A first-in-human, phase 1/2, open-label, multi-center, dose-escalation and dose-expansion study to evaluate safety, tolerability, pharmacokinetics, and anti-tumor activity of the ATR inhibitor IMP9064 monotherapy and in combination with PARP inhibitor senaparib in patients with advanced solid tumors

IMP9064 is designed to inhibit the function of ATR, a component of the DNA damage repair system in all cells. Inhibition of DNA damage repair interferes with the replication of rapidly dividing cells. Senaparib (IMP4297) is an inhibitor of PARP 1 and PARP 2, components of the DNA damage repair system.

In this study, the sponsor and investigators want to learn:

• How much of the study drug can be given with an acceptable level of side effects
• The effects of the IMP9064 when given alone and in combination with Senaparib (good and bad)
• How much of the study drug is absorbed into the blood and how fast it is removed
• If research tests can be used in the future to predict who will benefit from study drug

This is a dose escalation/expansion study and will be conducted in four parts. In Parts 1 and 2 of the study, IMP9064 will be evaluated when given alone. Part 1 of the study is dose escalation, which means that the amount of IMP9064 given will be increased in each group of research participants, to find the most appropriate dose for further study in Part 2.  In Part 2, the dose expansion part of the study, a larger number of people will receive IMP9064 at the dose determined to be appropriate in Part 1 of the study.

Participants enrolled in Part 2 of the study will receive IMP9064 at the recommended dose and dosing schedule as determined in Part 1 of the study. Participation in Part 2 is dependent on specific findings in the tumor, including loss or low levels of some of the DNA repair proteins mentioned previously. Participants will be assigned to one of the following cohorts (groups) based on tumor type and biomarker analysis:

1. Metastatic prostate cancer with loss of function of ATM
2. Advanced solid tumors refractory to or intolerant to available treatment or where no standard treatment exists with loss of function of ATM (for example: gastric [stomach] cancer, pancreatic cancer, endometrial [uterine] cancer, colorectal [bowel] cancer, breast cancer, etc.)
3. Clear cell ovarian cancer or clear cell endometrial cancer with ARID1A loss of function
4. Advanced solid tumors refractory to or intolerant to treatment where no standard treatment exists with ARID1A loss of function
5. Advanced ovarian cancer that got worse on or after completing previous treatment with 1 PARP inhibitor

In Parts 3 and 4 of the study, IMP9064 will be evaluated in combination with Senaparib. In Part 3, multiple dose levels of IMP9064 available in combination with Senaparib will be evaluated to determine the most appropriate dose for further study of the combination regimen in Part 4.

In Part 4, a larger number of people will receive IMP9064 and Senaparib at the dose determined to be appropriate in Part 3. The dose of IMP9064 you receive and whether or not you receive Senaparib will be determined by when you enroll into the study.

The study regimen in each part will be given in cycles. Each cycle is 21 days. Two separate dosing schedules for IMP9064 may be evaluated during Part 1 of the study. During Part 1, participants will receive a single dose of IMP9064 to be taken orally (by mouth) on an empty stomach, followed by a 7-day washout in which participants will receive no IMP9064. After the 7-day washout, participants will receive IMP9064 once daily for 3 days, followed by 4 days off each week. Depending upon the results obtained from the 3 days on, 4 days off schedule, some additional groups of participants in Part 1 may receive IMP9064 twice daily for 3 days, followed by 4 days off. You will be informed if an alternative regimen will be used based on efficacy and safety of the study drug during the study. After a full evaluation of the results from Part 1, one of the two IMP9064 dosing schedules will be selected for use in Parts 2, 3 and 4. If you are in Part 3 or 4, in addition to receiving IMP9064, you will also receive Senaparib once daily, taken orally. Senaparib will be started at a fixed dose based on prior clinical studies but could potentially be increased or decreased based on accumulated study data.