safety and tolerability study of gim-531 in advanced solid tumors

Conditions: Melanoma Stage IV; Solid Tumor

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).

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.

Keywords: pd-1 resistance pd-1 resistant/refractory akt3