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

NCT00968981 | Completed Phase 1 Results

• 1 other identifier: SHH4610g
• Study Type: interventional
• Target: 67
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Solid Cancers

Keywords

Hedgehog; BCC; basal cell carcinoma

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• Percentage of Participants With Disease Progression or Death

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

• Percentage of Participants With a Response by Best Overall Response (BOR)

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

• Progression-Free Survival (PFS) Time

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

• Duration of Response (DR)

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

Study Arms (3)

A

EXPERIMENTAL

Drug: GDC-0449

B

EXPERIMENTAL

Drug: GDC-0449

C

EXPERIMENTAL

Drug: GDC-0449

Interventions

GDC-0449 DRUG

Daily oral repeating dose

A

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Related Publications (1)

• 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.

  PMID: 28250200 DERIVED

MeSH Terms

Conditions

Carcinoma, Basal Cell

Interventions

HhAntag691

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Basal Cell

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-LaRoche

genentech@druginfo.com

800-821-8590

Study Officials

• Jennifer Low, M.D.

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: August 28, 2009
• First Posted: August 31, 2009
• Study Start: September 1, 2009
• Primary Completion: October 1, 2010
• Study Completion: October 1, 2010
• Last Updated: July 11, 2017
• Results First Posted: December 9, 2015

Record last verified: 2017-06