A Dose-Escalation Study of GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, multicenter, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of GDC-0994 in patients with locally advanced or metastatic solid tumors. Patients will be enrolled in one of two stages: a dose-escalation stage (Stage I) or the subsequent expansion stage (Stage II). Stage I will evaluate the safety, tolerability, and pharmacokinetics of increasing doses of GDC-0994 administered daily. Stage II will gather additional data on safety, tolerability, and pharmacokinetics of the recommended dose of GDC-0994 determined in Stage I.

Official Title
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An Open-Label, Phase I, Dose-Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: GDC-0994
* Drug: GDC-0994


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable Evaluable disease or disease measurable per RECIST 1.1 Life expectancy >= 12 weeks Adequate hematologic and end organ function Consent to provide archival tissue Exclusion Criteria: History of prior significant toxicity from another MEK or ERK inhibitor requiring discontinuation of treatment History of parathyroid disorder or history or malignancy-associated hypercalcemia requiring therapy in the past 6 months Evidence of visible retinal pathology as assessed by ophthalmologic examination that is considered a risk factor for retinal vein thrombosis or neurosensory retinal detachment History of glaucoma Intraocular pressure > 21 mmHg as measured by tonometry Predisposing factors to retinal vein occlusion, including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy History of retinal vein occlusion (RVO), neurosensory retinal detachment, or neovascular macular degeneration Allergy or hypersensitivity to components of the GDC-0994 formulation Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment in Cycle 1 Experimental therapy within 4 weeks prior to first dose of study drug treatment in Cycle 1 Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose of study drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment Prior anti-cancer therapy within 28 days or 5 times the half-life whichever is longer Current severe, uncontrolled systemic disease History of clinically significant cardiac dysfunction Pregnancy, lactation, or breastfeeding Active autoimmune disease Inability or unwillingness to swallow pills Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms Clinically significant history of liver disease (including cirrhosis), current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus Any condition requiring warfarin or thrombolytic anticoagulants Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage I-Dose Escalation<br> | Drug: GDC-0994<br>* Escalating doses of GDC-0994 until maximum tolerated dose is reached<br>|
| Experimental: Stage II-Cohort-Expansion<br> | Drug: GDC-0994<br>* Recommended dose determined in Stage I-Dose Escalation phase, until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of adverse events |  | Approximately 2 years | 
| Maximum tolerated dose |  | Approximately 2 years | 
| Dose-limiting toxicities |  | Approximately 2 years | 
| Pharmacokinetics: Area under the concentration-time curve |  | Approximately 2 years | 
| Pharmacokinetics: Maximum plasma concentrations |  | Approximately 2 years | 
| Pharmacokinetics: Minimum plasma concentrations |  | Approximately 2 years | 
| Pharmacokinetics: Time to maximum plasma concentration |  | Approximately 2 years | 
| Pharmacokinetics: Apparent terminal elimination half-life |  | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the PD effects of GDC-0994, as measured by changes in molecular biomarkers in pre- and post-treatment tumor tissues\n |  | Approximately 2 years | 
| Objective Response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) |  | Approximately 2 years | 
| Progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) |  | Approximately 2 years | 
| Duration of response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) |  | Approximately 2 years |