Trial Title:
To Evaluate the Phase I Clinical Study of JSKN016 in Chinese Patients With Advanced Malignant Solid Tumors
NCT ID:
NCT06592417
Condition:
Advanced Malignant Solid Tumor
Conditions: Official terms:
Neoplasms
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
JSKN016 injection
Description:
JSKN016 is a bispecific antibody drug conjugate targeting HER3 and TROP2.
Arm group label:
Dose escalation/expansion
Summary:
This is a Phase I open, multi-center, first-in-human study evaluating JSKN016 in subjects
with advanced metastatic solid tumors, divided into dose escalation and dose extension.
Detailed description:
A total of seven (Q3W, the first day of intravenous administration every 3 weeks) dose
groups were designed during the dose escalation period. The dose groups were 0.5, 1.0,
2.0, 4.0, 6.0, 7.0 and 8.0 mg/kg, respectively. The DLT observation period was 21 days
with accelerated titration BOIN design.
The specific steps for conducting a clinical trial using the BOIN design are as follows:
1. The accelerated titration is performed as follows: the first patient is assigned to
dose level 1. If this patient does not develop dose-limiting toxicity (DLT), the
second patient will be treated at the next higher dose level. Only one patient at a
time is treated, and the dose-climbing process continues until the first DLT is
observed, or a second grade 2 toxicity is present, or the highest dose is reached,
or a Safety Inspection Committee (SMC) discussion decides to end accelerated
titration, whichever occurs first. At least two more patients are then treated on
the current dose. After that, follow steps 2 and 3 below with at least 3 patients in
each group to treat follow-up patients (≥3 patients in the non-accelerated titration
dose group).
2. Assign the dose to the next group of subjects according to the dose rise and fall
rule shown in the Bayesian optimal interval (BOIN). Note the following:
1. "Elimination" means the removal of current and higher doses from the trial. The
removed dose is a hypertoxic dose and will no longer be used to treat any newly
enrolled patients.
2. If the current dose is removed, the dose is automatically lowered to the next
lower level and administered to the subject for treatment. If the lowest dose
is eliminated, the trial is terminated early to ensure subject safety. In this
case, the MTD cannot be determined.
3. If none of the decision conditions (i.e., raise, lower, or remove the dose) are
met, continue to treat the next group (3 subjects) with the current dose.
4. If the current dose is the minimum dose but the dose is still required to be
reduced by the rules, the new subject is still treated at the current minimum
dose. If the number of subjects with DLT reaches the exclusion threshold, the
trial is terminated early to ensure subject safety.
5. If the current dose is the maximum dose but a higher dose is required by rule,
the new subject is treated at the current maximum dose.
3. Repeat Step 2 until the set dose escalation phase has a maximum sample size of 20,
or the number of evaluable subjects treated at the current dose reaches 9 and the
current decision is to maintain the current dose according to the rise and fall rule
of the dose escalation decision table.
During dose escalation, the SMC will conduct an ongoing safety assessment. The safety
data for each dose group is reviewed by the SMC before the next dose group is
administered. For the 6th dose group 7 mg/kg, SMC can decide whether to skip this dose
group by comprehensively considering the previous safety, PK and other data. The
composition and responsibilities of the SMC will be further detailed in the SMC
Constitution.
In each dose group, the administration of the second subject was initiated at least 24
hours after the administration of the first subject to identify some acute toxicities,
such as infusion-related reactions.
Allow patients to proceed with intragroup dose escalation to minimize the potential for
undertreatment of patients. Intrapatient dose escalation will be performed in the
following manner: (1) Intrapatient dose escalation will only be performed if ≤ grade 2
toxicity is observed during the previous treatment cycle; (2) Does not increase to the
next higher dose level until the full DLT observation period is evaluated for the next
higher dose level and the SMC does not confirm safety concerns; (3) Patients receiving
the first dose escalation should be dosed for at least 4 cycles without disease
progression. For example, if patients in the 1 mg/kg group completed DLT observation and
4 cycles of dosing, only if patients in the 2 mg/kg cohort completed a complete DLT
evaluation, the SMC did not confirm safety concerns, and no grade 2 toxicity was observed
in patients in the 1 mg/kg cohort during the previous treatment cycle. Subsequent doses
may be increased to 2 mg/kg with the consent of the SMC.
