Dose-escalation Study to Assess Safety and Pharmacokinetics of Nab-Sirolimus in Patients With Locally Advanced or Metastatic Solid Tumors and Moderate Liver Impairment

Inclusion Criteria:

• For All Patients

1. Willing and able to provide informed consent and comply with protocolrequirements for the duration of the study.

2. Male or female patients at least 18 years of age at the time of signing theinformed consent form.

3. Histologically confirmed locally advanced or metastatic solid tumors that ismeasurable or non-measurable.

4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or

6. Adequate hematologic counts:

• Absolute neutrophil count (ANC) ≥1.0 × 109 /L (growth factor supportallowed)
• Platelet count ≥75,000/mm 3 (75 × 10 9 /L) (transfusion and/or growthfactor support allowed)
• Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)

6. Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation:Creatinine Clearance ≥30 = (140 - age) × (weight[kg] / (72 x SCr[mL/min]_ x 0.85, if female

7. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol mustbe ≤350 mg/dL.

8. Male or non-pregnant and non-breastfeeding female:

• Females of child-bearing potential must agree to use highly effectivecontraception or abstinence without interruption from 28 days prior tofirst dose throughout 3 months after last dose and have a negativepregnancy test (urine or serum) result at screening and after the end ofstudy treatment. A second form of birth control is required even if shehas had a tubal ligation.
• Male patients must practice abstinence or agree to use a condom duringsexual contact with a pregnant female or a female of childbearingpotential while participating in the study and throughout 3 months afterlast dose. A second form of birth control is required even if he hasundergone a successful vasectomy.

9. Minimum of 4 weeks since major surgery, completion of radiation, or completionof all prior systemic anticancer therapy, or at least 5 half-lives if the priortherapy is a single agent small-molecule therapeutic, and in either caseadequately recovered from the acute toxicities of any prior therapy (includingneuropathy) to Grade ≤1. For Patients with Normal Hepatic Function

10. Normal hepatic function (total bilirubin ≤ upper limit of normal [ULN] andaspartate aminotransferase [AST] ≤ULN). For Patients with Moderate HepaticImpairment

11. Moderate hepatic impairment (total bilirubin 1.5-3.0 × ULN and any level ofAST)

Exclusion Criteria:

1. Received prior treatment with an mTOR inhibitor within 4 weeks prior to first dose.

2. Patients who have any severe and/or uncontrolled medical or psychiatric conditionsor other conditions that could affect their participation including:

3. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinalcord compression, untreated brain metastases or symptomatic or unstable brainmetastases. Note: Patients with stable brain metastases (defined asasymptomatic or no requirement for high-dose [defined as dexamethasone 10 mgdaily or higher] or increasing dose of systemic corticosteroids) and withoutimminent need of radiation therapy are eligible. If applicable, patients musthave completed brain radiation therapy and recovered adequately from anyassociated toxicity and/or complications prior to eligibility assessment. Forpatients who have received prior radiation therapy, post-treatment magneticresonance imaging (MRI) scan should show no increase in brain lesionsize/volume.

4. Unstable angina pectoris, symptomatic congestive heart failure (New York HeartAssociation, NYHA class III or IV), myocardial infarction ≤6 months prior tofirst study treatment, serious uncontrolled cardiac arrhythmia or any otherclinically significant cardiac disease.

5. Pre-existing severely impaired lung function. If a patient has a pre-existingpulmonary condition, eligible patients should have a spirometry and diffusingcapacity for carbon monoxide (DLCO) that is >50% of the normal predicted valueand/or O2 saturation that is >88% at rest on room air (Note: spirometry andpulmonary function tests [PFTs] not required to be performed unless clinicallyindicated).

6. Nonmalignant medical illnesses that are uncontrolled or whose control may bejeopardized by the treatment with the study therapy. Note, controlled nonmelanoma skin cancers, carcinoma in situ of the cervix, resected incidentalprostate cancer, or other adequately treated carcinoma-in-situ may be eligible,after documented discussion with the Medical Monitor.

7. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolicblood pressure ≥100 mmHg).

8. Patients with history of interstitial lung disease and/or pneumonitis, orpulmonary hypertension.

9. Individuals with known human immunodeficiency virus (HIV) infection areexcluded from this study as combination antiretroviral therapy couldpotentially result in significant pharmacokinetic interactions. In addition,these individuals are at increased risk of serious infections due to theimmunosuppressive effects of mTOR inhibition.

10. Active Hepatitis B or Hepatitis C, with detectable viral load. Note: A detailedassessment of Hepatitis B/C medical history and risk factors must be done atscreening for all patients.

11. Have active severe (Grade ≥3) infection requiring intravenous (IV) antibiotics (contact medical monitor for clarification).

12. High-dose systemic corticosteroids (>10 mg of prednisone or its equivalent) are notpermitted within 2 weeks of first dose. However, inhaled, intranasal, intraarticular, and topical steroids are allowed.

13. Have a history of Gilbert's disease.

14. Any condition that in the opinion of the Investigator would place the patient at anunacceptable risk or cause the patient to be unlikely to fully participate or complywith study procedures. For Patients with Moderate Hepatic Impairment

15. Had a clinical exacerbation of liver disease within the 2-week period prior to firstdose (ie, abdominal pain, nausea, vomiting, anorexia, or fever).

16. Have clinically demonstrable, tense ascites.

17. Had evidence of acute viral hepatitis within 1 month prior to first dose.

18. Have evidence of hepatorenal syndrome.

19. Have a transjugular intrahepatic portosystemic shunt.

20. Have active stage 3 or 4 encephalopathy.