Trial Title:
A Dose Escalation and Dose Expansion Clinical Study of STI-7349 in Subjects With Advanced Solid Tumors
NCT ID:
NCT05978102
Condition:
Advanced Solid Tumor
Conditions: Official terms:
Neoplasms
Pembrolizumab
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
STI-7349
Description:
Administered by intravenous infusion (IV)
Arm group label:
STI-7349 alone
Arm group label:
STl-7349 in combination with Pembrolizumab
Other name:
IL2v mRNA
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
Administered by intravenous infusion (IV)
Arm group label:
STl-7349 in combination with Pembrolizumab
Other name:
anti-PD-1 monoclonal antibody
Intervention type:
Drug
Intervention name:
Standard treatment（SoC）
Description:
Depending on the treatment stage of enrolled subjects, the investigator will determine
the standard treatment regimen and dosage with reference to the CSCO or other current
guidelines.
Arm group label:
STl-7349 in combination with Pembrolizumab
Other name:
Standard treatment
Summary:
This is a first-in-human, Phase Ⅰ, open-label, 2-period dose escalation and expansion
study of STI-7349 administered intravenously to subjects with advanced solid tumors:
- Period I is divided into two parts: Dose escalation for STI-7349 alone (1A) and dose
expansion for STI-7349 alone (1B). In Part 1A, a rapid titration approach and
traditional 3 + 3 trial design will be used to assess the safety, dose-limiting
toxicities (DLTs), maximum tolerated dose (MTD), PK/biomarker profile, and to
determine the recommended Phase 2 dose (RP2D) of STI-7349 alone; in Part 1B, an
expansion study of STI-7349 alone will be conducted in target tumor types that may
potentially benefit to assess the safety and preliminary efficacy of STI-7349 alone.
- Period Ⅱ is divided into two parts: Dose escalation for STI-7349 in combination with
Pembrolizumab (2A) and dose expansion for STI-7349 in combination with Pembrolizumab
(2B). In Part 2A, a dose escalation study of STI-7349 in combination with
Pembrolizumab is planned to be conducted using ½ RP2D of STI-7349 alone as the
starting dose, which will use a traditional 3 + 3 trial design to assess the safety,
DLTs, MTD, PK/biomarker profile of STI-7349 in combination with Pembrolizumab, and
to determine the RP2D of STI-7349 in combination with Pembrolizumab; in Part 2B, an
expansion study of STI-7349 in combination with Pembrolizumab or add standard
treatment on the basis of STI-7349 combined with pembrolizumab will be conducted in
target tumor types that may potentially benefit to assess the safety and preliminary
efficacy of the combination.
Detailed description:
Period I: Dose escalation of STI-7349 alone (1A) According to the preclinical trial data,
1mg was used as the initial dose and the accelerated titration test design was adopted.
If no adverse events have occurred as specified in the following acceleration titers, the
dose increment ratio of 60%, 50%, 50%, 33.3%, 25% is recommended by the modified
Fibonacci method. The six initial dose groups of STI-7349 were 1mg, 1.6mg, 2.4mg, 3.6mg,
4.8mg and 6.0 mg.respectively. Eligible subjects will be placed into 6 dose groups in
sequence from low to high dose.
Subjects in all dose groups will receive 21 days per dosing cycle and Day 1 of each cycle
will be the dosing day.
Part 1A of this trial will use rapid titration and a traditional 3 + 3 trial design.
Period I: Dose expansion of STI-7349 alone (1B) Based on data from the 1A escalation
period, target tumor types with potential benefit are selected, and subjects are expanded
to 20 to 30 at the RP2D of STI-7349 alone to conduct an expansion study of STI-7349 alone
to further assess the safety and preliminary efficacy of the RP2D of STI-7349 alone.
STI-7349 will be administered at the same frequency as that in Part 1A and continued
until the maximum 2-year dosing period, disease progression/relapse, death, intolerable
toxicity, inability of the subject to benefit from study treatment as judged by the
investigator, withdrawal from clinical study treatment by the subject or his/her legal
representative, loss to follow-up, or completion of the entire study, whichever comes
first.
Period II: Dose escalation for STI-7349 in combination with Pembrolizumab (2A) According
to the single-agent RP2D of STI-7349 determined in phase I, the dose of STI-7349 combined
with palibrizumab was increased in subjects with advanced solid tumors. ≤ ½RP2D of
STI-7349 single agent was used as the starting dose of the combined dose increase, and
the expected RP2D dose was 4.8mg. The initial dose of combined administration was ≤2.4mg.
