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

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is a central component of
the RAS/MAPK signal transduction pathway, an intracellular network of proteins
that transmit extracellular growth factor signals to regulate cell
proliferation, differentiation, and survival. Mutations in KRAS can result in
alterations at several amino acids, including glycine 12 (G12), glycine 13, and
glutamine 61, commonly found in solid tumors and associated with tumorigenesis
and aggressive tumor growth (Der et al. 1982; Parada et al. 1982; Santos et al.
1982; Taparowsky et al. 1982; Capon et al. 1983). Oncogenic KRAS mutations
that result in the change from G12 to cysteine (G12C) are prevalent in
non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and
other tumor types (~4%) (Bailey et al. 2016; Campbell et al. 2016; Giannakis et
al. 2016; Hartmaier et al. 2017; Jordan et al. 2017).

Advanced stage tumors harboring the KRAS G12C mutation (hereafter referred to
as KRAS G12C-positive tumors), including NSCLC, CRC, and other solid tumors,
are incurable and carry a poor prognosis (Roman et al. 2018; Wan et al. 2019).
In addition, patients with advanced stage KRAS G12C*positive cancers may derive
limited benefit from select chemotherapies and targeted therapies, thus,
restricting effective available treatment options (Roman et al. 2018).

Initial systemic treatment options for advanced stage or metastatic NSCLC
(without known oncogenic drivers that have available targeted therapies)
include PD-1/PD-L1 inhibitors with or without chemotherapy (Gong et al. 2018).
Subsequent treatment options may include platinum-containing chemotherapy
combinations followed by single-agent chemotherapy with limited duration of
disease control (NCCN 2020a). Although a minority of patients achieve
long-term disease control, in general, advanced stage or metastatic NSCLC
remains an incurable disease. Recent data suggest that KRAS mutation status
may be associated with response to single-agent PD-1 inhibitor therapy and that
chemotherapy plus a PD-1 inhibitor may be effective regardless of KRAS mutation
status (Gadgeel et al. 2019; Herbst et al. 2019).

For advanced or metastatic CRC, systemic treatment can consist of combinations
of active agents or select individual agents and includes
5-fluorouracil/leucovorin, capecitabine, irinotecan, oxaliplatin, bevacizumab,
cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib,
trifluridine-tipiracil, pembrolizumab, nivolumab, ipilimumab, and encorafenib.
Treatment is selected based on the goals of care, type and timing of prior
therapy, mutational profile of the tumor, anticipated toxicity profile, and
patient*s performance status (NCCN 2020b). Specifically, KRAS mutations were
associated with resistance to anti-EGFR therapies (Lièvre et al. 2006;
Karapetis et al. 2008; Van Cutsem et al. 2009; Misale et al. 2012). Thus,
patients whose cancers harbor KRAS mutations are not eligible for treatment
with cetuximab or panitumumab (NCCN 2020b) and treatment options remain
limited.

Other tumor types with the KRAS G12C mutation include cancers of the pancreas,
breast, ovary, endometrium, and appendix, as well as gastric cancer and myeloma
(Hartmaier et al. 2017). Treatment is based on tumor type as well as patient*s
performance status, goals of care, and prior therapy. However, because the
prevalence of KRAS G12C-positive tumors is low, there is no specific guidance
on treatment or management.
Although previously considered an *undruggable* cancer target, the landmark
discovery of the switch II pocket within KRAS has enabled the development of
covalent inhibitors specific for KRAS G12C (Ostrem et al. 2013). The clinical
development of covalent inhibitors of KRAS G12C offers a potential therapeutic
intervention to prevent or delay the progression of cancers that harbor a KRAS
G12C mutation (McCormick 2019). Early clinical data from covalent inhibitors
specific for KRAS G12C demonstrate single-agent anti-tumor activity and
potential to improve treatment options and outcomes for patients with advanced
stage cancer that harbors the KRAS G12C mutation (Jänne et al. 2019; Hong et
al. 2020).

