A Study of PT0253 in Participants With KRAS G12D Mutated Advanced Solid Tumors

Inclusion Criteria

• Histologically or cytologically confirmed advanced or metastatic solid malignancy
• Participant has a pathologically documented, locally advanced or metastatic malignancy with KRAS p.G12D mutation identified through molecular testing using a Clinical Laboratory Improvement Amendments (CLIA) certified, validated institutional or commercial test.
• Measurable disease (RECIST 1.1 Criteria).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
• Willingness to avoid pregnancy or fathering children from screening through 90 days after the last dose of study treatment.

Exclusion Criteria

• Active brain metastasis or carcinomatous meningitis. If participants have had brain metastases resected or have received radiation therapy, they may be eligible if: (1) study treatment begins at least 4 weeks from the end of brain-specific therapy, (2) residual neurological symptoms Grade less than or equal to (<=) 2, (3) currently on stable doses of corticosteroids, and (4) pre-study brain magnetic resonance imaging (MRI) documents no new/worsening brain lesions.
• History of any other malignancy within the past 2 years, except:
• Malignancy treated with curative intent and with no known active disease present >=2 years before enrolment and felt to be at low risk for recurrence by the investigator
• Basal or squamous cell carcinoma of the skin, in situ cervical cancer, early -stage endometrial cancer that has been definitively treated, superficial bladder cancer, Gleason 6/7 treated prostate cancer, and ductal carcinoma in situ or lobular carcinoma in situ of the breast.
• Unresolved toxicities from prior anti-cancer therapies (Common Terminology Criteria for Adverse Events [CTCAE] grades >1), except for alopecia. Grade <=2 toxicities from prior anti-tumor therapies that are considered irreversible may be allowed, provided that they are not described in the exclusion criteria AND the investigator and medical monitor are in agreement to proceed.
• Concurrent participation in another interventional clinical study.
• Treatment with anticancer medications or investigational drugs within the following intervals before the first administration of study drug:
• At least 14 days for chemotherapy or targeted small-molecule therapy.
• At least 28 days for a prior monoclonal antibody
• At least 4 months for checkpoint inhibitors
• At least 4 months for antibody-drug conjugates
• At least 28 days or 5 half-lives (whichever is longer) for all other investigational study drugs or devices. For drugs with very long half-lives, participants may be allowed to enroll prior to 5 half-lives at the discretion of the investigator in discussion with the medical monitor. Note: Concurrent hormonal therapy for prostate or breast cancer is allowable.
• Thoracic radiation within 4 months of starting study therapy.
• Significant cardiovascular disease within 6 months of starting study therapy.
• Active infection requiring antibiotics within 1 day of study treatment.
• History of non-infectious interstitial lung disease (ILD) or pneumonitis.
• Known HIV infection with a cluster of differentiation 4+ (CD4+) T-cell count less than (<) 200 cells per microliter [/mcL] and/or a detectable viral load per parameters of assay and/or on an anti-retroviral regimen containing a strong or moderate cytochrome (CY)P3A4/5 inhibitor or inducer and/or on a new anti-retroviral regimen for less than 28 days prior to the initiation of study treatment.
• Known history of drug-induced liver injury; primary biliary cirrhosis; or ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver, or portal hypertension.
• Major surgery within 4 weeks of the start of study therapy or postoperative complications preventing the participant from adhering to protocol assessments and procedures.
• Known hypersensitivity to any of the products to be administered during dosing.
• Any disease or disorder that, in the opinion of the investigator, may compromise the ability of the participant to provide written informed consent and/or to comply with all required study procedures.
• Part 1a (Dose escalation): Use of a strong or moderate CYP3A4/5 inhibitor or inducer, strong P-glycoprotein (P-gp) inhibitor or inducer or P-gp substrate.
• Use of multidrug and toxin extrusion protein 1 (MATE) or MATE2-K substrates that cannot be discontinued prior to the start of study treatment.
• Participants with laboratory values indicating inadequate hematology, hepatic, or renal function.
• Clinically significant abnormalities in rhythm, conduction, or morphology of resting electrocardiogram (ECG) or baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) >=450 milliseconds (msec).
• Female participants who are pregnant or lactating/breast feeding or who plan to breastfeed while on study through 28 days after receiving the last dose of study drug.
• Active hepatitis B virus (HBV) infection. Participants with resolved infection or who are on stable antiviral therapy are eligible.
• Active hepatitis C virus (HCV) infection. Participants who have completed definitive antiviral therapy with post treatment confirmation of eradication are eligible.