The approved standard therapeutic dose of pabolizumab is 200mg IV. According to the
results of the Phase I study, the three dose groups of STI-7349 combined with pabolizumab
were initially set as 1mg, 1.6mg and 2.4mg, respectively. Qualified subjects will be
selected into 3 dose groups in sequence from low to high dose.
Period II: Dose expansion for STI-7349 in combination with Pembrolizumab (2B) According
to the data from the 2A escalation period, target tumor types with potential benefit are
selected, and subjects are expanded to 20 to 30 at the RP2D of the combination to conduct
a dose expansion study of STI-7349 in combination with Pembrolizumab or add standard
treatment on the basis of STI-7349 combined with pembrolizumab to further assess the
safety and preliminary efficacy of the RP2D of the combination. STI-7349 will be
administered at the same frequency as that in Part 2A and continued until the maximum
2-year dosing period, disease progression/relapse, death, intolerable toxicity, inability
of the subject to benefit from study treatment as judged by the investigator, withdrawal
from clinical study treatment by the subject or his/her legal representative, loss to
follow-up, or completion of the entire study, whichever comes first.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- To be enrolled in this study, subjects must meet all of the following inclusion criteria:
1. Subjects should have fully understood the study and voluntarily signed an informed
consent form.
2. Age 18 to 80 years (inclusive).
3. ECOG(Eastern U.S. Oncology Collaborative Group) score of 0 to 1.
4. Expected survival ≥ 12 weeks.
5. According to Response Evaluation Criteria in Solid Tumors (RECIST1.1), the subject
has at least one measurable lesion, that is, the subject has at least one lymph node
lesion (minimum diameter ≥ 1.5 cm) or non-lymph node lesion (maximum diameter ≥ 1
cm) diagnosed by computed tomography (CT)/magnetic resonance imaging (MRI)
examination; if the lesion that previously received local therapy (radiotherapy,
ablation, vascular intervention, etc.) is the only lesion, there must be a clear
imaging basis for disease progression of this lesion after local therapy.
6. Subjects with malignant advanced solid tumors confirmed by histopathology or
cytology who have failed standard treatment, or cannot tolerate standard treatment,
or cannot obtain standard treatment for various reasons, or have no standard
treatment.
7. The subject has major organ function meeting the following criteria within 7 days
prior to first dose [The subject had not received blood component transfusion within
14 days prior to testing. Subjects had not received supportive treatment with human
granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), thrombopoietin
receptor agonist, interleukin-11, and erythropoietin (EPO) within 7 days prior to
testing.]:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L;
2. Platelet (PLT) ≥ 100 × 109/L;
3. Hemoglobin (HGB) ≥ 90 g/L;
4. Alanine aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN(Upper limit of normal
value) if liver involvement is known);
5. Aspartate aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if liver involvement is
known);
6. Total bilirubin (TBIL) ≤ 1.5 × ULN (≤ 3.0 × ULN if Gilbert's syndrome is
diagnosed);
7. Serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate (eGFR,
calculated according to the Cockcroft-Gault formula, or by measuring 24-hour
urine) ≥ 40 mL/min;
8. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin
time (APTT) ≤ 1.5 × ULN.
8. The toxic reaction of previous anti-tumor therapy returned to ≤ grade 1 (except for
the following cases: Grade 2 neurotoxicity and grade 2 hypothyroidism caused by
anti-tumor therapy, hair loss and pigmentation of any grade, grade 2 AE that cannot
be returned to ≤ grade 1 and will remain stable for a long time as determined by the
investigator based on the actual clinical situation, laboratory detection indicators
are shown in inclusion Criterion 7) .
9. Subject is willing and able to comply with the study schedule and all other study
protocol requirements.
10. Women of childbearing potential (women of non-childbearing potential are defined as
sexually mature women who have undergone hysterectomy or bilateral oophorectomy or
bilateral salpingectomy or bilateral tubal ligation/occlusion, or who are unable to
have children because of congenital or acquired disease, or have natural menopause
for ≥ 12 months) must have a negative blood pregnancy test during screening. Female
subjects of childbearing potential and male subjects must use a highly effective
method of contraception at screening through 6 months after the last treatment.
Exclusion Criteria:
- To be enrolled in this study, subjects must not meet any of the following exclusion
criteria:
1. The subject has a known hypersensitivity to any component of the investigational
product or IL-2.
2. Subjects have participated in any therapeutic clinical study within 28 days prior to
first dose, were enrolled and treated. In addition, subjects are in the survival
follow-up phase of observational or interventional studies.
3. Subjects have used immunomodulatory drugs within 14 days or 5 half-lives (whichever
is longer) prior to the first dose, including but not limited to thymosin, IL-2,
IL-15, interferon, etc.
4. The subject has received chimeric antigen receptor T-cell immunotherapy (CAR-T)
within 3 months prior to the first dose; the subject has received chemotherapy (at
least 6 weeks for chemotherapeutic agents nitrosoureas and mitomycin C, and at least
14 days for oral fluoropyrimidines), endocrine therapy, targeted therapy (washout
period of 14 days or 5 half-lives for small-molecule targeted therapy, whichever is
longer), immunotherapy (for immunomodulatory agents see exclusion criterion 3),
tumor embolization, etc. within 28 days prior to the first dose; the subject has
received radiotherapy within 14 days prior to the first dose, palliative
radiotherapy for symptom control is allowed to be completed at least 7 days prior to
the first dose; the subject has received traditional Chinese medicine for an
approved indication of anti-tumor within 7 days prior to the first dose.Except when
subjects assessed by the investigator could be enrolled.
5. The subject has undergone major surgery within 28 days or minor surgery within 7
days prior to the first dose, or had an unhealed wound, ulcer, or bone fracture or
required elective surgery during the study (except for diagnostic biopsy, insertion
of vascular access device).
6. Subjects have received a live attenuated vaccine within 28 days prior to the first
dose or plan to receive it during the study.
7. Subjects have received systemic immunosuppressants within 28 days prior to first
dose excluding:
1. Intranasal inhaled topical steroid therapy or topical steroid injection (eg,
intra-articular injection);
2. Systemic corticosteroid therapy not exceeding 10 mg/day prednisone or its
physiologic equivalent doses;
3. Corticosteroids as prophylaxis for allergic reactions (eg, premedication for
CT);
4. As prophylaxis for infusion reactions.
5. See exclusion criteria 8 for systemic use of sex hormones in patients with
brain metastases.
8. Active central nervous system (CNS) metastases or cancerous meningitis with known or
symptomatic symptoms at the screening stage (Note: ① Patients with CNS metastases
with symptoms prior to initial administration who have been treated and stable for
≥4 weeks and have been off systemic sex hormone therapy (at any dose) for >3 days
may be included. ②Asymptomatic brain metastases (i.e. no neurological symptoms, no
need for corticosteroids, and no lesions >1.5cm) can be enrolled, but regular brain
imaging examinations are required as a disease site).
9. Subjects had uncontrolled third space effusions requiring repeated drainage, such as
pleural effusion, ascites, pericardial effusion, etc. (subjects who do not require
drainage of effusion or have no significant increase in effusion after stopping
drainage for 3 days may be enrolled), or third space effusions that are bloody by
diagnostic puncture.
10. The subject had another malignancy within 5 years prior to the first dose, except
for radically treated early malignancies (carcinoma in situ or Stage I tumor), such
as adequately treated basal or squamous cell carcinoma of the skin, carcinoma in
situ of the cervix or breast after radical resection, early papillary thyroid
carcinoma, or prostate cancer with local Gleason score ≤ 6.
11. The subject had active autoimmune or inflammatory diseases, including inflammatory
bowel disease (eg, ulcerative colitis or Crohn's disease), diverticulitis (other
than diverticular disease), celiac disease, systemic lupus erythematosus,
Sarcoidosis syndrome or Wegener' s syndrome (granuloma with polyangiitis), Graves'
disease, rheumatoid arthritis, hypophysitis, uveitis, etc.), or a history of the
disease within the previous 2 years (subject with vitiligo, psoriasis, alopecia, or
Graves' disease not requiring systemic therapy within the last 2 years,
hypothyroidism requiring thyroid hormone replacement therapy only, and Type 1
diabetes mellitus requiring insulin replacement therapy only may be enrolled).
12. The subject has active or uncontrolled HBV（Hepatitis B Virus） (HBsAg positive and/or
HBcAb positive and HBV DNA titer positive), HCV (HCV-Ab positive and HCV RNA titer
positive), HIV(Human Immunodeficiency Virus) positive.
13. The subject had an active bacterial, viral, or fungal infection (defined as a
subject demonstrating persistent signs/symptoms related to infection that do not
improve despite appropriate antibiotic or other therapy) or required intravenous
(IV) antibiotics within 72 hours prior to the first dose.
14. Severe or uncontrolled cardiovascular or cerebrovascular disease requiring
treatment, including but not limited to:
1. New York Heart Association (NYHA) cardiac functional classification > 2;
2. Unstable angina not controlled by medication;
3. Subject has had a myocardial infarction within 6 months prior to first dose;
4. History of myocarditis;
5. Cardiac tamponade;
6. Poorly controlled arrhythmias (eg, subjects who develop ventricular tachycardia
during antiarrhythmic drug therapy will be excluded; subjects with first degree
atrioventricular block or asymptomatic left anterior bundle branch block/right
bundle branch block will not be excluded);
7. 12-lead electrocardiogram QTcF（The QT interval values were corrected for heart
rate using Fridericia's formula） > 470 msec;
8. Left ventricular ejection fraction (LVEF) < 50%;
9. Poorly controlled hypertension (On the basis of lifestyle modification, the
subject has been taking adequate doses of 2 or more antihypertensive agents
reasonably tolerated for more than 1 month, but blood pressure remains
substandard. Or subjects have been taking 4 or more antihypertensive drugs for
effective blood pressure control) or hypotension;
10. Epilepsy not controlled by medication;
11. The subject had a stroke, cerebrovascular accident, or transient ischemic
attack within 6 months prior to first dose.
15. The subject has known chronic obstructive pulmonary disease (COPD) and forced
expiratory volume in one second (FEV1) < 50% of predicted normal. It should be noted
that subjects suspected of having COPD must have FEV1 testing and must be excluded
if FEV1 is < 50% of predicted normal.
16. The subject has known moderate or severe persistent asthma, or had a history of
asthma within the past 2 years, or has uncontrolled asthma of any classification
currently (note that subjects with current controllable intermittent asthma or
controllable mild persistent asthma are allowed).
17. The subject has previous and current pulmonary disease such as interstitial
pneumonia (including drug-induced), pneumoconiosis, pulmonary fibrosis, or severely
impaired pulmonary function; the subject has active pulmonary tuberculosis and is
receiving anti-tuberculosis treatment or has received anti-tuberculosis treatment
within 1 year prior to the first dose.
18. The subject has experienced clinically significant bleeding symptoms within 3 months
prior to first dose. The subject had evident symptoms of coughing up blood within 28
days prior to the first dose with hemoptysis of half a teaspoon (2.5 mL) or more per
session.
19. The subject had a history of abdominal fistula, gastrointestinal perforation,
intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to
the first dose.
20. The subject had a history of deep vein thrombosis, pulmonary embolism, or any other
serious thromboembolism (except thrombosis caused by a vascular access device, or
superficial venous thrombosis) within 3 months prior to the first dose.
21. The subject has hepatic encephalopathy, or hepatorenal syndrome, or Child-Pugh class
B (> 7 points) or more severe cirrhosis.
22. The subject had a known history of primary immunodeficiency.
23. The subject had a known history of allogeneic organ transplantation and allogeneic
hematopoietic stem cell transplantation (except corneal transplantation).
24. Pregnant or lactating women.
25. Subject has any active serious psychiatric disorder, medical condition, or other
symptoms/conditions that could affect treatment, compliance, or ability to give
informed consent at the discretion of the investigator.
The following exclusion criteria apply only to combined dosing subjects:
26. Previous allergy to pabolizumab.
27. Permanent discontinuation of drug related AE due to pabolizumab or similar drugs.
28. Permanent discontinuation of the drug due to previous allergy to standard treatment
or occurrence of drug-related AE.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The Fourth Affiliated Hospital of Zhejiang University School of Medicine.
Address:
City:
Yiwu
Country:
China
Status:
Recruiting
Contact:
Last name:
kai wang, Doctor(M.D.)
Phone:
13957158572
Email:
Doctorhuxi@163.com
Start date:
August 23, 2023
Completion date:
December 2025
Lead sponsor:
Agency:
The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Agency class:
Other
Source:
The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05978102
