A Phase 1, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Ascending Doses of G1T48 Alone and in Combination with Palbociclib in Women with Estrogen Receptor Positive, HER2-Negative Advanced Breast Cancer

Approximately 80% of breast cancers express estrogen receptors (ERs),
progesterone receptors, or both. The relapse rate after presentation with
early-stage disease of these hormone receptor (HR)-positive cancers has been
substantially reduced with the use of endocrine therapies, namely aromatase
inhibitors (AIs) and tamoxifen. Despite the success of these therapies, relapse
of disease often occurs either during or after completion of adjuvant endocrine
therapy. The established standard of care following disease progression in the
adjuvant setting is combination therapy with a cyclin-dependent kinase (CDK)4/6
inhibitor and an endocrine therapy, based on a significant improvement in
progression-free survival (PFS) when compared to endocrine therapy alone. To
date, 3 CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been
approved for use in postmenopausal women with ER-positive, human epidermal
growth factor receptor-2 (HER2)-negative advanced breast cancer. Palbociclib in
combination with letrozole was approved as initial endocrine-based therapy in
the United States (US) in February 2015, and use of palbociclib in combination
with fulvestrant in patients with disease progression following endocrine
therapy was approved in the US in February 2016. Palbociclib in combination
with AI or fulvestrant was approved in the European Union (EU) in August 2017.
However, disease progression eventually ensues in the majority of patients and
additional effective treatment options are limited. The standard of care in
these patients is not yet established as CDK4/6 inhibitors are a relatively new
addition to the treatment of HR positive breast cancer. Additionally, the
mechanisms of resistance are for the most part unknown. Treatment options
include a steroidal AI, tamoxifen, AI plus everolimus, fulvestrant (if not
previously used), chemotherapy and other targeted agents where appropriate.
While the efficacy of these agents in this setting is unknown, studies of these
agents prior to the use of CDK4/6 inhibitors have shown only modest activity.
Therefore, the development of effective therapies that can overcome resistance
to previously administered endocrine therapies is of clinical importance.

Fulvestrant is a clinically effective selective estrogen receptor degrader
(SERD), and a standard of care medicine in HR-positive advanced breast cancer.
However, intramuscular injection of fulvestrant may be painful to the patient
and also limits the maximum dose to 500 mg. Acquired mutations in the
ligand-binding domain (LBD) of ESR1 (the gene encoding ER alpha) in patients
with advanced breast cancer can cause the ER to remain constitutively active
without estrogen; a major mechanism of resistance to AIs. Although some
evidence suggests that cancers with ESR1 mutations may retain relative
sensitivity to fulvestrant, higher relative doses and systemic exposures of ER
degraders or novel therapies could improve efficacy. Therefore, developing an
agent that has a more favorable route of administration (ie, oral), with the
potential to achieve higher plasma concentrations than fulvestrant, and thus
potentially improved ER degradation in patients with and without ESR1
mutations, is desirable.

G1T48 is an oral SERD that may be administered at doses with the potential to
achieve higher relative exposure, enhanced target engagement, without painful
injections, and potentially superior clinical benefit in the management of
patients with ER-positive advanced breast cancer. Oral administration could
provide a more convenient and effective solution for patients over injectable
drug formulations.

Parts 1 and 2 of this study will characterize the safety, tolerability, and
preliminary antitumor activity of G1T48 monotherapy in patients with
ER-positive, HER2-negative advanced breast cancer. Furthermore, as the
combination of CDK4/6 inhibitor with endocrine therapy has emerged as the
current standard of care, Part 3 will evaluate the safety, tolerability, and
preliminary antitumor activity of G1T48 in combination with palbociclib.

The primary objective of the study are to: 1) Determine the safety and
tolerability of G1T48 alone (Parts 1 and 2) or in combination with palbociclib
(Part 3), 2) Determine the MTD and RP2D of G1T48 alone (Parts 1 and 2) or in
combination with palbociclib (Part 3)

The secondary objectives of the study are to: 1) Characterize single and
multiple dose PK parameters of G1T48 and metabolite(s), including PopPK, 2)
Characterize PK parameters of palbociclib (Part 3), 3) Characterize the effect
of food on the relative bioavailability of G1T48 and 4) Assess antitumor
activity

The exploratory objectives of the study are to: 1) Assess correlation between
cfDNA and response endpoints, 2) Assess changes in FES PET, 3) Assess CTCs, 4)
Assess pharmacodynamic changes in fresh tumor tissue, 5) Assess PK/
pharmacodynamic relationships and 6) Assess biomarkers as predictors of
response or resistance.

This is a Phase 1, open-label, first-in-human (FIH) study of G1T48 alone and in
combination with palbociclib administered orally in patients with advanced
ER-positive, HER2 negative breast cancer. This open-label study consists of 3
parts: Part 1 will evaluate the safety, tolerability, PK, including the effect
of a high-fat meal on bioavailability, MTD, and RP2D of escalating doses of
G1T48 monotherapy; Part 2 will include an expansion cohort at the RP2D to
further characterize the safety and preliminary antitumor activity of G1T48
monotherapy; and Part 3 will evaluate the safety, tolerability, PK, and
preliminary antitumor activity of G1T48 in combination with palbociclib.

