MC# 22-23

General Inclusion Criteria:

• Signed written informed consent
• Have not received a previous treatment targeting the ATR/CHK1 pathway
• Discontinued all previous treatments for cancer for at least 21 days or 5 half-lives, whichever is shorter, and recovered from the acute effects of therapy to CTCAE Grade ≤1.  Palliative radiotherapy must have completed 1 week prior to start of study treatment.
• If patients have a known germline BRCA mutation or a cancer with a somatic BRCA mutations or which is HRD positive and for which there is an approved PARP inhibitor, participants should have received such treatment before participating in the study unless contra-indicated
• At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation by RECIST v1.1 or Prostate Cancer Working Group-3 Guidelines (PCWG-3)
• Acceptable hematologic, renal, hepatic, and coagulation functions independent of transfusions and granulocyte colony-stimulating factor
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis via immunohistochemistry (IHC) for loss of ATM protein
• Female patients of childbearing potential and male patients with female partners of childbearing potential are required to use highly effective contraception plus one barrier method during their participation in the study and for 4 or 16 weeks respectively following the last dose.  For male and female patients given gemcitabine or irinotecan, highly effective contraception plus one barrier method must be used from study entry until 6 months after the last dose of study treatment.  Male patients are required to refrain from donating sperm during their participation in the study and for 6 months following last dose.
• Estimated life expectancy of ≥12 weeks
• Reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures

Additional inclusion criteria for participants in dose expansion (Part B1):

• Patients with advanced or metastatic solid tumors with alterations to the ATM gene likely to predict for loss of ATM protein
• Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1
• Performance status of 0-1 on the ECOG scale

• Women who are pregnant, breast feeding, or who plan to become pregnant while in the study or within 4 weeks after the last administration of study treatment
• Men who plan to father a child while in the study or within 16 weeks after the last administration of study treatment
• Serious concomitant systemic disorder that would compromise the participants ability to adhere to the protocol including: one or more opportunistic HIV/AIDs-related infections within the past 12 months, hepatitis B virus, or hepatitis C virus; known history of clinical diagnosis of tuberculosis; malignancy prior to the one currently being treated that is not in remission
• Evidence of interstitial lung disease or pneumonitis (whether symptomatic or asymptomatic).  Patients with a previous history of these conditions which have resolved may be permitted to enter the study after discussion with the medical monitor (applicable to US population only).
• Moderate or severe cardiovascular disease
• Valvulopathy that is severe, moderate, or deemed clinically significant
• Documented major electrocardiogram (ECG) abnormalities which are clinically significant
• Symptomatic or uncontrolled brain metastases, spinal cord compression, or leptomeningeal disease requiring concurrent treatment
• Received a live vaccine within 30 days before the first dose of study treatment
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate
• Recent major surgery within 4 weeks prior to entry into the study or minor surgery within 1 week of entry into the study
• Significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment
• Currently enrolled in a clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study