Phase 1 Study of PLX7486 as Single Agent and With Gemcitabine Plus Nab-Paclitaxel in Patients With Advanced Solid Tumors

Inclusion Criteria:

1. Male or female ≥18 years old

2. Patients with solid tumors who:

   1. Part 1: have tumor progression following standard therapy, have treatment-refractory disease, or for whom there is no effective standard of therapy
   2. Part 2a: have received ≤2 prior chemotherapy regimens for the treatment of their primary malignancy and for whom nab-paclitaxel and gemcitabine would be considered a reasonable chemotherapy option
   3. Part 2b: have previously untreated locally advanced, non-resectable or metastatic pancreatic adenocarcinoma that, in the opinion of the Principal Investigator, are not candidates for FOLFIRINOX treatment (i.e., bolus and infusional leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin). Patients who received prior neoadjuvant or adjuvant therapy with recurrent disease ≥6 months following completion of the regimen are also eligible.
   4. Part 2c: have advanced, non-resectable tumors of any histology with activating Trk (NTRK) point or NTRK fusion mutations (e.g., mammary analogue secretory carcinoma, secretory breast cancer, papillary thyroid cancer, congenital fibrosarcoma, congenital mesoblastic nephroma, lung cancer, melanoma, and colon cancer) AND have received prior treatment, if there is a known therapy that results in increased survival for that particular disease (e.g., patients with melanoma should have received treatment with ipilimumab or BRAF inhibitors, patients with colon cancer should have received at least 2 prior lines of therapy with a fluoropyrimidine in combination with oxaliplatin and irinotecan, etc.).
3. Patients in Part 2b must have measurable disease by RECIST criteria v1.1
4. Women of child-bearing potential must have a negative pregnancy test within 7 days prior to initiation of dosing and must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 3 months after the last dose of study drug, Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Fertile men must also agree to use an acceptable method of birth control while on study drug and up to 3 months after the last dose of study drug.
5. All associated toxicity from previous or concurrent cancer therapy must be resolved (to ≤ Grade 1 or Baseline) prior to study treatment administration.
6. Patients with stable, treated brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening.
7. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements.
8. Karnofsky Performance Status ≥70%
9. Life expectancy ≥3 months.
10. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 X 109/L, Hgb >9 g/dL, platelet count ≥100 X 109/L, AST/ALT ≤2.5 X ULN or <5 X ULN in the presence of liver metastases, creatinine ≤1.5 X ULN or calculated CrCl >60 mL/min using Cockcroft-Gault formula). Note: patients must not have received RBC transfusions (within 4 weeks), platelet transfusions (within 1 week) or growth factors (within 1 week).

Exclusion Criteria:

1. Other than the primary malignancy, active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g., chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix.
2. Chemotherapy within 28 days prior to C1D1
3. Biological therapy within 28 days prior to C1D1
4. Radiation therapy within 28 days prior to C1D1
5. Investigational drug use within 28 days or 5 half-lives, whichever is longer, prior to C1D1
6. Part 1 only: (a) Patients with active or a history of glucose intolerance or diabetes mellitus and (b) Hemoglobin A1c ≥7%.
7. Part 2a and 2b only: (a) Patients with a known hypersensitivity to nab-paclitaxel or gemcitabine and (b) Hemoglobin A1c >8%.
8. Part 2a and 2b: Patients with uncontrolled diabetes. Patients with glucose intolerance or diabetes whose blood glucose levels are consistently well-controlled with the use of oral hypoglycemic agents and/or insulin are permitted.
9. Part 2b only: Patients who have received radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic pancreatic adenocarcinoma. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study.
10. ≥ Grade 2 sensory neuropathy at baseline
11. Uncontrolled intercurrent illness (i.e., active infection) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the patient's ability to participate
12. Refractory nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption.
13. QTcF ≥450 msec (for males) or ≥470 msec (for females) at Screening
14. The presence of a medical or psychiatric condition that makes the patient inappropriate for inclusion in this study.