The investigational medicinal products (IMPs) for this study are GDC-6036,
atezolizumab, cetuximab, bevacizumab, and erlotinib.
GDC-6036 is an oral, covalent, anti-cancer therapeutic agent that selectively
inhibits KRAS G12C, but not other mutations in KRAS, the wild-type form of
KRAS, or other members of the RAS family. Nonclinical studies demonstrate that
treatment of KRAS G12C-positive cancer cell lines or tumor xenograft models
with GDC-6036 results in decreased KRAS pathway signaling, suppression of
proliferation, and induction of apoptosis. Results from nonclinical toxicity
and safety pharmacology studies completed to date characterize the toxicology
profile of GDC-6036 and support the administration of GDC 6036 to patients with
advanced cancer. Toxicities observed in nonclinical species are expected to be
manageable and/or monitorable in a clinical setting. Refer to the GDC-6036
Investigator's Brochure for details on nonclinical studies.

Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD L1 and
inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also
known as CD80), both of which function as inhibitory receptors expressed on T
cells. Atezolizumab shows anti tumor activity in both nonclinical models and
cancer patients and is being investigated as a potential therapy in a wide
variety of malignancies. Atezolizumab is being studied as a single agent in
the advanced cancer and adjuvant therapy settings, as well as in combination
with chemotherapy, targeted therapy, and cancer immunotherapy.

Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed
against the epidermal growth factor receptor (EGFR, also known as HER1 or
c-ErbB-1). Cetuximab binds specifically to the EGFR on both normal and tumor
cells and competitively inhibits the binding of epidermal growth factor (EGF)
and other ligands, such as transforming growth factor-alpha.

Bevacizumab is a recombinant humanized monoclonal antibody that is specifically
directed against vascular endothelial growth factor (VEGF) that recognizes all
isoforms of VEGF. It may exert a direct anti-angiogenic effect by binding to
and clearing VEGF from the tumor environment.

Erlotinib is an orally active, potent, selective inhibitor of the EGFR tyrosine
kinase. EGFR is expressed on the cell surface of both normal and cancer cells.
Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R)
mutations is higher than its affinity for the wild-type receptor. In
nonclinical models, inhibition of EGFR autophosphorylation results in cell
stasis and/or death.

Atezolizumab, cetuximab, bevacizumab, and erlotinib are approved (as single
agent and/or in combination with other anti-cancer therapies) for the treatment
of different types of carcinomas.

This study has been transitioned to CTIS with ID 2023-506311-18-00 check the CTIS register for the current data.

This Phase Ia/Ib study will evaluate the safety, pharmacokinetics,
immunogenicity (as applicable for study biotherapeutics), preliminary activity,
and biomarkers of GDC-6036 as a single agent (Arm A) and in combination with
other anti-cancer therapies in patients with advanced or metastatic solid
tumors with a KRAS G12C mutation. Combination therapies will include
atezolizumab (Arm B), cetuximab (Arm C), bevacizumab (Arm D), and erlotinib
(Arm E) in NSCLC, CRC, and other solid tumors. Specific objectives and
corresponding endpoints for the study are outlined below.

Safety Objective (Primary Study Objective)
The safety objective for this study is to evaluate the safety of GDC-6036 as a
single agent and in combination with other anti-cancer therapies on the basis
of the following endpoints:
• Incidence and severity of adverse events, with severity determined according
to National Cancer Institute Common Terminology Criteria for Adverse Events,
Version 5.0 (NCI CTCAE v5.0)
• Incidence and nature of dose-limiting toxicities (DLTs)
• Change from baseline in targeted vital signs
• Change from baseline in targeted clinical laboratory test results
• Change from baseline in targeted ECG parameters

Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are to characterize the PK
profile of GDC 6036 when administered as a single agent and in combination with
other anti cancer therapies and to characterize the PK profile of these
anti-cancer therapies when administered in combination with GDC-6036, on the
basis of the following endpoints:
• Plasma concentrations of GDC-6036 and erlotinib at specified timepoints
• Serum concentrations of atezolizumab, cetuximab, and bevacizumab at specified
timepoints

