The primary purpose of this study is to define the maximum tolerated dose (MTD) and determine a recommended Phase 2 dose (RP2D) and schedule of orally-administered RP-3500 (camonsertib) alone or in combination with talazoparib, a PARP inhibitor, or Gemcitabine in patients with advanced solid tumors with ATR inhibitor-sensitizing mutations. This study will also evaluate the safety and tolerability of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine, examine both the pharmacokinetics (PK)and pharmacodynamics (PD)and investigate its anti-tumor activity in solid tumors.

This is a first-in-human, Phase 1/2a, multi-center, open-label, dose-escalation and expansion study to:

• Evaluate the safety profile and MTD of RP-3500 (camonsertib) when administered orally, alone and in combination with talazoparib or gemcitabine, to establish the dose and schedule recommended for the Phase 2
• Characterize the PK profile of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine
• Identify anti-tumor activity associated with RP-3500 (camonsertib) given alone or in combination with talazoparib or gemcitabine

The initial cohorts will test RP-3500 (camonsertib) as monotherapy. Additional cohorts will enroll with RP-3500 (camonsertib) in combination with talazoparib or gemcitabine.

After the RP2D and schedule is determined, expansion cohort(s) for RP-3500 (camonsertib) will be enrolled to study the anti-tumor effect, and further examine the safety and PK of RP-3500 (camonsertib) at the RP2D

Inclusion Criteria:

• Written informed consent, according to local guidelines, signed and dated by the patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
• Male or female and ≥ 18 years-of-age at the time of signature of the consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• Histologically confirmed solid tumors resistant or refractory to standard treatment and/or patients who are intolerant to standard therapy.
• Measurable disease as per RECIST v1.1
• Existing biomarker profile (tumor tissue or plasma) reported from a local test obtained in a certified lab per institutional guidelines:
• Available tumor tissue
• Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments.
• Ability to swallow and retain oral medications.
• Acceptable organ function at screening
• Acceptable blood counts at screening
• Negative pregnancy test (serum) for females of childbearing potential at Screening and prior to first study drug.
• Resolution of all toxicities of prior treatment or surgery.
• Male patients with female partners of childbearing potential and females of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study and for at least 6 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug.
• Life expectancy ≥12 weeks after the start of the treatment according to the investigator's judgment.
• Module 1c only: Ability to consume a high-fat meal and fast for 12 hours.

Exclusion Criteria:

• Chemotherapy, small molecule anticancer or biologic anticancer therapy given within 14 days prior to first dose of study drug.
• History or current condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment.
• Prior therapy with an ATR or DNA-dependent protein kinase (DNA-PK) inhibitor.
• Known hypersensitivity to any of the ingredients of RP-3500 (camonsertib).
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the patient's safety.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled high blood pressure
• Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
• Moderate or severe hepatic impairment (ie, Child-Pugh class B or C).
• History or presence of an abnormal ECG that is clinically significant in the investigator's opinion.
• History of ventricular dysrhythmias or risk factors such as structural heart disease, coronary heart disease (clinically significant electrolyte abnormalities or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well-known to prolong the QT interval
• History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
• Module 3 only: Known sensitivity to any of the ingredients of talazoparib.