First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors

This is a phase 1a / 1b, first-in-human, open-label, dose-escalation, safety,
pharmacokinetics, and pharmacodynamic study of TP-0903 administered once daily for the first
21 out of 28 days.

There are 2 phases in this study. In Phase 1a (dose escalation), sequential cohorts of three
(3) patients will be treated with escalated doses until the MTD is established. In the
absence of dose-limiting toxicities (DLTs), the dose will be increased using a modified
Fibonacci dose escalation scheme.

Once the MTD has been established, dosing will change from BSA-dependent to a flat dose based
on the average of the dose administered in the MTD expansion safety cohort. Once the MTD has
been established, in Ph 1b (expansion), 5 additional cohorts of up to 20 patients each with
specific tumor types (up to 100 additional patients total) may be enrolled at the MTD dose
level to confirm safety, explore potential biomarkers, and evaluate potential signals of
activity when TP-0903 is administered to specific groups of heavily pretreated patients or
given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI). Ten patients in
each of these 5 Expansion Cohorts will be required to consent to undergo pre- and post-dose
tumor biopsies. All patients who undergo these biopsies will comprise the 'Biopsy Cohorts'
(Phase 1b).

Patients who successfully complete a 4-week treatment cycle without evidence of significant
treatment-related toxicity or progressive disease will be permitted to continue to receive
treatment with the same dose and dosing schedule.

Inclusion Criteria:

To be eligible for participation in the study, patients must meet all of the following
inclusion criteria:

1. Patients enrolled in the Phase 1a study must:

1. Have a histologically confirmed diagnosis of advanced metastatic or progressive
solid tumor

2. Be refractory to, or intolerant of, established therapy known to provide clinical
benefit for their condition

2. Patients enrolled in the Phase 1b study must meet criteria for one of the following
tumor types:

1. Have tumors that have progressed after achieving a best documented response of at
least stable disease (ie, SD, PR, or CR documented per iRECIST following at least
2 cycles (8 weeks) of immunotherapy and are felt to be appropriate for this type
of treatment*

2. Have EGFR+ NSCLC and have demonstrated recent progression following a best
documented response of at least stable disease (ie, SD, PR, or CR documented per
per RECIST v1.1 on ≤2 lines of oral TKIs and are felt to be appropriate for this
type of treatment* Prior chemotherapy ± immunotherapy is allowed as long as the
patient is clearly demonstrating current progression on an EGFR TKI.

3. Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy
remaining

4. Have persistent/recurrent ovarian cancer who would be platinum refractory/
resistant and have had any number of lines of prior therapy

5. Have BRAF-mutated melanoma that has not responded to immunotherapy or a
combination BRAF/MEK inhibitor

3. Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1 or
iRECIST

4. Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO])
performance of ≤1

5. Have a life expectancy ≥3 months

6. Be ≥18 years of age

7. Have a negative pregnancy test (if female of childbearing potential)

8. Have acceptable liver function:

1. Bilirubin ≤1.5x upper limit of normal (ULN)

*Patients receiving immunotherapy should have a bilirubin level <3.0x ULN.

2. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and
alkaline phosphatase ≤2.5x upper limit of normal (ULN)

- If liver metastases are present, then ≤5x ULN is allowed.

- Patients receiving immunotherapy should have AST and ALT levels <5.0x ULN.

9. Have acceptable renal function:

a. Calculated creatinine clearance ≥30 mL/min

10. Have acceptable hematologic status:

1. Granulocyte ≥1500 cells/mm3

2. Platelet count ≥100,000 (plt/mm3)

3. Hemoglobin ≥9 g/dL

11. Have no clinically significant abnormalities on urinalysis

12. Have acceptable coagulation status:

1. Prothrombin time (PT) within 1.5x normal limits

2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits

13. Be nonfertile or agree to use an adequate method of contraception. Sexually active
patients and their partners must use an effective method of contraception (hormonal or
barrier method of birth control; or abstinence) prior to study entry and for the
duration of study participation and for at least 30 days after the last study drug
dose (see Section 4.6.3). Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

14. Have read and signed the IRB-approved informed consent form prior to any study related
procedure. (In the event that the patient is re-screened for study participation or a
protocol amendment alters the care of an ongoing patient, a new informed consent form
must be signed.)

15. Patients enrolled in each of the five Expansion Cohorts must be willing to consider
pre-study and on-study biopsies, if safe and medically feasible, as determined by
local interventional radiology (3 to 5 core samples requested at each biopsy
timepoint)

Patients meeting any one of these exclusion criteria will be prohibited from participating
in this study:

1. Have New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial
infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence
of ischemia on electrocardiogram (ECG) or during Cardiac Stress Testing within 14 days
prior to Day 1 (Appendix C)

2. Have a corrected QT interval (QTcF, Fridericia's method) of >450 msec in men and >470
msec in women

3. Have a seizure disorders requiring anticonvulsant therapy

4. Presence of symptomatic central nervous system metastatic disease or disease that
requires local therapy such as radiotherapy, surgery, or increasing dose of steroids
within 2 weeks prior to Day 1

5. Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting
O2 saturation of ≤88% breathing room air)

6. Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to
Day 1

7. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy

8. Are pregnant or nursing

9. Received treatment with radiation therapy, surgery, chemotherapy, or investigational
therapy within 28 days or 5 half lives, whichever occurs first, prior to study entry
(6 weeks for nitrosoureas or Mitomycin C)

a. This exclusion criterion is not applicable for patients with EGFR+ NSCLC or
immunotherapy-resistant tumors who are enrolled in expansion cohorts at the MTD.

10. Are unwilling or unable to comply with procedures required in this protocol

11. Have known infection with human immunodeficiency virus (HIV), hepatitis B, or
hepatitis C. Patients with history of chronic hepatitis that is currently not active
are eligible

12. Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other
conditions) that could compromise protocol objectives in the opinion of the
investigator and/or the sponsor

13. Are currently receiving any other investigational agent

14. Have exhibited allergic reactions to a similar structural compound, biological agent,
or formulation

15. Have undergone significant surgery to the gastrointestinal tract that could impair
absorption or that could result in short bowel syndrome with diarrhea due to
malabsorption

16. Have a history of severe adverse reaction (eg, hypersensitivity reaction, anaphylaxis)
to sulfonamides

17. Patients scheduled to receive immunotherapy or TKI regimens plus TP-0903 must not be
currently taking high-dose steroids (ie, physiologic dose approximately equivalent to
15 mg/day of prednisone)