A Study of PT0511 in Participants With KRAS Mutated or Amplified Advanced Solid Tumors

Exclusion Criteria33

• Cancer History
• 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 \<=2, (3) currently on stable doses of corticosteroids, and (4) pre-study brain 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.
• Prior Cancer Therapy
• Unresolved toxicities from prior anti-cancer therapies. Participants with prior endocrine replacement therapies are eligible for entry even if administered to treat endocrine deficiency due to the prior anti-cancer therapy.
• 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 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
• Prior treatment with a KRAS/RAS degrader.
• Medical History
• Significant cardiovascular disease within 6 months of starting study therapy.
• Active infection requiring antibiotics within 7 days of study treatment.
• Known HIV infection with a CD4+ T-cell count \<200 cells/mcL and/or a detectable viral load per parameters of assay and/or on an anti-retroviral regimen containing a strong or moderate CYP3A4/5 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.
• Medications
• Part 1a (Dose escalation): Use of a strong or moderate CYP3A4/5 inhibitor or inducer, Use of a strong P-gp inhibitor or inducer.
• Organ Function
• Participants with laboratory values indicating inadequate hematology, hepatic, or renal function.
• Diagnostic Assessments
• Clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG.
• Baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) \>=470 msec
• Female participants of childbearing age with a positive urine or serum test within 7 days of study start or confirmation from Ob/Gyn that any positive bHCG test is not representative of an ongoing pregnancy.
• Women who are lactating/breast feeding or who plan to breastfeed while on study through 28 days after receiving the last dose of study drug.
• Active HBV infection. Participants with resolved infection or who are on Stable antiviral therapy are eligible.
• Active HCV infection. Participants who have completed definitive antiviral therapy with post treatment confirmation of eradication are eligible.