The recommended dose for cohort expansion (RDE) will be determined by the SMC based on
safety/tolerability, PK data, and preliminary antitumor activity, as well as other
available data. RDE can be at the same dose level as MTD or at a lower dose level than
MTD; Rdes may also be different for different indications.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
-
1. Subjects can understand the informed consent form, voluntarily participate in
and sign the informed consent form; 2. The subjects were ≥18 years old on the
day of signing the informed consent, male or female; 3. Subjects with
histologically and/or cytologically confirmed advanced unresectable or
metastatic epithelial malignancies that have failed or are intolerable to
previous standard therapies, preferentially but not limited to the following
types: AGA-positive non-small cell lung cancer, HER2 IHC 0 breast cancer, etc.
4. For AGA-positive NSCLC, the presence of at least one of the following mutations
is required; EGFR, ALK, ROS1, NTRK, BRAF V600, MET exon 14, RET, KRAS G12C, or
HER2;
- For the enrolled subjects, the above driver gene mutations were not tested, but
the previous test results confirmed by the investigators were accepted;
- If only EGFR overexpression without driver gene mutation can not be included;
- Prior osimertinib therapy is required if EGFR T790M mutation is present;
- Participants had to have failed at least one prior targeted therapy and at
least platinum-based chemotherapy with or without an immune checkpoint
inhibitor or antiangiogenic agent; 5. Breast cancer patients with HER2 IHC 0
expression, regardless of hormone receptor (HR) expression, could be enrolled
according to the results of IHC examination in our center.
6. At least one measurable lesion at baseline according to RECIST 1.1
criteria. Measurable disease required either no previous local treatment
(e.g., radiotherapy) or evidence of disease progression after local
treatment.
7. Expected survival time ≥3 months; 8. ECOG score 0 or 1; 9. Female subjects
of childbearing potential or male subjects with a fertile partner agreed
to use highly effective contraception from the time they provided written
informed consent until 24 weeks after the last dose. Female subjects of
childbearing potential had to have a negative serum/urine pregnancy test
within 7 days before randomization (for women of childbearing age, see
Appendix 2).
10. Adequate organ function within 7 days before randomization:
- Bone marrow function: absolute neutrophil count ≥1.5×109/L; Hemoglobin ≥90 g/L;
Platelet count ≥100×109/L (no whole blood or blood component transfusion within
14 days before randomization; No administration of hematopoietic cytokines
within 7 days before randomization).
- Liver function (based on the normal value of each clinical research center) :
total bilirubin < 1.5 times the upper limit of normal value (ULN, total
bilirubin in subjects with liver metastasis ≤3 x ULN); ALT/AST≤3×ULN (≤5×ULN in
patients with liver metastasis); Albumin ≥28g/L; Renal function: serum
creatinine ≤1.5 times the upper limit of normal, or creatinine clearance (Ccr)
calculated according to Cockcroft-Gault formula (see Appendix 4) ≥ 60 mL/min;
Coagulation function: INR or PT≤ 1.5x ULN, and aPTT≤ 1.5x ULN (low stable dose
of anticoagulant, such as aspirin 100 mg/ day is allowed); 11. Left ventricular
ejection fraction (LVEF) ≥50% (by echocardiography [ECHO]); 12. Participants
were able and willing to comply with protocol-specified visits, treatment
plans, laboratory tests, and other study-related procedures.
Exclusion Criteria:
-
1. Patients with symptoms of active central nervous system metastases, except
those with stable parenchymal brain metastases as assessed by investigators,
were defined as seizure-free for more than 12 weeks with or without the use of
antiepileptic drugs; No need for glucocorticoids; At least one MRI showed that
the patient was stable on imaging. Or stable after treatment for more than 1
month without symptoms; 2. Received any investigational drug within 28 days
before dosing; 3. Receipt of other antineoplastic therapy within 28 days before
dose or within 5 half-lives of previous antineoplastic drugs, whichever is
shorter but requires a minimum of 14 days; Received Chinese herbal medicine
with clear anti-tumor indications within 14 days before drug administration; 4.
Local palliative treatment within 14 days before administration; 5. Major
surgical treatment (such as transabdominal or transthoracic surgery) within 28
days before drug administration; Excluding minor procedures such as diagnostic
punctures or infusion device implantation or biliary stenting) or anticipated
need for major surgical treatment during the study period; 6. Gastrointestinal
abnormalities with obvious clinical manifestations, including but not limited
to: intestinal obstruction or the presence of symptoms and signs of intestinal
obstruction within 6 months before drug administration, but if the obstruction
was completely removed after surgical treatment, screening could be performed
(patients with previous intestinal stent implantation and the intestinal stent
was not removed during the screening period were not allowed); Patients with
gastrointestinal perforation, gastrointestinal fistula, intra-abdominal abscess
and non-gastrointestinal fistula (such as tracheoesophageal fistula) within 6
months before administration; Patients with gastrointestinal bleeding (CTCAE≥
grade 3) within 6 months before treatment, or gastrointestinal bleeding
(melena, bloody stool, etc.) within 1 month before randomization were eligible
if hemorrhoid bleeding was confirmed or only showed positive fecal occult
blood.
