A Phase 1 Dose Escalation and Dose Expansion Trial of KST-6051 in Participants With Advanced Solid Tumors With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Mutation

The main purpose of the trial is to assess whether the trial drug, KST-6051, is safe and tolerable when administered orally, alone or in combination with other anticancer agents, to adults with advanced or metastatic solid tumors with certain KRAS mutations.

This is a first-in-human, phase 1, open-label, multicenter clinical trial designed to evaluate safety, tolerability, pharmacokinetics, biomarkers, pharmacodynamics and preliminary activity of orally administered KST-6051 as monotherapy or in combination with other anticancer agents. The trial seeks to enroll adults with advanced or metastatic KRAS mutant solid tumors including but not limited to pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer whose cancers have progressed after prior therapy or in whom standard therapy was not tolerated. The trial includes a dose escalation phase in which higher doses of KST-6051 will be given in subsequent groups of participants. The trial also includes a dose expansion phase to further investigate KST-6051. Participants can stay in the trial as long as they benefit from the treatment and can tolerate it.

Drug: KST-6051. KST-6051 will be administered orally as a tablet.

Drug: Gemcitabine/nab-paclitaxel. Gemcitabine/nab-paclitaxel will be administered intravenously (IV).

Drug: Cetuximab. Cetuximab will be administered IV.

Drug: Pembrolizumab. Pembrolizumab will be administered IV.

Drug: mFOLFOX6. mFOLFOX6 will be administered IV.

Drug: FOLFIRI. FOLFIRI will be administered IV.

Drug: Pemetrexed. Pemetrexed will be administered IV.

Drug: Carboplatin. Carboplatin will be administered IV.

KST-6051 Dose Escalation Monotherapy (experimental): Sequential cohorts with increasing doses of KST-6051 as monotherapy will be evaluated to determine recommended dose(s) for expansion (RDE\[s\]).

KST-6051 Dose Escalation Combination Therapy with Gemcitabine/Nab-paclitaxel (experimental): Sequential cohorts with increasing doses of KST-6051 as combination therapy with a standard dose of gemcitabine/nab-paclitaxel will be evaluated in participants with previously treated PDAC.

KST-6051 Dose Escalation Combination Therapy with Cetuximab (experimental): Sequential cohorts with increasing doses of KST-6051 as combination therapy with a standard dose of cetuximab will be evaluated in participants with previously treated KRAS-mutant mCRC.

KST-6051 Dose Escalation Combination Therapy with Pembrolizumab (experimental): Sequential cohorts with increasing doses of KST-6051 as combination therapy with a standard dose of pembrolizumab will be evaluated in participants with first- or second-line KRAS-mutant NSCLC.

KST-6051 Dose Expansion Monotherapy in PDAC After 1 or 2 Prior Lines of Therapy (experimental): Dose expansion cohorts will be evaluated to further investigate KST-6051 as monotherapy in PDAC after 1 or 2 prior lines of therapy.

KST-6051 Dose Expansion Monotherapy in mCRC After 1 or 2 prior Lines of Therapy (experimental): Dose expansion cohorts will be evaluated to further investigate KST-6051 as monotherapy in mCRC after 1 or 2 prior lines of therapy.

Dose Escalation Cohorts: Number of Participants With Dose-limiting Toxicities (DLTs) at the end of Cycle 1 (Each Cycle is 21 Days). Time frame: Up to Day 21 of Treatment Cycle 1.

Dose Escalation Cohorts: Number of Participants With Treatment-emergent Adverse Events (TEAEs). Clinically significant changes in safety assessments (vital signs, physical examinations, electrocardiograms, and clinical laboratory tests) are to be reported as adverse events. Time frame: Up to approximately 2 years.

Dose Escalation Cohorts: Number of Participants With Treatment-related Adverse Events (TRAEs). Clinically significant changes in safety assessments (vital signs, physical examinations, electrocardiograms, and clinical laboratory tests) are to be reported as adverse events. Time frame: Up to approximately 2 years.

Dose Expansion Cohorts: Confirmed Objective Response Rate (ORR). Time frame: Up to approximately 2 years.

Dose Escalation Cohorts: Maximum Observed Blood Concentration (Cmax) of KST-6051 Alone. Time frame: Up to Week 6.

Dose Escalation Cohorts: Cmax of KST-6051 in Combination with Other Agents. Time frame: Up to Week 6.

Dose Escalation Cohorts: Time to Achieve Cmax (Tmax) of KST-6051 Alone. Time frame: Up to Week 6.

Dose Escalation Cohorts: Tmax of KST-6051 in Combination with Other Agents. Time frame: Up to Week 6.

Dose Escalation Cohorts: Half-life (t1/2) of KST-6051 Alone. Time frame: Up to Week 6.

Dose Escalation Cohorts: t1/2 of KST-6051 in Combination with Other Agents. Time frame: Up to Week 6.

Inclusion Criteria: 1. Age ≥ 18 years. 2. Willing and able to give written informed consent. 3. Histologically documented locally advanced and unresectable or metastatic NSCLC, PDAC, CRC, or other solid tumor. 4. Documentation of KRAS mutation prior to the first dose of trial drug(s). 5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 6. Adequate cardiovascular, hematological, liver, and renal function. 7. Measurable disease at baseline per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1). Exclusion Criteria: 1. Central nervous system (CNS) tumors or untreated or unstable metastases. 2. Inability to swallow oral medications. 3. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial. Other inclusion/exclusion criteria are specified in the protocol.

Enrollment: 545 participants (estimated).