The exploratory PK objectives for this study are as follows:
• To evaluate potential relationships between drug exposure and the safety and
activity of GDC-6036
• To evaluate the exposure of potential circulating metabolites of GDC-6036
following a single or repeat oral dose(s) of GDC-6036
• To assess ex vivo plasma protein binding of GDC-6036 and its impact on
pharmacokinetics (Arm A only)
• To evaluate the effect of GDC-6036 on plasma levels of 4b-hydroxy
cholesterol, an endogenous biomarker of CYP3A4 induction (Arm A only)

Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response
to study biotherapeutics on the basis of the following endpoints:
• Incidence of anti-drug antibodies (ADAs) to each study biotherapeutic
(atezolizumab, cetuximab, and bevacizumab) during the study relative to the
prevalence of ADAs at baseline

The exploratory immunogenicity objective for this study is to evaluate
potential effects of detectable ADAs on the basis of the following endpoints:
• Correlation between ADA status for each study biotherapeutic and efficacy,
safety, and PK endpoints

Activity Objectives
The activity objective for this study is to make a preliminary assessment of
the activity of GDC 6036 as a single agent and in combination with other
anti-cancer therapies on the basis of the following endpoints:
• Objective response rate (ORR), defined as the proportion of patients with a
complete response (CR) or partial response (PR) on two consecutive occasions >=
4 weeks apart, as determined by the investigator according to Response
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
• Duration of response (DOR), defined as the time from the first occurrence of
a documented objective response to disease progression or death from any cause
during the study (whichever occurs first), as determined by the investigator
according to RECIST v1.1
• Progression-free survival (PFS), defined as the time from first treatment at
Cycle 1 Day 1 to the first occurrence of disease progression or death from any
cause during the study (whichever occurs first), as determined by the
investigator according to RECIST v1.1

Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or
evaluate biomarkers that are potentially predictive of response to GDC-6036 as
a single agent or in combination with other anti-cancer therapies (i.e.,
predictive biomarkers), early surrogates of activity, associated with
progression to a more severe disease state (i.e., prognostic biomarkers),
associated with acquired resistance to KRAS G12C inhibitors (e.g., GDC 6036),
associated with susceptibility to developing adverse events or can lead to
improved adverse event monitoring or investigation (i.e., safety biomarkers),
can provide evidence of GDC-6036 activity as a single agent or in combination
with other anti-cancer therapies (i.e., pharmacodynamic [PD] biomarkers), or
can increase the knowledge and understanding of disease biology and drug
safety. Corresponding biomarker endpoints include the following:
• Relationship between exploratory biomarkers in blood, plasma, and tumor
tissue and safety, PK, activity, or other biomarker endpoints

This is a first-in-human Phase Ia/Ib, open-label, multicenter dose-escalation
and dose-expansion study designed to evaluate the safety, pharmacokinetics, and
preliminary activity of GDC-6036 as a single agent and in combination with
other anti-cancer therapies in patients with advanced or metastatic solid
tumors that harbor the KRAS G12C mutation. The combination therapies in this
study are atezolizumab (Arm B), cetuximab (Arm C), bevacizumab (Arm D), and
erlotinib (Arm E) in NSCLC, CRC, and solid tumors. The study is designed with
the intention to include new, additional treatment arms during study conduct
(via protocol amendments) to explore combinations of GDC-6036 with other
anti-cancer therapies based on emerging nonclinical and clinical data with
GDC-6036, other KRAS G12C inhibitors, or evolving standard-of-care treatment.
Anticipated future combinations with GDC-6036 may include RTK/RAS/MAPK
pathway-targeting therapies, agents that target compensatory pathways that may
mediate intrinsic or acquired resistance to treatment, immunotherapies, agents
that modulate the tumor microenvironment, and standard-of-care agents to
further explore safety, pharmacokinetics, and preliminary activity.

