

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Histologically documented, incurable, locally advanced or metastatic solid malignancy that has progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit); patients with basal cell carcinoma will be excluded from this study unless they do not qualify for another open GDC-0449 clinical trial
• For patients with disease that is evaluable by physical examination only, diagnosis must also include biomarker confirmation
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Documented negative pregnancy test for women of childbearing potential and agreement to use an effective form of contraception for the duration of the study
• Adequate hematopoietic capacity
• Adequate hepatic function
• Adequate renal function
• At least 3 weeks since 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

• Known, untreated central nervous system (CNS) malignancies or treated brain metastases that are not radiographically stable for ≥ 3 months
• Active infection requiring intravenous (IV) antibiotics
• Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis
• Any medical condition or diagnosis that would likely impair absorption of an orally administered drug (e.g., gastrectomy, ileal bypass, chronic diarrhea, gastroparesis)
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
• Pregnant or lactating
• Treatment with excluded medications, including strong CYP450 inhibitors and inducers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A	Drug: GDC-0449; Daily oral repeating dose; Drug: GDC-0449; Three times weekly oral repeating dose; Drug: GDC-0449; Once weekly oral repeating dose
Experimental: B	Drug: GDC-0449; Daily oral repeating dose; Drug: GDC-0449; Three times weekly oral repeating dose; Drug: GDC-0449; Once weekly oral repeating dose
Experimental: C	Drug: GDC-0449; Daily oral repeating dose; Drug: GDC-0449; Three times weekly oral repeating dose; Drug: GDC-0449; Once weekly oral repeating dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady-State for Both Total and Unbound GDC-0449		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
Number of Participants With Greater Than (>) 50 Percent (%) Decrease in Trough Concentration at Steady State (Css, Trough)	Percent change = ([trough concentration on Day 15 minus trough concentration on Day 57] divided by trough concentration on Day 15) multiplied by 100.	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
Ratio of Total and Unbound Trough GDC-0449 Concentration Between Day 57 to Day 15	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.	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
Plasma Concentration at Steady State (Css) for Total and Unbound GDC-0449	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.	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
Maximum Plasma Concentration (Cmax) of Total and Unbound GDC-0449	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.	0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1, 15 and 57 post-dose
Area Under the Curve From Time Zero to 24 Hour (AUC0-24) for Total and Unbound GDC-0449	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.	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
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) for Total and Unbound GDC-0449	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.	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
Time to Achieve Maximum Observed Plasma Concentration (Tmax) After a Single Dose of GDC-0449		0, 1, 2, 4, 6, 24, 48, 72 hours on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Disease Progression or Death	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.	Screening, Day 57, and every 8 weeks thereafter up to 52 weeks
Percentage of Participants With a Response by Best Overall Response (BOR)	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.	Screening Day 57, and every 8 weeks thereafter up to 52 weeks
Progression-Free Survival (PFS) Time	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).	Screening Day 57, and every 8 weeks thereafter up to 52 weeks
Duration of Response (DR)	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.	Screening Day 57, and every 8 weeks thereafter up to 52 weeks

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Jennifer Low, M.D., Genentech, Inc.

Publications and helpful links

General Publications

• Jia G, Chandriani S, Abbas AR, DePianto DJ, N'Diaye EN, Yaylaoglu MB, Moore HM, Peng I, DeVoss J, Collard HR, Wolters PJ, Egen JG, Arron JR. CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis. Thorax. 2017 Sep;72(9):780-787. doi: 10.1136/thoraxjnl-2015-207682. Epub 2017 Mar 1.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: August 28, 2009
• First Submitted That Met QC Criteria: August 28, 2009
• First Posted (Estimate): August 31, 2009

Study Record Updates

• Last Update Posted (Actual): July 11, 2017
• Last Update Submitted That Met QC Criteria: June 8, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: BCC; basal cell carcinoma; Hedgehog
• Other Study ID Numbers: SHH4610g