Study of PARPi 2X-121 as Monotherapy and in Combination With Dovitinib in Patients With Advanced Solid Tumors

Part 1

This part of the study will follow an accelerated titration method followed by a standard "3+3" design to determine the MTD of 2X-121. The MTD is defined as one dose level (cohort) below the dose in which dose limiting toxicities (DLTs) were observed in ≥ 33% of the participants.

The calculation of the sample size for this trial is based on the traditional 3 + 3 dose escalation scheme which is conducted as follows:

• Subjects are treated in cohorts of one (Cohort 1) or three (Cohorts 2-3) subjects, each receiving the same dose. For the assessment of a DLT, subjects are observed for 14 days.
• In Cohort 1, if the one subject does not exhibit a DLT, the next cohort of three subjects will receive the next higher dose (Cohort 2). In Cohort 2, if none of the three subjects exhibits a DLT, the next cohort of three subjects will receive the next higher dose (Cohort 3).
• Otherwise, if at least one subject of a cohort exhibits a DLT, a further cohort of three subjects is treated at the same dose level (cohort) without escalating the dose.
• If exactly one out of the six subjects treated at this dose exhibits a DLT, the trial continues as planned at the next higher dose level (cohort).
• If two or more subjects out of the six subjects treated at this dose exhibit a DLT, the dose escalation stops at that level and the next lower dose is considered as the MTD. When the escalation has stopped, additional subjects will be treated at the MTD to a total of six subjects.

Cohort escalation in Part 1 and Part 2 (i.e., the decision to progress from one cohort (dose level) to another) will not proceed until all of the following events have occurred:

1. All study subjects in a given cohort (dose level) have been enrolled, and
2. All such subjects have been followed for at least 14 days from the initiation of study treatment, and
3. The Investigator (PI), Sponsor's Medical Officer, and Medical Monitor have reviewed the available safety data, determined that none of the DLTs outlined below have occurred, and recommends further dose escalation

• Hematological
• Grade 4 neutropenia [or Grade 3 neutropenia with fever (>38.5 °C in axilla)] for ≥ 7 days
• Grade 4 thrombocytopenia (Grade 3 thrombocytopenia with bleeding) lasting >7 days.
• Other non-hematological toxicity
• Grade 3 fatigue, or a 2-point decline in Eastern Cooperative Oncology Group (ECOG) performance status that persists for >7 days.
• Nausea, vomiting or diarrhea that persists at Grade 3 or 4 despite maximal medical therapy.
• Any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization.

The dose levels to be evaluated in Part 1 are shown below:

Cohort 1 600 mg (morning dose: 200 mg + evening dose: 400 mg)

Cohort 2 800 mg (morning dose: 400 mg + evening dose: 400 mg)

Cohort 3 1000 mg (morning dose: 400 mg + evening dose: 600 mg)

On Day 1 of first treatment cycle (C1D1), patients will be administered 2X-121 monotherapy as oral capsules taken twice daily. Each treatment cycle will consist of 28 days.

Blood samples will be collected for 2X-121 PK analysis at the following time points:

• C1D1: prior to drug administration (morning dose), 1 h (± 15 min), 3h (± 15 min), 4h (± 15 min), 6h (± 15 min), 12h (± 1 h, the sample should be taken before the evening dose)
• C1D2: prior to drug administration (morning dose)
• C1D7: prior to drug administration (morning dose)
• C1D15: prior to drug administration (morning dose)
• CXD1: prior to drug administration (morning dose) for the first day of all subsequent treatment cycles

Once the MTD has been determined, subjects enrolled in lower dose cohorts will be allowed to escalate the dose to the MTD, if acceptable per the Investigator's discretion. Subjects will be eligible for continuing treatment in absence of progressive disease or unacceptable toxicity or withdrawal of consent.

Part 2

In Part 2 of the study, patients will receive dovitinib in combination with the MTD of 2X-121 determined in Part 1. Part 2 will follow a "3+3" design to determine the MTD of dovitinib when given in combination with 2X-121. The MTD is defined as one dose level (cohort) below the dose in which dose limiting toxicities (DLTs) were observed in ≥ 33% of the participants. See Part 1 above for definition of DLTs.

The dose levels to be evaluated in Part 2 are shown below:

Cohort 1 2X-121 (MTD) + 300 mg dovitinib

Cohort 2 2X-121 (MTD) + 400 mg dovitinib

Cohort 3 2X-121 (MTD) + 500 mg dovitinib

Dovitinib will be administered once daily (morning) on a 5 days on/2 days off schedule. In a 28 day cycle, dovitinib will be administered C1D1 - C1D5, C1D8 - C1D12, C1D15 - C1D19, and C1D22 - C1D26.

Blood samples will be collected for 2X-121 and dovitinib PK analyses at the following time points:

• C1D1: prior to drug administration (morning dose), 0.5h (± 15 min), 1h (± 15 min), 2h (± 15 min), 3h (± 15 min), 4h (± 15 min), 6h (± 15 min), 8h (± 15 min), 10h (± 1 h), 12h (± 1 h, to be taken before the evening dose)
• C1D2: prior to drug administration (morning dose)
• C1D7: prior to drug administration (morning dose)
• C1D15: prior to drug administration (morning dose), 0.5h (± 15 min), 1h (± 15 min), 2h (± 15 min), 3h (± 15 min), 4h (± 15 min), 6h (± 15 min), 8h (± 15 min), 10h (± 1 h), 12h (± 1 h, to be taken before the evening dose)
• CXD1: prior to drug administration (morning dose) for the first day of all subsequent treatment cycles

Once the MTD has been determined, subjects enrolled in lower dose cohorts will be allowed to escalate the dose to the MTD, if acceptable per the Investigator's discretion. Subjects will be eligible for continuing treatment in absence of progressive disease or unacceptable toxicity or withdrawal of consent.

An additional 3-6 patients will receive 2X-121 in combination with dovitinib once the MTD dose is determined.