Clinical trial NCT06425926: Safety and Tolerability Study of GIM-531 in Advanced Solid Tumors
Official title: A Phase 1/2, Open-label, Multi-center Study of the Safety, Tolerability, and Efficacy of GIM-531 as a Single Agent and in Combination With Anti-PD-1 in Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Melanoma Stage IV
Solid Tumor
Keywords: PD-1 resistance
PD-1 resistant/refractory
AKT3
Lead sponsor: Georgiamune Inc
Sponsor class: INDUSTRY
First posted: 2024-05-23
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Primary outcomes:
measure: Incidence and severity of adverse events (AEs) / serious adverse events (SAEs) and tolerability
timeFrame: Through study completion, an average of 1 year
measure: Dose limiting toxicities (DLT) with GIM-531
timeFrame: 21 days
Secondary outcomes:
measure: Maximum plasma concentration (Cmax)
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose
measure: Time to maximum plasma concentration (Tmax)
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose
measure: Objective response rate (ORR)
timeFrame: From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
measure: Best overall response (BOR)
timeFrame: From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
measure: Duration of response (DOR)
timeFrame: From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
measure: Disease control rate (DCR)
timeFrame: From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
measure: Progression-free survival (PFS)
timeFrame: From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years)
measure: Overall survival (OS) rates
timeFrame: From study enrollment until death from any cause (OS rate assessed at 12 months)
measure: Tumor expression of immunological markers
timeFrame: Cycle 1 Days 1, 2 and 8; Cycle 2 Days 1 and 8; Cycle 3 Day 1 (each Cycle is 14 days)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Honor Health Research Institute
state: Arizona
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer Center
state: California
city: Fullerton
country: United States
facility: Providence Medical Foundation
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Billings
country: United States
facility: Intermountain Health St. Vincent Regional Hospital - Cancer Centers of Montana
state: Montana
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
References: