This is an open-label, two-part, phase 1-2 dose-finding study designed to determine the
safety, tolerability, PK, PD, and proof-of-concept efficacy of ST101 administered IV in
patients with advanced solid tumors. The study consists of two phases: a phase 1 dose
escalation/regimen exploration phase and a phase 2 expansion phase.
Dose escalation / regimen exploration phase During the dose escalation/regimen exploration
phase, only patients diagnosed with locally advanced or metastatic melanoma, carcinoma or
sarcoma of any tumor type who are refractory or intolerant to all available therapies that
would impact survival will be enrolled.
ST101 will be administered intravenously (IV), initially once per week. The dose escalation
cohorts will be recruited using a standard 3+3 design. At each new dosing cohort, there will
be a 1-week observation period after dosing the first patient in order to assess safety prior
to dosing the remainder of the patients in that cohort. The dose cohorts will be 0.5, 1, 2,
4, 8 and 16 mg/kg with once weekly (QW) dosing in all cohorts except for the highest dose
level which will be dosed every other week (Q2W).
The expansion phase consists of 4 specific tumor-type cohorts, which each follow the same
Simon 2-stage design. Fifteen (15) patients will be enrolled in each cohort and treated with
the ST101 RP2D. If one or more responses is observed that cohort will be expanded to a total
of 30 patients to further assess efficacy.
Responses will be graded using response evaluation criteria in solid tumors (RECIST) 1.1
(Eisenhauer 2009) for hormonal receptor positive (HRpos) locally advanced/metastatic breast
cancer (LA/MBC) and melanoma, modified response assessment in neuro-oncology (RANO)
(Ellingson 2017) for GBM and prostate cancer clinical trials working group 3 (PCWG3) (Scher
2016) for castration-resistant prostate cancer (CRPC).During the expansion phase, only
patients diagnosed with the following tumor types will be allowed into this phase of the
study:
- HRpos LA/MBC that has progressed after prior 1-2 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.
- Melanoma that has progressed after/or on treatment with an immune checkpoint inhibitor
(CPI) and have received 1-2 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.
- Primary (de novo) GBM that has recurred or progressed (per modified RANO criteria) after
1 standard treatment regimen. Standard therapy is defined as maximal surgical resection,
radiotherapy, and concomitant temozolomide with radiotherapy or adjuvant chemotherapy
with temozolomide. Patients that undergo tumor treating fields as an adjuvant to first
line therapy are allowed.
- CRPC that has progressed after previous treatment with taxanes, abiraterone and
enzalutamide/apalutamide.
The tumor types in the expansion phase may change based on emerging data from the dose
escalation phase of this study. Additional mini cohorts of 10 patients may be added to the
expansion phase based on efficacy signals during the dose escalation phase.
Inclusion Criteria:
- Inclusion Criteria
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 as follows:
1. For the dose escalation/regimen exploration phase: melanoma, carcinoma, or
sarcoma
2. For the expansion phase: HR positive LA/MBC, melanoma, GBM, 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.
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:
a. For the dose escalation/regimen exploration phase up to 3 previous lines of
systemic anticancer therapies are allowed. Since this is a FIH study, it's
important that patients are not refractory to therapeutic intervention due to
multiple lines of prior therapies.
a. For the expansion phase: i. HRpos LA/MBC must have progressed after prior 1-2
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 ii. Melanoma that has
progressed after or on treatment with a CPI and have received 1-2 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 iii.
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.
iv. CRPC that has progressed after previous treatment with taxanes, abiraterone
and enzalutamide/apalutamide or that are intolerant to these treatments.
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.
Exclusion Criteria
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. Known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate
provided they are clinically stable for at least 4 weeks prior to study entry,
have no evidence of new or enlarging brain metastases, and are off steroids for
at least 14 days prior to first dose of study drug. This criterion does not apply
to patients on the GBM cohort.
6. Presence of any other active malignancy requiring systemic therapy other than the
disease under study.
7. 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.
8. Active infection with hepatitis B or hepatitis C, defined by a detectable viral
load. Testing is not required for eligibility.
9. 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.
10. 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.
11. Active infection requiring systemic therapy.
12. Active immune thrombocytopenic purpura or other chronic thrombocytopenic
condition.
13. Therapeutic anticoagulation that cannot be interrupted for a biopsy or had a
thromboembolic event within the last 6 months.
14. 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
15. 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.
16. Exclusion Criteria for GBM Cohort:
a) Any prior therapy for GBM other than that which is considered SOC for primary
GBM, including but not limited to the following: i. more than one line of
adjuvant temozolomide ii. prior treatment with another investigational drug iii.
prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth
factor (VEGF) inhibitors or VEGF-receptor signaling inhibitors iv. prior
treatment with nitrosoureas v. prior therapy that included interstitial
brachytherapy or Gliadel® Wafers (carmustine implants) b) secondary GBM (i.e.,
GBM that progressed from low-grade diffuse astrocytoma or AA) c) tumor with a
clinically significant mass effect (>5 mm midline shift) while on a stable
corticosteroid dose d) prednisone or equivalent dose of >10mg per day e) known
history of allergy
