Trial Title:
A Study to Evaluate LB1410 in Combination With LB4330 in Patients With Advanced or Metastatic Solid Tumors
NCT ID:
NCT06468358
Condition:
Solid Tumor
Conditions: Official terms:
Neoplasms
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
This is a Phase Ib/II, open, dose-escalation and expansion study of LB1410 in combination
with LB4330 in patients with advanced or metastatic solid tumors. The study includes 2
parts, Part 1 Dose Escalation and Part 2 Dose Expansion. Initially, participants with
pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, ovarian,
fallopian tube, or primary peritoneal cancer, non-small cell lung cancer, gastric and
gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma,
hepatocellular carcinoma, renal cell carcinoma, cervical squamous cell carcinoma, and
endometrial carcinoma will be enrolled in the study; additional tumor types may be
explored and added in a future amendment to the CSP.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
LB1410
Description:
anti-PD-1/TIM3 bispecific antibody
Arm group label:
Phase II, Expansion Cohorts of LB1410 in combination with LB4330
Arm group label:
Phase Ib, Dose Escalation of LB1410 in combination with LB4330
Intervention type:
Drug
Intervention name:
LB4330
Description:
anti-claudin18.2/IL-10 fusion protein
Arm group label:
Phase II, Expansion Cohorts of LB1410 in combination with LB4330
Arm group label:
Phase Ib, Dose Escalation of LB1410 in combination with LB4330
Summary:
This is a phase Ib/II, open, dose-escalation and expansion study of an anti-PD1/TIM3
bispecific antibody，LB1410 in combination with an anti-Claudin18.2/IL-10 fusion protein,
LB4330 in patients with advanced or metastatic solid tumors.
Detailed description:
The phase Ib/II clinical study in Chinese patients with advanced or metastatic solid
tumors to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), anti-tumor
efficacy, and biomarkers of LB1410 in combination with LB4330.
The study will include 2 parts: dose escalation (Phase Ib) and dose expansion (Phase II).
Repeated intravenous infusion of LB1410 in combination with LB4330 in patients with
metastatic or advanced pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal
cancer, ovarian, fallopian tube, or primary peritoneal cancer, non-small cell lung
cancer, gastric and gastroesophageal junction adenocarcinoma, esophageal squamous cell
carcinoma, hepatocellular carcinoma, renal cell carcinoma, cervical squamous cell
carcinoma, and endometrial carcinoma.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Must be ≥ 18 years of age when signing informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 without
deterioration in the past 2 weeks.
3. Estimated life expectancy of ≥12 weeks.
4. Baseline IL-6 levels below 40 pg/mL.
5. Histologically or cytologically documented advanced and metastatic solid tumors for
which can't tolerate standard treatment, standard treatment fails, or no standard
treatment is available at this stage.
6. Must have at least one measurable lesion according to Response Evaluation Criteria
in Solid Tumors (RECIST) v1.1 at screening.
7. Adequate hematologic function prior to registration for protocol therapy defined as
the following criteria:
1. absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, without the use of granulocyte
colony-stimulating factor such as filgrastim in the 2 weeks prior to study
treatment (≤ 14 days);
2. platelet count ≥ 120 × 10^9/L, without transfusion or use of drugs like
recombinant human platelet growth factor in the 2 weeks prior to study
treatment (≤ 14 days), for HCC patients, platelet count ≥ 100 × 10^9/L;
3. hemoglobin ≥ 90 g/L, without transfusion or use of drugs like erythropoietin in
the 2 weeks prior to study treatment (≤ 14 days).
8. Both AST and ALT ≤ 3 × ULN (both AST and ALT < 5 × ULN for subjects with known
hepatocellular carcinoma or hepatic metastases); total bilirubin ≤ 1.5 × ULN (except
for subjects with elevated serum bilirubin due to documented underlying conditions
such as Gilbert's syndrome or familial benign unconjugated hyperbilirubinemia); for
bile duct cancer patients, total bilirubin ≤ 2 × ULN; and serum albumin ≥ 30 g/L.