7. Subjects with uncontrolled massive serous effusion or moderate to massive
serous effusion requiring repeated drainage (recurrence within 2 weeks after
intervention) such as pleural effusion, pericardial effusion, ascites,
cachexia, etc.
8. Always received including the antibody coupling of topoisomerase inhibitors
class I drug therapy, such as DS-8201, HER3-DXd, DS-1062, etc; 9. A history of
(noninfectious) interstitial lung disease (ILD) or noninfectious pneumonia
requiring steroid therapy, current ILD or noninfectious pneumonia, or ILD or
noninfectious pneumonia that could not be ruled out by imaging at screening;
10. Other malignant tumors within 5 years before drug administration, Cured
cutaneous squamous cell carcinoma, basal cell carcinoma, non-primary invasive
bladder cancer (defined as stage ≤T2a, Gleason score ≤6, and at the time of
prostate cancer diagnosis) were excluded Patients with PSA≤10ng/mL (if
measured) who had received radical treatment and had no PSA biochemical
recurrence could participate in the study), in situ prostate/cervix/breast
cancer; 11. Have uncontrolled comorbidities, including but not limited to the
following:
- Active HBV or HCV infection Patients with HBsAg (+) and HBV-DNA< 2500 copies /mL or
500 IU/mL were allowed to be enrolled. HCV-Ab (+) and HCV-RNA negative were allowed
to enroll.
- HIV infection;
- Known active tuberculosis; Active syphilis;
- Active or uncontrolled infection requiring systemic anti-infective treatment;
Uncontrolled hypertension (systolic blood pressure ≥160mmHg, Diastolic blood
pressure > 100 mmHg), symptomatic heart failure (NYHA II-IV), unstable angina
or myocardial infarction within 6 months, history of heart failure or systolic
dysfunction (LVEF<50%), or risk of QTc prolongation or arrhythmia (baseline
QTc>470 msec) ), intractable hypokalemia, long QT syndrome, tachycardia at rest
with a heart rate >100 bpm, atrial fibrillation or clinically symptomatic
valvular heart disease (if well controlled by treatment), moderate-severe
pulmonary hypertension, or a history of other arrhythmias of medical
importance).
Newly diagnosed thromboembolic events requiring treatment within 6 months (patients with
well-controlled deep-vein thrombosis of the lower extremities or venous access ports were
allowed).
12. The toxicity of previous antineoplastic therapy did not recover to CTCAE grade ≤1
(NCI-CTCAE v5.0); Note: Subjects with stable CTCAE grade 2 toxicity related to
previous antineoplastic therapy (defined as stable toxicity severity and no CTCAE
grade greater than 2 within 3 months before dose administration) could be enrolled,
such as: Chemotherapy-induced neurotoxicity, alopecia, skin pigmentation, fatigue,
endocrine toxicity caused by previous immunotherapy (such as thyroid dysfunction,
diabetes, hyperglycemia, adrenal insufficiency); 13. Previous history of allogeneic
bone marrow or organ transplantation; 14. Previous history of allergic reaction or
anaphylaxis to antibody drugs; 15. Previous history of severe dry eye, severe
meibomian gland disease and/or blepharitis, keratopathy and maculopathy resulting in
untreatable or delayed corneal healing of the subject; 16. Pregnant and/or lactating
women; 17. Other conditions considered by the investigators to affect the safety or
compliance of the study drug treatment, including but not limited to mental
disorders, alcohol or drug abuse, etc.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Fujian Cancer Hospital
Address:
City:
Fuzhou
Zip:
350014
Country:
China
Status:
Recruiting
Contact:
Last name:
zhangzhou huang
Phone:
13609578088
Email:
1609305255@qq.com
Facility:
Name:
Sun Yat-sen Hospital, Sun Yat-sen University
Address:
City:
Guangzhou
Zip:
510080
Country:
China
Status:
Recruiting
Contact:
Last name:
herui yao
Phone:
13500018020
Email:
yaoherui@163.com
Start date:
April 30, 2024
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Jiangsu Alphamab Biopharmaceuticals Co., Ltd
Agency class:
Industry
Source:
Jiangsu Alphamab Biopharmaceuticals Co., Ltd
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06592417