Patients who do not meet the criteria for participation in this study (screen
failure) may qualify for up to two re-screening opportunities (for a total of
three screenings per participant) at the investigator's discretion. Patients
are not required to re-sign the consent form if they are re-screened within 30
days after previously signing the consent form. For patients who are
re-screened, all eligibility criteria must be re-evaluated and screening
assessments should be repeated as applicable to meet the eligibility criteria.
The investigator will record reasons for screen failure in the screening log.

Patients will be enrolled in two stages: a dose-escalation stage (Stage I) and
a dose-expansion stage (Stage II). Patients will be assigned to one of five
regimens: A) Single-agent GDC-6036 (patients with NSCLC, CRC and solid tumors),
B) GDC-6036 + atezolizumab (NSCLC only), C) DC-6036 + cetuximab (CRC only), D)
GDC-6036 + bevacizumab (solid tumors only) of E) GDC-6036 + bevacizumab (NSCLC
only).

During the dose-escalation stage, patients will be evaluated for DLTs at
escalating dose levels to determine the maximum tolerated dose (MTD) or maximum
administered dose (MAD, if the MTD was not identified) for GDC-6036 as a single
agent and in combination with other anti cancer therapies.

In Stage I Arm A (single agent GDC-6036), the starting dose of GDC-6036 will be
50 mg by mouth (PO) once a day (QD).
In the combination arms in Stage I, the starting dose of GDC-6036 will be no
higher than one dose level below the last cleared dose level in Stage I Arm A
(GDC-6036 single-agent dose escalation).

The starting dose and schedule of the combination therapy agents will be as
follows: atezolizumab 1200 mg IV on Day 1 of 21-day cycles; cetuximab as an
initial dose of 400 mg/m2 IV followed by 250 mg/m2 IV weekly in 21-day cycles;
bevacizumab 15 mg/kg IV on Day 1 of 21-day cycles; and erlotinib 150 mg PO QD
in 21 day cycles.

To acquire additional PK and safety data, and tumor PD data related to the
mechanism of action of GDC-6036, patients with advanced or metastatic KRAS
G12C-positive solid tumors may be enrolled in backfill cohorts in Stage I Arm A
(single agent GDC-6036) at dose levels that do not exceed the last cleared dose
in Arm A based on the dose-escalation rules described in the protocol.
Patients may be enrolled in the Stage I Arm A Backfill Biopsy or Stage I Arm A
Backfill Non-Biopsy NSCLC cohort, as described in the protocol. Patients
enrolled to backfill cohorts will not be included as part of the DLT-evaluable
population.

Approximately 140 additional patients may be enrolled in the dose-expansion
stage (Stage II) at or below the MTD (or MAD, if the MTD was not identified)
established during Stage I in each arm to further assess the safety,
tolerability, PK, and preliminary anti-tumor activity of GDC-6036 as a single
agent and in combination with other anti cancer therapies. Furthermore, a
subset of up to approximately 15 patients enrolled in Stage II Arm A1, Arm A2,
or Arm A3 will participate in the tablet PK assessment.

The study consists of a screening period of up to 28 days, a treatment period,
and a safety follow-up period during which patients will be followed for safety
outcomes for a treatment-specific period after their final dose of study drug
or until they receive another anti-cancer therapy, whichever occurs first.
Patients who provide a separate consent may be screened for KRAS G12C mutation
status through central testing of circulating tumor DNA (ctDNA).

In the absence of unacceptable toxicities and unequivocal disease progression
as determined by the investigator, patients may continue treatment with
GDC-6036 until the end of the study.

All patients will be closely monitored for adverse events throughout the study
and for a treatment-specific period after the final dose of study treatment or
until initiation of another anti-cancer therapy, whichever occurs first.
Adverse events will be graded according to the NCI CTCAE v5.0.
To characterize the PK properties of GDC-6036, plasma samples will be taken at
various timepoints before and after dosing.
Approximately 236 patients are expected be enrolled in this study, at
approximately 70 investigative sites in North America, Europe, and Asia-Pacific.