9. Adequate renal function defined as: serum creatinine ≤ 1.5 × ULN, and creatinine
clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
10. Requirements for coagulation function are as follows:
1. activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;
2. international normalized ratio (INR) ≤ 1.5 × ULN (INR ≤ 3 × ULN for subjects
receiving warfarin anticoagulant therapy).
11. Any prior anti-tumor therapies (including endocrine/chemotherapy/targeted
therapy/immunotherapy) before treatment should washout:
1. at least 4 weeks for biological therapy (e.g., antibodies);
2. at least 2 weeks or 5 half-lives (whichever is longer) for small molecule
drugs, including 5-FU or its derivatives; at least 6 weeks for nitrosoureas and
mitomycin;
3. at least 2 weeks for Chinese herbal medicine used for indications of anti-tumor
activity;
4. at least 4 weeks for any systemic therapeutic investigational drugs;
5. at least 2 weeks for any radiotherapy;
6. any related toxicities or prior adverse events resolved to baseline or ≤ NCI
CTCAE 5.0 grade 1 (excluding toxicities without safety risk judged by the
investigator, such as alopecia, grade 2 peripheral neuropathy, stable
hypothyroidism under hormone replacement therapy, etc.).
12. Phase Ib dose escalation additional inclusion criteria: histologically or
cytologically documented advanced malignant solid tumors (preferably pancreatic
ductal adenocarcinoma, cholangiocarcinoma, ovarian cancer, microsatellite stable
colorectal cancer, advanced solid tumors previously treated with anti-PD-1/PD-L1
inhibitors, such as gastric or gastroesophageal junction adenocarcinoma, or other
solid tumors determined by the investigator and sponsor);
13. Phase II (phase IIa and IIb) dose expansion cohort A additional inclusion criteria:
1. must have received at least one but no more than two prior lines of systemic
therapy;
2. CA199 < 1000 IU/mL during screening period
3. must not have received any immune checkpoint inhibitor (ICI) therapy.
14. Phase II (phase IIa and IIb) dose expansion cohort B additional inclusion criteria:
1. must have received at least one but no more than three prior lines of systemic
therapy;
2. without C-Met, FGFR, IDH1 mutations or the genotype is unknown;
3. CA199 < 1000 IU/mL during screening period.
15. Phase II (phase IIa and IIb) dose expansion cohort C additional inclusion criteria:
1. must have received at least one but no more than three prior lines of systemic
therapy;
2. CA199 < 1000 IU/mL during screening period;
3. must not have received any immune checkpoint inhibitor (ICI) therapy;
4. KRAS, NRAS and BRAF are wild type;
5. without hepatic metastasis.
16. Phase II (phase IIa and IIb) dose expansion cohort D additional inclusion criteria:
1. recurrent epithelial ovarian cancer, fallopian tube cancer or primary
peritoneal cancer;
2. must have received at least one but no more than three prior lines of systemic
therapy;
3. must not have received any immune checkpoint inhibitor (ICI) therapy;
4. PD-L1 positive;
5. have received one prior treatment regime of platinum-based chemotherapy;
6. subjects with BRCA germline mutation (gBRCA mut) should been treated with a
polyADP ribose polymerase inhibitor (PARPi), such as Olaparib, Rucaparib, or
Niraparib.
17. Phase II (phase IIa and IIb) dose expansion cohort E additional inclusion criteria:
1. includes non-small cell lung cancer, gastric or gastroesophageal junction
adenocarcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma,
kidney carcinoma, cervical squamous cell carcinoma, and endometrial carcinoma;
2. must have received at least one but no more than two prior lines of systemic
therapy, of which only one prior line of therapy contained an anti-PD-1/PD-L1;
3. subjects with PD-1/PD-L1 primary resistance are required to be known PD-L1
positive.
For NSCLC,
1. non-squamous NSCLC must have documented test results of EGFR mutation, ALK
fusion and ROS1 fusions, and the above driver genes must be wild type;
2. non-squamous NSCLC, if RET, MET, NTRK gene testing has been performed
previously, the results must be wild type;
3. squamous NSCLC, if EGFR, ALK fusion gene and ROS1 fusion gene testing has
been performed previously, the results must be wild type.
