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 or TSC2
   alteration. Genetic alterations should be identified using NGS in tumor tissue or
   liquid biopsy).

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

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

   3. Patients must have received all standard therapies appropriate for their tumor type
   and stage of disease or, in the opinion of the Investigator, the patient would be
   unlikely to tolerate or derive clinically meaningful benefit from appropriate standard
   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 Karnofsky
   Performance Status (KPS) ≥80 or Lansky play-performance scale for pediatric patients
   ≥80.

   7. Adequate liver function:

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

      2. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to liver
      metastases)

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

   9. Adequate hematologic parameters:

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

      2. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factor
      support allowed)

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

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

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

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

      1. Females of childbearing potential must agree to use effective contraception or
      abstinence without interruption from 28 days prior to starting investigational
      product (IP) throughout 3 months after last dose of IP and have a negative serum
      pregnancy test (beta human chorionic gonadotropin, β-hCG) result at screening and
      agree to ongoing pregnancy testing during the course of the study, and after the
      end of study treatment. A second form of birth control is required even if she
      has had a tubal ligation.

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

13. The patient or the patient's parent(s) or legal guardian(s) understand(s) and sign(s)
   the informed consent.

14. Willingness and ability to comply with scheduled visits, laboratory tests, and other
   study procedures.

Exclusion Criteria:

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

   2. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infective
   treatment, 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 conditions or
   other conditions that could affect their participation including:

      1. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal
      cord compression, untreated brain metastases or symptomatic or unstable brain
      metastases. Note: Patients with stable brain metastases (defined as asymptomatic
      or no requirement for high-dose [defined as dexamethasone 10 mg daily or higher]
      or increasing dose of systemic corticosteroids) and without imminent need of
      radiation therapy are eligible. If applicable, patients must have completed brain
      radiation therapy and recovered adequately from any associated toxicity and/or
      complications prior to eligibility assessment. For patients who have received
      prior radiation therapy, post-treatment MRI scan should show no increase in brain
      lesion size/volume.

      2. Unstable angina pectoris, symptomatic congestive heart failure (New York Heart
      Association, NYHA class III or IV), myocardial infarction ≤6 months prior to
      first study treatment, serious uncontrolled cardiac arrhythmia or any other
      clinically significant cardiac disease.

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

      4. Nonmalignant medical illnesses that are uncontrolled or whose control may be
      jeopardized by the treatment with the study therapy.

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

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

      7. Patients with history of interstitial lung disease and/or pneumonitis, or
      pulmonary hypertension.

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

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

   5. 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 the
   first dose of nab-sirolimus, whichever is longer.