A First-in-Human Study of Mutant-selective PI3K alpha; Inhibitor, RLY-2608, as a Single Agent in Advanced Solid Tumor Patients and in Combination With Fulvestrant in Patients With Advanced Breast Cancer

Key Inclusion Criteria

Patient has ECOG performance status of 0-1

One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per

local assessment

- Other potentially oncogenic PIK3CA mutations may be considered but must be approved

by the Sponsor prior to enrollment.

Part 1 - Ability to provide archived tumor tissue or be willing to undergo pretreatment

tumor biopsy to assess PIK3CA status retrospectively Part 2 - Submit tumor tissue prior

to study drug initiation for determination of PIK3CA mutation retrospectively.

Key Inclusion for RLY-2608 Single Agent Arm

- [For Part 1]: Evaluable disease per RECIST v1.1

- [For Part 2]: Measurable disease per RECIST v1.1

- Disease that is refractory to standard therapy, intolerant to standard therapy, or

has declined standard therapy.

- Part 1- histologically or cytologically confirmed diagnosis of unresectable or

metastatic solid tumor

- Part 2 - Unresectable or metastatic solid tumor with PIK3CA mutation(s) and one of

the following tumor types:

Group 1: clear cell ovarian cancer Group 2: head and neck squamous cell carcinoma Group

3: cervical cancer Group 4: other solid tumors, excluding colorectal, clear cell ovarian,

head and neck squamous cell, and cervical cancers Group 5: unresectable or metastatic

solid tumors with PIK3CA double mutations

Key Inclusion for Combination Arms

- [For Part 1 and Part 2]: Evaluable disease per RECIST v1.1

- [For Part 1 and Part 2]: Male or female with histologically or cytologically

confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is

not amenable to curative therapy. Females may be postmenopausal, premenopausal, or

perimenopausal. Premenopausal or perimenopausal females must have a histologically

or cytologically confirmed diagnosis of HR+ HER2- advanced or metastatic breast

cancer that is not amenable to curative therapy and must have been previously

treated with GnRH agonist at least 4 weeks prior to start of study drug

- [For Part 1 and Part 2]: Had previous treatment for breast cancer with:

1. ≤1 line of chemotherapy in the metastatic setting

2. ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, in either the adjuvant and/or

metastatic setting

3. ≥1 antiestrogen therapy in either adjuvant and/or metastatic setting,

including, but not limited to, selective estrogen-receptor degraders (eg,

fulvestrant), selective estrogen receptor modulators (eg, tamoxifen), and

aromatase inhibitors (AI) (letrozole, anastrozole, exemestane), and

4. ≥1 PARP inhibitor, if appropriate, if documented germline BRCA1/2 mutation

Note: Systemic local, loco-regional, or adjuvant treatment with chemotherapy

and PARP inhibitors is not to be included in enumeration or previous treatment

[For RLY-2608 + fulvestrant arm; Part 2, Group 2]: Received prior treatment with a PI3Kα

inhibitor and discontinued the inhibitor due to intolerance and not disease progression,

where intolerance is defined as treatment discontinuation due to treatment related AE

(eg. hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity

reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson

syndrome.

Key Exclusion Criteria

Prior treatment with PI3Kα, AKT, or mTOR inhibitors (except for RLY-2608 + fulvestrant

arm, Part 2, Group 2).

Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma

glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.

History of hypersensitivity to PI3K inhibitors. For combination arms only:

hypersensitivity to fulvestrant, palbociclib, and/or ribociclib, as appropriate for the

combination.

For triple combination arms only: history of pneumonitis or interstitial lung disease.

For the single agent and combination arms other than with ribociclib: mean QT interval

corrected using Fridericia's formula (QTcF) >480 msec. For the combination arms with

ribociclib: mean QTcF ≥450 msec.

Patient has a history of prolonged QT syndrome or torsades de pointes. Patient has a

familial history of prolonged QT syndrome.

Clinically significant, uncontrolled cardiovascular disease CNS metastases or primary CNS

tumor that is associated with progressive neurologic symptoms