Inclusion Criteria:

• Patients enrolled in the Phase 1a study must:
  • Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor;
  • Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.
• Patients enrolled in the Phase 1b study must meet criteria for one of the following tumor types:
  • Have tumors that have progressed after achieving a best documented response of at least stable disease (i.e., SD, PR, or CR documented per iRECIST [Appendix F-2]) following at least 2 cycles (8 weeks) of immunotherapy and are felt to be appropriate for this type of treatment;
  • Have EGFR+ NSCLC and have demonstrated recent progression following a best documented response of at least stable disease (i.e., 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;
  • Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy remaining;
  • Have persistent/recurrent ovarian cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy;
  • Have BRAF-mutated melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor.
• Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1 (Appendix F-1) or iRECIST.
• Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of ≤1.
• Have a life expectancy ≥ 3 months.
• Be ≥ 18 years of age.
• Have a negative pregnancy test (if female of childbearing potential).
• Have acceptable liver function:
  • Bilirubin ≤ 1.5× upper limit of normal (ULN);
    • *Patients receiving immunotherapy should have a bilirubin level < 3.0 × ULN.
  • Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase ≤ 2.5 × ULN. If liver metastases are present, then  ≤ 5 × ULN is allowed;
  • *Patients receiving immunotherapy should have AST and ALT levels < 5.0 × ULN.
• Have acceptable renal function:
  • Calculated creatinine clearance ≥30 mL/min.
• Have acceptable hematologic status:
  • Granulocyte ≥ 1500 cells/mm^3;
  • Platelet count ≥100,000 (plt/mm^3);
  • Hemoglobin ≥ 9 g/dL.
• Have no clinically significant abnormalities on urinalysis.
• Have acceptable coagulation status:
  • Prothrombin time (PT) within 1.5 × normal limits;
  • Activated partial thromboplastin time (aPTT) within 1.5 × normal limits.
• 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 including for 30 days after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Have read and signed the IRB-approved informed consent form prior to any study related procedure. (In the event that the patient is rescreened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed).
• Patients enrolled in the Phase 1b study must be willing to consider a pre-study and on-study biopsy, if safe and medically feasible, as determined by local interventional radiology (3 to 5 core samples requested at each biopsy timepoint).

Exclusion Criteria:

• 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.
• Have a corrected QT interval (QTcF, Fridericia’s method) of > 450 msec in men and > 470 msec in women.
• Have a seizure disorders requiring anticonvulsant therapy.
• 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.
• Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of ≤ 88% breathing room air).
• Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Day 1.
• Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
• Are pregnant or nursing.
• 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).
  • This exclusion criterion is not applicable for patients with EGFR+ NSCLC or immunotherapy-resistant tumors who are enrolled in expansion cohorts at the MTD.
• Are unwilling or unable to comply with procedures required in this protocol.
• 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.
• Have a serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• Are currently receiving any other investigational agent.
• Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation.
• 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.
• Have a history of severe adverse reaction (eg, hypersensitivity reaction, anaphylaxis) to sulfonamides.
• Patients scheduled to receive immunotherapy or TKI regimens plus TP-0903 must not be currently taking high-dose steroids (i.e., physiologic dose approximately equivalent to 15 mg/day of prednisone).