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

A Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the ATR Kinase Inhibitor ART0380 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors

This clinical trial is evaluating a drug called ART0380 in participants with advanced or metastatic solid tumors. The main goals of this study are to: Find the recommended dose of ART0380 that can be given safely to participants alone and in combination with gemcitabine or irinotecan Learn more about the side effects of ART0380 alone and in combination with gemcitabine or irinotecan Learn more about the effectiveness of ART0380 alone and in combination with gemcitabine or irinotecan

ART0380 is a new investigational medicinal product that is a potent and selective inhibitor of Ataxia telangiectasia and Rad3-related (ATR). ART0380 is being developed as an oral anti-cancer agent for the treatment of participants with cancers that harbor defects in deoxyribonucleic acid (DNA) repair and in combination with agents including those that cause DNA damage. This study is an open-label Phase I/IIa study designed to evaluate the safety, tolerability, PK and preliminary efficacy of ART0380 as monotherapy or in combination with gemcitabine or irinotecan in participants with advanced or metastatic solid tumors, advanced or solid tumors that fail to express Ataxia-Telangiectasia Mutated protein kinase (ATM) by immunohistochemistry, and high grade serous ovarian, primary peritoneal or fallopian tube carcinoma.

Part A1 will evaluate intermittent and continuous dosing of ART0380 monotherapy. Treatment will be given in 21-day cycles. Up to 50 participants will participate in this dose-escalation arm.

Part A2 will evaluate intermittent dosing of ART0380 in combination with gemcitabine in 21-day cycles. Up to 21 participants will participate in this dose escalation arm.

Part A3 will evaluate intermittent dosing of ART0380 in combination with irinotecan in 21-day cycles. Up to approximately 12 participants will participate in this dose escalation arm.

In Part B1, up to 3 cohorts making up to a total of approximately 90 participants with solid cancers with alterations in the ATM (ataxia-telangiectasia mutated) gene likely to predict for loss of ATM protein will be treated with either ART0380 monotherapy Or ART0380 in combination with irinotecan Or ART0380 in combination with gemcitabine

In Part B2, up to 60 participants with high grade serous ovarian, primary peritoneal, or fallopian tube carcinoma will be randomized (open-label) 1:1 to either ART0380 in combination with gemcitabine or gemcitabine alone.

Participants will receive ART0380 by mouth either intermittently (either once daily 3 days on, 4 days off; days 2-4 and 9-11;or days 1-3 and 8-10) or continuously (once daily each day) in 21 day cycles.

Part A: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities (DLTs) from ART0380 monotherapy and in combination with gemcitabine or irinotecan

Part B1: Number of participants with adverse events following administration of ART0380 monotherapy and in combination with gemcitabine or irinotecan monotherapy and in combination with gemcitabine or irinotecan

Part B2: Progression free survival by RECIST 1.1 in participants receiving ART0380 in combination with gemcitabine or gemcitabine alone

Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.

Part B2: Number of participants with adverse events following administration of ART0380 in combination with gemcitabine or gemcitabine alone

From Cycle 1 Day 1 until up to 30 days after the last dose of ART0380 or gemcitabine. Each cycle is 21 days.

Pharmacokinetic Analysis (single dose): determine the plasma concentration of ART0380 when given alone and in combination

Pharmacokinetic Analysis (multiple dose): determine the plasma concentration of ART0380 when given alone and in combination

Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.

Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.

Every 6 weeks from Cycle 1 Day 1 for 18 weeks, then every 9 weeks up to approximately 24 months. Each cycle is 21 days.

Assess tumor biopsies by immunohistochemistry (IHC) for loss of Ataxia Telangiectasia Mutated (ATM) protein

Where available archival tumor samples will be obtained for analysis of loss of ATM protein by IHC. If an archival tumor sample is not available, a pre-dose tumor biopsy must be taken.

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. 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 7 months and 5 months 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 and female patients are required to refrain from donating eggs, 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 escalation (Part A1): Advanced or metastatic cancer which is refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for the duration of the study Performance status of 0-2 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 0-2 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 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 For France only ART0380 Monotherapy; Patient that is not eligible for curative treatment, for whom all standard of care therapies have failed and no therapies known to provide clinical benefit are available. Combination arms; Patients for which irinotecan or gemcitabine is an appropriate treatment. Prior treatment with irinotecan or gemcitabine is permitted. Additional inclusion criteria for participants in dose expansion (Part B2): Patients with a known germline BRCA mutation, or a cancer with a known somatic BRCA mutation, or which is known to be HRD positive, and for which there is an approved PARP inhibitor should have received such treatment before participating in the study, unless contra-indicated. Females with histologically-confirmed diagnosis of high grade serous carcinoma of the ovary, fallopian tube or primary peritoneum that is not amenable to curative therapy Platinum-resistant disease, defined as disease progression within 6 months of last receipt of platinum-based chemotherapy. Patients must not have had primary platinum-refractory disease (disease that progressed during first-line platinum-based therapy). No more than one prior regimen in the platinum-resistant setting. Hormonal therapies and antiangiogenic therapies (as single agents) and PARP inhibitors used as maintenance therapy are not considered as separate lines of therapy. Patients should have previously received bevacizumab and chemotherapy unless contra-indicated. Have not received prior treatment with gemcitabine unless administered in combination with a platinum with no disease progression within 12 months after completion of that regimen Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1 Performance status of 0-1 on the on the ECOG scale General Exclusion Criteria: Women who are pregnant, breast feeding, or who plan to become pregnant while in the study 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 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 Have ongoing interstitial lung disease or pneumonitis (whether symptomatic or asymptomatic). 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 Additional exclusion criteria for participants in dose escalation (Part A3 and B1 in combination with irinotecan): Patients who are known to be homozygous for the UGT1A1 *6 or *28. (UGT1A1 7/7 genotype), or simultaneously heterozygous for the UGT1A1 *6 and *28. (UGT1A1 7/7 genotype) Patients receiving inhibitors of UGT1A1 within 2 weeks before the first dose of study treatment