Dose-Escalation Stage (Stage I Arm A)

Approximately 96 patients will be enrolled in the dose-escalation stage of the
study.

Dose Escalation of Single Agent GDC-6036 (Arm A)
Approximately 48 patients will be enrolled in the dose-escalation stage (Stage
I Arm A), including backfill cohorts. The starting dose of GDC-6036 in the
dose-escalation stage will be 50 mg PO QD. Single-patient dose-escalation
cohorts will be treated at escalating dose levels of GDC-6036. Upon occurrence
of a DLT, as defined in the protocol, or a Grade >= 2 adverse event involving
major organ toxicity that, per investigator, has no clear identifiable cause
other than study drug, dose escalation will convert to a 3+3 design, and the
cohort will be expanded to a minimum of 3 patients and follow the
dose-escalation rules for 3+3 dose-escalation cohorts (see the protocol). In
addition, dose escalation will convert to a 3+3 design at any dose level that
exceeds 200 mg QD. Dose escalation may also convert to a 3+3 design based on
cumulative PK data relative to exposure targets from nonclinical studies (e.g.,
in vitro apparent KRAS G12C alkylation concentration associated with 90% target
inhibition [IC90]).

Once single-patient dose escalation converts to a 3+3 dose-escalation design,
the cohort undergoing assessment, and all subsequent cohorts, will continue in
accordance with the 3+3 dose-escalation cohort rules described in the
protocol. Enrollment of the first 2 patients in all 3+3 dose-escalation
cohorts will be separated by at least 24 hours.

Patients will be closely monitored for adverse events during a DLT assessment
window, defined as Days 1*-1 of Cycle 1. Adverse events identified as DLTs, as
defined in the protocol, will be reported to the Sponsor within 24 hours.

Patients who discontinue from study treatment prior to completing the DLT
assessment window for reasons other than a DLT will be considered non-evaluable
for dose-escalation decisions and MTD or MAD assessments, and will be replaced
by an additional patient at that same dose level. Patients who miss more than
5 doses of GDC-6036 during the DLT assessment window for reasons other than a
DLT will also be replaced. Patients who reduce the GDC-6036 dose during the
DLT assessment window for reasons other than DLT may be replaced. Patients who
receive supportive care during the DLT assessment

The investigational medicinal products for this study are GDC-6036,
atezolizumab, cetuximab, bevacizumab, and erlotinib.

GDC-6036
GDC-6036 will be supplied by the Sponsor as an active pharmaceutical ingredient
(API) powder-in-capsule (PIC) formulation in three strengths: 5 mg, 25 mg, and
100 mg (free base equivalent). Additionally, a film-coated tablet formulation
in a dose strength of 100 mg (free base equivalent) will also be supplied for
clinical use.

In Stage I Arm A, the starting dose of GDC-6036 is 50 mg PO QD. Dose
escalations will occur as described in the protocol.

On Day 1 of Cycle 1 of each DLT-evaluable cohort and Stage I Arm A backfill
cohort (non-biopsy NSCLC patients only), a single dose of GDC-6036 will be
administered to patients in a clinical setting that can accommodate frequent
blood draws over a period of up to 8 hours after the first dose is administered
and at 24 and 48 hours postdose. QD dosing will begin on Day 3 of Cycle 1.
From Cycle 2 onwards, patients will be administered GDC-6036 PO QD on all days
of the cycle. The length of Cycle 1 and all subsequent cycles will be 21 days.

In Stage I Arm A backfill cohorts (biopsy patients only) and Stage II expansion
cohorts, QD dosing of GDC-6036 will begin on Day 1 of Cycle 1 and each cycle
will be 21 days in length.

For GDC-6036 doses to be administered at home, a sufficient number of capsules
or tablets should be dispensed to the patient to last until the next visit, or
at the investigator*s discretion, through one cycle. Patients will
self-administer GDC-6036 as detailed below, except on study visit days when
GDC-6036 will be administered in the clinic.

