Safety and Tolerability Study of GIM-531 in Advanced Solid Tumors

GIM-531 is a first-in-class, orally bioavailable small molecule that is being developed for the treatment of advanced solid tumors as a single agent and rescue therapy. GIM-531 exhibits its primary effect through selective inhibition of regulatory T-cells (Tregs).

GIM531-CT01 is a Phase 1/2 open label, first-in-human, multicenter study. The Phase 1 portion will include a dose escalation with GIM-531 administered as a single agent. Additionally, there will be a dose expansion portion at the safety-cleared dose levels with participants allocated 1:1 within the proposed therapeutic range to accrue additional data for determining the safety profile, pharmacokinetics (PK) profile, pharmacodynamic (PD) effects and early anti-tumor activity of GIM-531. In Phase 2, GIM-531will be administered to participants with advanced/metastatic cutaneous melanoma who have progressed following treatment with an anti-PD-1 therapy.

Eligibility Criteria:
Key Inclusion Criteria:

* Written informed consent
* Cytologically or histologically confirmed locally advanced or metastatic solid tumor that has progressed on standard therapy or for which no standard therapy exist; or be intolerant of standard therapy
* Have not received an experimental drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug treatment or already be enrolled in a clinical study
* ECOG performance status 0-1
* Laboratory and ECG assessments within 28 days of enrollment including acceptable cardiac, renal, and hepatic functions
* Agree to baseline core needle biopsy or archival (within 12 months of screening) tumor submission; Note: Participants whose only site(s) of disease are in areas considered moderate or high risk for biopsy complications may be enrolled without a fresh biopsy upon Sponsor approval.
* Non pregnant participants; female participants of child bearing potential with non-sterile partners agree to use an effective form of contraception from the time of first dose of study drug (or 14 days prior to first dose for oral contraception) until 7 months after the last dose of study drug. Effective forms of contraception include hormonal (injection or oral), double barrier method, or intrauterine device. Non-sterile male participants with sexual partners of childbearing potential agree to use a barrier contraception method and agree to not donate sperm from the time of first dose of study drug until 4 months after the last dose of study drug.
* Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1

Phase 1 Expansion Cohorts Specific Inclusion Criteria (in addition to above inclusion criteria):

* NSCLC: Participants must have locally advanced/unresectable or metastatic NSCLC. Participants must have received ≤2 prior lines of therapy in the advanced/metastatic setting.
* TNBC: Participants must have locally advanced unresectable, recurrent, or metastatic TNBC. Participants must have received ≤2 prior lines of therapy in the advanced/metastatic setting. TNBC participants with germline BRCA1/2 mutations must have received ≤3 prior lines of therapy in the advanced/metastatic setting.
* Ovarian Cancer: Participants must have locally advanced unresectable, recurrent, or metastatic ovarian cancer. Participants must have received ≤2 prior lines of therapy in the advanced/metastatic setting with or without maintenance treatment.
* Tumors with AKT3 mutation/amplification: Participants must have a locally advanced unresectable, recurrent, or metastatic solid malignancy. Participants with known AKT3 mutation/amplification based on next generation sequencing (NGS) performed per local standard of care.

Phase 2 Specific Inclusion Criteria (in addition to above inclusion criteria):

* Have confirmed unresectable Stage III or metastatic Stage IV cutaneous melanoma that has radiographically progressed (as confirmed by imaging assessed by the Investigator) on an approved first-line single-agent or combination anti-PD-1 therapy
* Receiving anti-PD-1 therapy as their first line of treatment at the time of enrollment and amenable to continuing anti-PD-1 therapy during the study

Key Exclusion Criteria:

* Ongoing \>Grade 1 toxicity from prior therapy according to Common Terminology Criteria for Adverse Events v5.0 (Note: Grade 2 alopecia and Grade 2 sensory neuropathy are not exclusionary)
* Has melanoma with documented BRAF mutation (Phase 2 only)
* Has known leptomeningeal disease, spinal cord compression, or brain metastases, except participants with the following:

  * Brain metastases that have been treated and are clinically stable for at least 4 weeks prior to the first administration of study drug; Note: Participants receiving steroids for brain metastases must be either off steroids or on a stable, or decreasing dose, of \<10 mg daily of prednisone (or equivalent) in order to be eligible for enrollment; and
  * No ongoing neurological symptoms related to the anatomic location of the brain metastases.

Note: Neurological symptoms that are considered sequelae to treatment for brain metastases are allowed.

* Has known structural cardiac disease
* Has known serious arrythmia, serious dysrhythmia, history of long QT syndrome, or clinically relevant cardiac conduction abnormalities
* Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
* At time of screening, is receiving systemic steroid therapy (greater than or equal to 10 mg/day of prednisone or equivalent) or is taking any immunosuppressive therapy; Note: Use of topical, inhaled, nasal, or ophthalmic steroids is allowed.
* Has active and clinically significant bacterial, fungal, or viral infection, including known hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
* Has a history of, or currently has, an acquired or primary (congenital) immunodeficiency;
* Has had prior anti-cancer treatment with chemotherapeutic agents or immune modulating agents within \<4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study drug.
* Has received a live vaccine within 30 days of first dose of study drug;
* Has had or has planned major surgery within 2 weeks of the first dose of study drug;
* Inability to swallow an oral dose of a medication (eg, oral capsules)
* Is taking medications that are considered strong inducers or inhibitors of CYP2C8 or CYP3A4/5, P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), or sensitive substrates of P-gp and BCRP (Appendix C) that cannot be discontinued at least 1 week prior to first dose of study drug and for the duration of the study.
* Is taking drugs that modify gastric pH, such as proton-pump inhibitors (PPIs) or H2 blockers. Antacids such as calcium carbonate or aluminum hydroxide-based products are permitted.