Sponsor decision.

This is a Phase Ib, two-part, multi-center study. In Part 1, the study will evaluate the safety and tolerability, antitumor activity, pharmacokinetics, and determine the maximum tolerated dose (MTD) of 2X-121 monotherapy (at BID regimen) in patients with advanced solid tumors. In Part 2, the study will evaluate safety and tolerability, antitumor activity, pharmacokinetics and determine the MTD of dovitinib when given in combination with the MTD of 2X-121 determined in Part 1.

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.

Inclusion Criteria:

1. Age 18 years or older.

2. Histologically or cytological documented solid tumor.

3. Available tumor biopsy (most recent) for DRP® analysis.

4. Measurable disease by CT scan or MRI if possible.

5. Performance status of ECOG ≤ 1.

6. Recovered to Grade <1 or baseline from prior surgery or from acute toxicities of prior radiotherapy, or from treatment with cytotoxic, hormonal or biologic agents.

7. ≥ 2 weeks must have elapsed since any prior surgery or therapy with G-CSF and GM-CSF.

8. Patients with intracranial disease must be on stable or decreased level of steroid therapy (e.g. dexamethasone) for at least 7 days prior to baseline MRI. Non-enzymatic inducing anti-epileptic drugs are allowed.

9. Adequate conditions as evidenced by the following clinical laboratory values:

   1. Absolute neutrophils count (ANC) ≥ 1500/mm3 (1.5 x 10³/mL)
   2. Hemoglobin > 10.0 g/dL
   3. Platelets ≥ 100,000/mm3 (≥ 100 x 10⁹/L)
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN or ≤5x ULN in presence of liver metastases
   5. Serum bilirubin ≤ 1.5 ULN
   6. Alkaline phosphatase ≤ 2.5 x ULN
   7. Creatinine ≤ 1.5 ULN
   8. Blood urea nitrogen (BUN) ≤2X ULN.

10. Life expectancy equal or longer than 3 months.

11. The subject is willing to provide written informed consent to participate in the study after reading the informed consent form and the information provided and has had the opportunity to discuss the study with the investigator or designee.

12. The subject is able to communicate satisfactorily with the investigator and to participate in, and comply with, the requirements of the study.

13. The subject is able to understand the nature of the study and any potential hazards associated with participating in it.

14. Negative pregnancy test for female subjects of childbearing potential. Women of childbearing potential (WOCBP) and Women of non-childbearing potential are eligible to participate. Both women of childbearing potential and women of non-childbearing potential should use an approved method of birth control and agree to continue to use this method for the duration of the study (and for 90 days after taking the last dose of study drug).

Acceptable methods of contraception include abstinence, female subject/partner's use of hormonal contraceptive (oral, implanted, or injected) in conjunction with a barrier method (WOCBP only) (e.g., diaphragm, cervical cap, male condom, and female condom and spermicidal foam, sponges, and film), female subject/partner's use of an intrauterine device (IUD), or if the female subject/partner is surgically sterile for at least three months before screening or 2 years post-menopausal at time of screening. All male subjects/partners must agree to consistently and correctly use a condom for the duration of the study and for 90 days after taking the study drug. In addition, subjects may not donate sperm for the duration of the study and for 90 days after taking study drug.

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Exclusion Criteria:

1. Concurrent chemotherapy, radiotherapy, hormonal therapy, or other investigational drug except non-disease related conditions (e.g. insulin for diabetes) during study period.

2. Other malignancy with exception of curative treated non-melanoma skin cancer or cervical carcinoma in situ within 5 years prior to entering the study.

3. Any active infection requiring parenteral or oral antibiotic treatment.

4. History of coagulation or bleeding disorder or subject currently on therapeutic anticoagulant medication.

   Note: Prophylactic doses of heparin or low molecular weight heparin are allowed.

5. Known HIV positivity.

6. Known active hepatitis B or C.

7. Clinically significant (i.e. active) cardiovascular disease:

   1. Stroke within ≤ 6 months prior to day 1
   2. Transient ischemic attack (TIA) within ≤ 6 months prior to day 1
   3. Myocardial infarction within ≤ 6 months prior to day 1
   4. Unstable angina
   5. New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF)
   6. Serious cardiac arrhythmia requiring medication.

8. Other medications or conditions, including surgery, that in the Investigator's opinion would contraindicate study participation for safety reasons or interfere with the interpretation of study results.

9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of 2X-121 and dovitinib.

10. Requiring immediate palliative treatment of any kind including surgery and/or radiotherapy.

11. Female patients who are pregnant or breast-feeding (pregnancy test with a positive result before study entry).

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PI can publish and present results, provided that the Sponsor is given copies of any proposed publication or presentation at 30 days in advance of the submission of such proposed publication or presentation. Sponsor can object to the proposed publication/presentation, however approval will not be unreasonably withheld unless to protect proprietary/patent interests of the Sponsor or provide information to competitors that acts to reduce Sponsor's competitive edge in the marketplace.