A Phase 1/2 dose-escalation and expansion study of ST101 in patients with advanced unresectable and metastatic solid tumors

1. Able and willing to sign informed consent form (ICF) and comply with the protocol and the restrictions and assessments therein.
2. Male or female ≥18 years of age.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
4. Must have a locally advanced or metastatic inoperable tumor:
   1. For the dose escalation/regimen exploration phase: melanoma, carcinoma, or sarcoma
   2. For the expansion phase: HR^pos LA/MBC, cutaneous melanoma, recurrent/progressing GBM, or CRPC
5. Agrees to provide a newly obtained biopsy of an accessible lesion (if they can be biopsied based on the investigator's assessment) prior to the start of study treatment, and to repeat biopsy once during study treatment. Tissue obtained for the biopsy must not be previously irradiated (unless progressing following irradiation), but a new or progressing lesion in the radiation field is acceptable. Archived biopsies are acceptable for GBM patients and patients with bone-only disease if available.
6. In the investigator's opinion, the patient may not derive clinical benefit from, or is ineligible for, a particular form of standard therapy on medical grounds, or the patient failed or did not tolerate one or more of other anti-cancer therapies:
   1. For the dose escalation/regimen exploration phase:
      1. Refractory or intolerant to all available standard-of-care therapies
      2. Up to 3 previous lines of systemic anticancer therapies for metastatic disease are allowed.
   2. For the expansion phase:
      1. Primary (de novo) GBM that has recurred or progressed (per modified RANO criteria) after 1 standard treatment regimen (surgery, radiotherapy, and temozolomide therapy). Patients that undergo tumor treating fields as an adjuvant to first line therapy are allowed.
      2. HR^pos LA/MBC must have progressed after prior 1-3 hormone-based therapies. Previous treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, mammalian target of rapamycin (mTOR) inhibitor or chemotherapy is allowed as monotherapy or in combination.
      3. Cutaneous melanoma that has progressed after or on treatment with a CPI and have received 1-3 prior lines of therapy for their advanced/metastatic disease. Patients that have BRAF mutated disease should also have received one line of appropriate targeted therapy.
      4. CRPC that has progressed after at least 1 taxane and at least one next generation hormonal agent (NHA) or intolerant to these agents.
7. Evaluable disease per RECIST 1.1, modified RANO or PCWG3 with at least one target lesion.
8. Disease that progressed on, or is non-responsive to, the previous line of therapy per RECIST 1.1, modified RANO or PCWG3.
9. If not menopausal or surgically sterile, willing to practice at least one of the following highly effective methods of birth control for at least a (partner's) menstrual cycle before and for four months after ST101 administration: (1) total abstinence from sexual intercourse with a member of the opposite sex; (2) sexual intercourse with vasectomized male/sterilized female partner; (3) combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, parenteral, transvaginal or transdermal) for at least 3 consecutive months prior to investigational product administration; (4) other acceptable forms of birth control (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicide or cream); (5) use of an intrauterine contraceptive device.
10. All previous anti-cancer therapy-related adverse events should have resolved to grade 1 or baseline value with the exception of alopecia. Levothyroxine is allowed for patients that previously received a CPI and experienced thyroid dysfunction.
11. Adequate organ function as indicated by the following laboratory values:
    1. Hematological function:
       1. Neurophils ≥ 1,500/μL
       2. Platelets ≥ 100,000/μL for the escalation cohort or ≥ 75,000 for expansion cohorts
       3. Hemoglobin ≥ 8 g/dL
    2. Renal function:
       1. eGFR (CKD-EPI calculation) ≥ 60 mL/min/1.73m²
    3. Hepatic function:
       1. Serum total bilirubin: ≤ 1.5 ULN or if > 1.5 ULN
       2. Direct bilirubin: ≤ ULN
    4. Coagulation (unless the patient is receiving anticoagulation):
       1. INR ≤ 1.5
       2. aPTT ≤ 1.5 ULN
    5. Albumin: > 30g/L
12. For prostate cancer patients, the prostate specific antigen (PSA) value at screening and baseline should be ≥ 2 μg/L (2 ng/mL).
13. For prostate cancer patients, ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analog or orchiectomy (i.e., surgical or medical castration).
1. For patients who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the trial.
14. For prostate cancer patients, serum testosterone level less than 1.7 nmol/L (50 ng/dL).

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

1. Use of small molecule or tyrosine kinase inhibitor within 2 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study drug; chemotherapy, investigational drug or biological cancer therapy within 3 weeks prior to the first dose of study therapy; nitrosourea or radioisotope within 6 weeks prior to first dose.
2. Known hypersensitivity to ST101 or any of its excipients.
3. Baseline corrected interval between q and t wave on electrocardiogram (ECG) (QTc) > 480 msec using Fredericia's formula.
4. Symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
5. Presence of any other active malignancy requiring systemic therapy other than the disease under study.
6. Active infection with human immunodeficiency virus (HIV) and CD4+ T-cell count 350/μL. Patients not on established ART for at least four weeks and having a detectable HIV viral load. Testing is not required for eligibility.
7. Active infection with hepatitis B or hepatitis C, defined by a detectable viral load. Testing is not required for eligibility.
8. Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo or resolved childhood asthma/atopy are exceptions to this rule. Patients requiring intermittent use of bronchodilators or topical steroids would not be excluded from the study. Patients with hypothyroidism that is stable on hormone replacement or controlled type 1 diabetes will not be excluded from the study.
9. Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15 days or other immunosuppressive drugs within 30 days prior to the start of the study. Inhaled and topical corticosteroids are permitted. Up to 10 mg/day prednisone or equivalent is permitted as replacement therapy for adrenal insufficiency only.
10. Active infection requiring systemic therapy.
11. Active immune thrombocytopenic purpura or other chronic thrombocytopenic condition.
12. Therapeutic anticoagulation that cannot be interrupted for a biopsy or had a thromboembolic event within the last 6 months.
13. History or clinical evidence of any surgical or medical condition which the investigator judges as likely to interfere with the results of the study or pose an additional risk in participating, or makes the patient unlikely to comply with the study related visits and assessments particularly any pre-existing condition that would put the patient at additional risk should they experience an infusion-related reaction, e.g., rapidly progressive or uncontrolled disease involving a major organ system - vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, or an immunodeficiency
14. Unable to comply with the visits and requirements of the protocol due to psychiatric condition or substance abuse. Pregnant or breastfeeding or planning to conceive or father children within the projected duration of the study.
15. Exclusion criteria for GBM cohort:
    1. Any prior therapy for GBM other than that which is considered SOC for primary GBM, including but not limited to the following:
       1. More than one line of adjuvant temozolomide
       2. Prior treatment with another investigational drug for recurrent/progressing disease (acceptable as an add-on to SOC first line treatment)
       3. Prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth factor (VEGF) inhibitors or VEGF-receptor signaling inhibitors
       4. Prior treatment with nitrosoureas
       5. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants)
    2. Secondary GBM (i.e., GBM that progressed from low-grade diffuse astrocytoma or AA)
    3. Tumor with a clinically significant mass effect (>5 mm midline shift) while on a stable corticosteroid dose
    4. Dexamethasone or equivalent dose of >4 mg per day. Patients receiving dexamethasone ≤4 mg/day must be stable for at least 1 week
    5. Known history of allergy to gadolinium contrast agents
    6. Brainstem tumors
    7. Known, clinically relevant leptomeningeal disease
    8. radiation within 3 months prior to enrollment

For the most up-to-date list of criteria, please visit clinicaltrials.gov.