A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation

Study Overview
=================
Brief Summary
-----------------
This is a Phase I dose-escalation and dose-expansion study that will evaluate the safety, pharmacokinetics (PK), and preliminary activity of GDC-6036 in patients with advanced or metastatic solid tumors with a KRAS G12C mutation.

Official Title
-----------------
A Phase Ia/Ib Dose-Escalation and Dose-Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-6036 as a Single Agent and in Combination With Other Anti-cancer Therapies in Patients With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation

Conditions
-----------------
Non-Small Cell Lung Cancer, Colorectal Cancer, Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: GDC-6036
* Drug: Atezolizumab
* Drug: Cetuximab
* Drug: Bevacizumab
* Drug: Erlotinib
* Drug: GDC-1971
* Drug: Inavolisib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically documented advanced or metastatic solid tumor with KRAS G12C mutation. Women of childbearing potential must agree to remain abstinent or use contraception, and agree to refrain from donating eggs during the treatment period and after the final dose of study treatment as specified in the protocol. Men who are not surgically sterile must agree to remain abstinent or use a condom, and agreement to refrain from donating sperm during the treatment period and after the final dose of study treatment as specified in the protocol. Exclusion Criteria: Active brain metastases. Malabsorption or other condition that interferes with enteral absorption. Clinically significant cardiovascular dysfunction or liver disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Dose-escalation (Stage I), Dose Expansion (Stage II)<br>Participants in Stage I will receive GDC-6036 administered orally once daily (PO QD). The dose will be increased in successive cohorts until a study-specific threshold is reached. Participants with select solid tumors will be treated with GDC-6036 PO QD in Stage II. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>|
| Experimental: Arm B: GDC-6036 + Atezolizumab (Stage I and Stage II)<br>Participants with non-small cell lung cancer will receive GDC-6036 in combination with atezolizumab. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: Atezolizumab<br>* A 1200 milligram (mg) intravenous (IV) infusion of atezolizumab will be administered on Day 1 of 21 day cycles.<br>|
| Experimental: Arm C: GDC-6036 + Cetuximab (Stage I and Stage II)<br>Participants with colorectal cancer will receive GDC-6036 in combination with cetuximab. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: Cetuximab<br>* Cetuximab will be administered at an initial dose of 400 milligram per square meter (mg/m^2) IV infusion followed by 250 mg/m^2 IV infusion weekly in 21 day cycles.<br>|
| Experimental: Arm D: GDC-6036 + Bevacizumab (Stage I and Stage II)<br>Participants with solid tumors will receive GDC-6036 in combination with bevacizumab. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: Bevacizumab<br>* A 15 milligram per kilogram (mg/kg) IV infusion of bevacizumab will be administered on Day 1 of 21 day cycles.<br>|
| Experimental: Arm E: GDC-6036 + Erlotinib (Stage I and Stage II)<br>Participants with non-small cell lung cancer will receive GDC-6036 in combination with erlotinib. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: Erlotinib<br>* 150 mg of erlotinib will be administered PO QD in 21 day cycles.<br>|
| Experimental: Arm F: GDC-6036 + GDC-1971 (Stage I and Stage II)<br>Participants with solid tumors will receive GDC-6036 in combination with GDC-1971 PO in Stage I. Participants with select solid tumors will be treated with GDC-6036 in combination with GDC-1971 PO in Stage II. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: GDC-1971<br>* The starting dose of GDC-1971 will be determined from its single-agent dose escalation.<br>|
| Experimental: Arm G: GDC-6036 + Inavolisib (Stage I and Stage II)<br>Participants with solid tumors will receive GDC-6036 in combination with inavolisib PO in Stage I. Participants with select solid tumors will be treated with GDC-6036 in combination with inavolisib PO in Stage II. | Drug: GDC-6036<br>* The starting dose of GDC-6036 in the combination Arms B, C, D, E, F and G will be determined from Stage I Arm A (single-agent dose escalation).<br>Drug: Inavolisib<br>* The starting dose of inavolisib will be determined from its single-agent dose escalation.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | Severity is determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) | From Cycle 1 Day 1 until 28 days after the final dose (or as specified in the protocol). A cycle is 21 days. | 
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) |  | From Cycle 1 Day 1 through Day 21. A cycle is 21 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of GDC-6036 |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Plasma Concentrations of Erlotinib |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Plasma Concentrations of GDC-1971 |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Plasma Concentrations of Inavolisib |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Objective Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) |  | Every 6 weeks from Cycle 1 Day 1 until study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 |  | Every 6 weeks from Cycle 1 Day 1 until study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Progression-free survival (PFS) as determined by the investigator according to RECIST v1.1 |  | Every 6 weeks from Cycle 1 Day 1 until study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Relationship Between GDC-6036 Exposure (Maximum Plasma Concentration Observed [Cmax]) |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Relationship Between GDC-6036 Exposure (Time to Maximum Plasma Concentration [Tmax]) |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Relationship Between GDC-6036 Exposure (Half-life [t1/2]) |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Relationship Between GDC-6036 Exposure (Area Under the Curve [AUC]) |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 
| Relationship Between Tumor Pharmacodynamic Effects of GDC-6036 |  | Various timepoints from Cycle 1 Day 1 through study treatment discontinuation (within 28 days after the final dose of study drug). A cycle is 21 days. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
KRAS G12C, Non-Small Cell Lung Cancer, Colorectal Cancer, GDC-6036, Metastatic Solid Tumor, Atezolizumab, Bevacizumab, Cetuximab, Erlotinib, Inavolisib, GDC-1971, SHP2