Patients should take GDC-6036 at approximately the same time each day unless
otherwise instructed. Patients will be instructed as to the number and
strength of capsules or tablets to take, according to their assigned dose level
and schedule. Patients will be asked to record the time and date that they
take each dose in a medication diary.

Atezolizumab
Atezolizumab will be supplied by the Sponsor as an IV formulation in 1200 mg/20
mL vials, or supplied by the study sites and reimbursed by the Sponsor.
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on
Day 1 of each 21-day cycle, following administration of GDC-6036.

Cetuximab
Cetuximab will be supplied by the Sponsor in commercially available
formulations, or supplied by the study sites and reimbursed by the Sponsor.
Cetuximab will be administered at an initial dose of 400 mg/m2 as a 120-minute
IV infusion on Day 1 followed by 250 mg/m2 as a 60-minute IV infusion weekly,
in 21-day cycles. The maximum infusion rate must not exceed 10 mg/min.
Cetuximab should be administered following administration of GDC-6036.

Bevacizumab
Bevacizumab will be supplied by the Sponsor as an IV formulation in 400 mg/16
mL vials, or supplied by the study sites and reimbursed by the Sponsor.
Bevacizumab will be administered by IV infusion at a fixed dose of 15 mg/kg IV
on Day 1 of each 21-day cycle, following administration of GDC-6036.

Erlotinib
Erlotinib will be supplied by the Sponsor as tablets in 25 mg, 100 mg, and 150
mg strengths, or supplied by the study sites and reimbursed by the Sponsor.
Erlotinib will be administered PO QD starting at 150 mg in 21-day cycles, at
the same time as GDC-6036, with sips of water in between.

GDC-1971
For GDC-1971 doses to be administered at home, a sufficient number of capsules
or tablets should be dispensed to the patient to last until the next visit, or
at the investigator*s discretion, through one cycle. Patients will
self-administer GDC-1971 as detailed below, except on study visit days when
GDC-1971 will be administered in the clinic.

Patients should take GDC-1971 at approximately the same time each day unless
otherwise instructed. Patients will be instructed as to the number and
strength of capsules or tablets to take, according to their assigned dose level
and schedule.

KRAS is the most frequently mutated oncogene in up to 25% of cancers and is
associated with resistance to select standard-of-care therapies and overall
poor prognosis. Although previously considered an *undruggable* cancer target,
the landmark discovery of the switch II pocket within KRAS has enabled the
development of covalent inhibitors specific for KRAS G12C. With this finding,
covalent small molecule inhibitors targeting KRAS, and specifically the KRAS
G12C mutation, are being evaluated in early clinical development.

The study assessments will be at the screening, C1D1 (cycle 1, day 1), (C1D2 -
arm A only), C1D3, C1D8, C1D15, C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1,
C5D15, C6D1, C6D15, CxD1 of each subsequent cycle. Treatment will continue
until disease progresses (as defined by RECIST criteria), unacceptable toxicity
occurs, patient is out of clinicial benefit, patient withdraws or dies, or
patient discontinues the study for any other reason, after which all patients
make a final visit.

The potential side effects, based on laboratory studies or knowledge of similar
drugs, for GDC-6036 are: Diarrhea, Nausea, Vomiting, Mouth or throat
irritation, Abnormal liver tests (possible liver damage), Sensitivity to
sunlight and Genotoxicity (damage to the genetic information within a cell).
During the study assessments the patient could experience the following
discomforts:
Response to contrast medium (used for CT scan / MRI)
Possible consequences of blood sampling (pain, bruising, infection, dizziness)
Radiation exposure on CT scan
Possible consequences of biopsy (pain, redness, swelling, bleeding)

Specific therapies aimed at KRAS G12C-positive cancer may provide more
tolerable and effective treatment options for patients with advanced stage
cancers that harbor KRAS G12C. Based on the nonclinical data available for
GDC-6036 and on clinical data from other covalent KRAS G12C inhibitors, the
benefit-risk profile of GDC-6036 as a single agent has been assessed to be
appropriate for initiating this first-in-human clinical study.