Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)

Inclusion Criteria:

1. Patients must have a malignant solid tumor with a pathogenic inactivating TSC1 orTSC2 alteration. Genetic alterations should be identified using NGS in tumor tissueor liquid biopsy).

• Patients will be enrolled after the central evaluation of NGS report confirmseligibility.

2. Patients must have solid tumors that are metastatic or locally advanced wheresurgical resection is not an option or likely to result in severe morbidity.

3. Patients must have received all standard therapies appropriate for their tumor typeand stage of disease or, in the opinion of the Investigator, the patient would beunlikely to tolerate or derive clinically meaningful benefit from appropriatestandard of care therapy, or the patient has no satisfactory alternative treatments.

4. Patients must have 1 or more measurable target lesions by computed tomography (CT)scan or magnetic resonance imaging (MRI) (RECIST v1.1).

5. Age: 12 years or older.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or KarnofskyPerformance Status (KPS) ≥80 or Lansky play-performance scale for pediatric patients ≥80.

7. Adequate liver function:

8. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert'ssyndrome, then ≤3 × ULN)

9. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to livermetastases)

10. Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault CCr = ((140-age) × weight[kg]) / (72 × SCr[mL/min]) × 0.85, if female

11. Adequate hematologic parameters:

12. Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed)

13. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factorsupport allowed)

14. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)

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

16. Minimum of 4 weeks since any major surgery, completion of radiation, or completionof prior systemic anticancer therapy, or at least 5 half-lives if the prior therapyis a single agent small-molecule therapeutic, and adequately recovered from theacute toxicities of any prior therapy, including neuropathy, to Grade ≤1.

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

18. Females of childbearing potential must agree to use effective contraception orabstinence without interruption from 28 days prior to starting investigationalproduct (IP) throughout 3 months after last dose of IP and have a negativeserum pregnancy test (beta human chorionic gonadotropin, β-hCG) result atscreening and agree to ongoing pregnancy testing during the course of thestudy, and after the end of study treatment. A second form of birth control isrequired even if she has had a tubal ligation.

19. Male patients must agree not to donate sperm and must practice abstinence oragree to use a condom during sexual contact with a pregnant female or a femaleof childbearing potential while participating in the study and throughout 3months after last dose of IP. A second form of birth control is required evenif he has undergone a successful vasectomy.

20. The patient or the patient's parent(s) or legal guardian(s) understand(s) andsign(s) the informed consent.

21. Willingness and ability to comply with scheduled visits, laboratory tests, and otherstudy procedures.

Exclusion Criteria:

1. Prior treatment with an mTOR inhibitor, including nab-sirolimus.

2. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infectivetreatment, either ongoing or completed ≤7 days prior to enrollment.

3. Patients with primary brain tumors or PEComa.

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

5. 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 MRI scanshould show no increase in brain lesion size/volume.

6. 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.

7. 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).

8. Nonmalignant medical illnesses that are uncontrolled or whose control may bejeopardized by the treatment with the study therapy.

9. A history of malignancies other than the one under treatment unless the patientis disease-free for more than 5 years from diagnosis. Note, controllednon-melanoma skin cancers, carcinoma in situ of the cervix, resected incidentalprostate cancer, certain low grade hematologic malignancies (eg CLL, follicularlymphoma, etc), or other adequately treated carcinoma-in-situ may be eligible,after discussion with the medical monitor.

10. Uncontrolled hypertension (systolic blood pressure ≥160 mm-Hg and/or diastolicblood pressure ≥100 mm Hg).

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

12. 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.

13. Active Hepatitis B or Hepatitis C, with detectable viral load.

14. Regarding concomitant medications with significant CYP3A4 and P-gp interactions,discontinuation of strong inhibitors (eg, ketoconazole, itraconazole, voriconazole,erythromycin, clarithromycin, telithromycin, and others), strong inducers (eg,rifampin, rifabutin), and known CYP3A4 substrates with a narrow therapeutic window (eg, fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide,quinidine, or terfenadine) is required at least 5 half lives prior to receiving thefirst dose of nab-sirolimus, whichever is longer.