A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors

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 5half-lives, whichever is shorter, and recovered from the acute effects of therapy toCTCAE Grade ≤1. Palliative radiotherapy must have completed 1 week prior to start ofstudy treatment.

• If patients have a known germline BRCA mutation or a cancer with a somatic BRCAmutations or which is HRD positive and for which there is an approved PARPinhibitor, participants should have received such treatment before participating inthe study unless contra-indicated

• At least 1 radiologically evaluable lesion (measurable and/or non-measurable) thatcan be assessed at baseline and is suitable for repeated radiological evaluation byRECIST v1.1 or Prostate Cancer Working Group-3 Guidelines (PCWG-3)

• Acceptable hematologic, renal, hepatic, and coagulation functions independent oftransfusions and granulocyte colony-stimulating factor

• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of atumor lesion) available for submission for analysis.

• Female patients of childbearing potential and male patients with female partners ofchildbearing potential are required to use highly effective contraception plus onebarrier method during their participation in the study and for 7 months and 5 monthsrespectively following the last dose. For male and female patients given gemcitabineor irinotecan, highly effective contraception plus one barrier method must be usedfrom study entry until 6 months after the last dose of study treatment. Malepatients are required to refrain from donating sperm and female patients arerequired to refrain from donating eggs, during their participation in the study andfor 6 months following last dose.

• Estimated life expectancy of ≥12 weeks

• Reliable and willing to make themselves available for the duration of the study andare willing to follow study procedures

Additional inclusion criteria for participants in dose escalation (Part A1):

• Advanced or metastatic cancer which is refractory to standard therapies, or forwhich no standard therapies exist, or for which the investigator feels no otheractive therapy is required for the duration of the study

• Performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale

Additional inclusion criteria for participants in dose escalation (Part A2):

• Advanced or metastatic cancer for which gemcitabine is an appropriate treatment.Prior treatment with gemcitabine is permitted.

• Performance status of 0-1 on the ECOG scale

Additional inclusion criteria for participants in dose escalation (Part A3):

• Advanced or metastatic cancer for which irinotecan is an appropriate treatment.Prior treatment with irinotecan is permitted.

• Performance status of 0-1 on the ECOG scale

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

• Patients with advanced or metastatic solid tumors with alterations to the ATM genelikely to predict for loss of ATM protein

• Have at least 1 measurable lesion assessable using standard techniques by RECISTv1.1

• Performance status of 0-1 on the ECOG scale

• For France only ART0380 Monotherapy; Patient that is not eligible for curativetreatment, for whom all standard of care therapies have failed and no therapiesknown to provide clinical benefit are available.

• Combination arms; Patients for which irinotecan is an appropriate treatment. Priortreatment with irinotecan is permitted.

• For Spain only ART0380 Combination therapy, Patient that is not eligible forcurative treatment, for whom standard of care therapies have failed.

Additional inclusion criteria for participants in dose expansion (Part B2):

• Patients with a known germline BRCA mutation, or a cancer with a known somatic BRCAmutation, or which is known to be HRD positive, and for which there is an approvedPARP inhibitor should have received such treatment before participating in thestudy, unless contra-indicated.

• Females with histologically-confirmed diagnosis of high grade serous carcinoma ofthe ovary, fallopian tube or primary peritoneum that is not amenable to curativetherapy

• Platinum-resistant disease, defined as disease progression within 6 months of lastreceipt of platinum-based chemotherapy. Patients must not have had primaryplatinum-refractory disease (disease that progressed during first-lineplatinum-based therapy).

• No more than one prior regimen in the platinum-resistant setting. Hormonal therapiesand antiangiogenic therapies (as single agents) and PARP inhibitors used asmaintenance therapy are not considered as separate lines of therapy. Patients shouldhave previously received bevacizumab and chemotherapy unless contra-indicated.

• Have not received prior treatment with gemcitabine unless administered incombination with a platinum with no disease progression within 12 months aftercompletion of that regimen

• Have at least 1 measurable lesion assessable using standard techniques by RECISTv1.1

• Performance status of 0-1 on the on the ECOG scale

Inclusion criteria specific to Part B3

• Persistent or recurrent endometrial cancer with biological selection.:

• Patients should have received taxane/platinum chemotherapy, unless contraindicated.

• Measurable disease.

• Performance status of 0-1 on the ECOG scale.

Inclusion criteria specific to Part B4

• Advanced or metastatic solid cancers of any histology with biological selection

• If a PD-1/PDL-1 inhibitor (eg, pembrolizumab) is approved and available for thepatient's cancer, the patient should have received such treatment beforeparticipating in this study.

• Radiologically evaluable disease

• Performance status of 0-1 on the ECOG scale

Inclusion criteria specific to Part B5

• Metastatic CRC with alterations to the ATM gene

• Participants should have previously received and failed appropriate prior lines oftherapy in this setting.

• Have at least 1 measurable lesion assessable using standard techniques by RECSITv1.1.

• Performance status of 0-1 on the ECOG scale.

• Prior treatment with irinotecan is permitted.

General Exclusion Criteria:

• Women who are pregnant, breast feeding, or who plan to become pregnant while in thestudy or within 7 months after the last administration of study treatment

• Men who plan to father a child while in the study or within5 months after the lastadministration of study treatment

• Serious concomitant systemic disorder that would compromise the participants abilityto adhere to the protocol including: one or more opportunistic HIV/AIDs-relatedinfections within the past 12 months, a known hepatitis B virus, or known hepatitisC virus; known history of clinical diagnosis of tuberculosis; malignancy prior tothe one currently being treated that is not in remission

• Have ongoing interstitial lung disease or pneumonitis (whether symptomatic orasymptomatic).

• Moderate or severe cardiovascular disease

• Valvulopathy that is severe, moderate, or deemed clinically significant

• Documented major electrocardiogram (ECG) abnormalities which are clinicallysignificant

• Symptomatic or uncontrolled brain metastases, spinal cord compression, orleptomeningeal 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 abnormalitythat might confound the results of the study, interfere with the patient'sparticipation for the full duration of the study, or is not in the best interest ofthe patient to participate

• Recent major surgery within 4 weeks prior to entry into the study or minor surgerywithin 1 week of entry into the study

• Significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episodewithin 12 weeks prior to enrollment

• Currently enrolled in a clinical trial involving an investigational product or anyother type of medical research judged not to be scientifically or medicallycompatible with this study

Additional exclusion criteria for participants in dose escalation (Part A3, B1, and B5 in combination with irinotecan):

• Patients who are known to be homozygous for the UGT1A1 *6 or *28. (UGT1A1 7/7genotype), or simultaneously heterozygous for the UGT1A1 *6 and *28. (UGT1A1 7/7genotype)

• Patients receiving inhibitors of UGT1A1 within 2 weeks before the first dose ofstudy treatment