Part 1
Part 1 Dose-Escalation Cohorts
This study will employ a standard 3 + 3 dose escalation design in Part 1.
Patients will receive a single oral dose of G1T48 on Cycle 1 Day 3 followed by
blood sampling over the next 72-hour period for PK analysis. Continuous oral
daily dosing of G1T48 will then commence on Cycle 1 Day 1. Each cycle will be
28 days in duration.
FES PET will be acquired prior to G1T48 administration (during screening), at
Cycle 2 Day 2, and at the time of treatment discontinuation to determine 18F
estradiol tracer uptake.
All dose escalation/de-escalation decisions will be made by the safety
monitoring committee (SMC) based on safety and available PK data from Cycle 1
Day -3 through Cycle 1 Day 28 of the current cohort (DLT period of the current
cohort), as well as available FES PET data and cumulative safety data from all
cohorts. The SMC will make the final dose determination for each subsequent
cohort (projected dose levels are presented in Table 6 1). The maximum G1T48
dose in this study will not exceed 2000 mg/day.

Food Effect Cohort(s)
An additional G1T48 cohort of 8 patients may be enrolled during Part 1 to
assess the effect of a high-fat meal on the rate and extent of the absorption
of G1T48. At the discretion of the Sponsor and/or SMC additional food effect
cohort(s) may be explored.

Definition of Dose-Limiting Toxicities
Dose-limiting toxicities are defined as follows:
- Grade 4 neutropenia
- >= Grade 3 neutropenic infection/febrile neutropenia
- Grade 4 thrombocytopenia
- >= Grade 3 thrombocytopenia with bleeding
- >= Grade 3 nonhematologic toxicity (the following Grade 3 toxicities only
qualify as a DLT if the toxicity persists for >= 24 hours despite maximal
medical management: nausea, vomiting, diarrhea; or >= 5 days with maximal
medical management: fatigue)
- Liver function test abnormalities meeting Hy*s Law criteria (aspartate
aminotransferase [AST] or alanine aminotransferase [ALT] >= 3 × upper limit of
normal [ULN] and total bilirubin >= 2 × ULN); G1T48 must be permanently
discontinued in any patient meeting Hy*s Law criteria
- Any Grade 3 or greater electrolyte abnormality lasting >72 hours
- Any Grade 3 or greater electrolyte abnormality AND the patient is
clinically symptomatic, regardless of duration
o NOTE: Grade 3 or greater amylase or lipase that is not associated with
symptoms or clinical manifestations of pancreatitis does not need to be
reported as a DLT
- Any death not clearly due to the underlying disease or extraneous causes

Part 2
After the G1T48 RP2D has been determined, an open-label expansion cohort (Part
2) will be enrolled at the RP2D to further characterize the safety and
preliminary antitumor activity of G1T48. Following screening, patients will
begin continuous oral daily dosing of G1T48 on Cycle 1 Day 1. Pre- or
perimenopausal patients will also receive luteinizing hormone-releasing hormone
(LHRH) agonist for the duration of study treatment.
FES PET will be acquired prior to G1T48 administration (during screening), at
Cycle 2 Day 2, and at the time of treatment discontinuation in approximately
50% of patients enrolled in Part 2 to determine 18F-estradiol tracer uptake as
a measure of G1T48 pharmacodynamic action. Only postmenopausal women may
provide FES PET scans in Part 2.

The SMC will review all cumulative safety data, as well as all available PK and
FES PET data, approximately every 4 months during the Treatment Phase of Part 2.

Part 3
An open-label cohort will be enrolled to evaluate the safety and preliminary
antitumor activity of G1T48 in combination with palbociclib. Based on similar
safety profiles seen in the 600 mg and 1000 mg dose cohorts in Parts 1 and 2,
patients enrolled in Part 3 will receive G1T48 at either dose (600 mg once
daily or 1000 mg once daily). Additional dose levels may be explored at the
discretion of the Sponsor and/or SMC based on emerging safety and efficacy
data. Palbociclib 125 mg oral daily will be administered on Days 1 to 21 of
each 28-day cycle, starting on Cycle 1 Day 1. Pre- or perimenopausal patients
will also receive LHRH agonist for the duration of study treatment.
The SMC will review all cumulative safety data, as well as all available PK and
biomarker data, after the first 6 patients in Part 3 have completed 1 cycle of
therapy, then approximately every 4 months during the Treatment Phase of Part
3.

The starting dose is 200 mg G1T48, taken orally once daily. Subsequent dose
levels will be determined by the SMC.

Please refer to appendix D of the subject information sheet for an overview of
the side effects and possible risks of the study.