For ESCC,
1. exclude a history of gastrointestinal perforation and/or fistula within 6
months prior to initial medication;
2. after esophageal or tracheal stent implantation is excluded.
For HCC
1. Barcelona Clinic Liver Cancer (BCLC) stage C and stage B;
2. liver function status Child-Pugh (CP) class A and class B in good
status(≤7 points);
3. exclude: a) known fibrolamellar HCC, sarcomatiod HCC, intrahepatic
cholangiocarcinoma, or mixed hepatocellular carcinoma and
cholangiocarcinoma and other histological types; b) tumor thrombus
intrudes into the main and branches of large blood vessels such as portal
vein, superior mesenteric vein or inferior vena cava, and causes
complications such as portal hypertension and jaundice, or has related
clinical risks judged by the researchers to be unsuitable for
participation in this study; c) local to regional treatment for the liver
(i.e., transarterial chemoembolization, transcatheter embolization,
hepatic arterial infusion, radiotherapy, radioembolization, or ablation)
within 4 weeks prior to initial medication.
For RCC Clear cell renal cell carcinoma with or without sarcomatoid components.
For EC
1. histopathology confirmed Stage III/IV epithelial endometrial carcinoma
including endometrioid carcinoma, non-endometrioid carcinoma, and
carcinosarcoma;
2. non-known ER, PR positive endometrial cancer.
Note: neoadjuvant ± adjuvant therapy is considered as one of treatment line;
maintenance treatment as part of the former first-line treatment.
PD-L1 positive is defined as PDL1 TPS≥1%, IPS≥1% or CPS≥1.
18. Non-pregnant women and willingness of female participants to avoid pregnancy or male
participants willing to avoid fathering children through highly effective methods of
contraception after signing informed consent, during the study period, and within 6
months after the last medication.
19. Fully understand the informed consent and sign voluntarily.
20. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.
exclusion criteria:
1. Pregnancy, lactation, or breastfeeding.
2. Any prior ≥ Grade 3 immune-related adverse events (irAEs) while receiving
immunotherapy or any grade irAE leading to discontinuation in prior immunotherapy;
or grade 4 myelosuppression during prior antitumor therapy.
3. Known history of allergy or severe hypersensitivity reactions to other monoclonal
antibodies or intravenous immunoglobulins such as anti-PD1/anti-PD-L1 antibodies,
TIM-3, interleukin-10, or any of its excipients.
4. Active autoimmune disease or symptomatic history of autoimmune disease (including
celiac disease) requiring pharmacological doses of systemic corticosteroids and/or
immunosuppressive. Exceptions include vitiligo, relieved asthma/atopic disease, type
1 diabetes or hypothyroidism treatable with alternative therapy and achieving
clinical stability during screening, or any other autoimmune disease after
discussion with the principal investigator and sponsor.
5. Requirement for systemic corticosteroids (≥ 10 mg/day prednisone or equivalent) or
other immunosuppressive therapy within 14 days prior to the planned first dose of
study intervention. Inhalational or topical corticosteroids and adrenal replacement
steroids (≤ 15 mg prednisone once daily equivalent) are allowed in the non-active
autoimmune disease. Ophthalmic, nasal, inhaled, and intra-articular corticosteroids
are allowed; short-term use of glucocorticoids for prophylactic treatment (e.g.,
prevention of contrast media allergy) is allowed.
6. Any of the following prior treatments:
1. major surgical procedure (e.g., laparotomy, thoracotomy, organ resection,
etc.), severe trauma, etc. (Replacement of intravenous drip droppers is
acceptable) within 4 weeks prior to first dose, or not recovered from prior
surgery; surgery within 14 days prior to the first dose to improves tumor
complications or reduces tumor risk (e.g., cervical cancer subjects undergoing
nephrostomy or urethral stent placement); significant surgery planned within 30
days after the first dose (except for local surgeries such as placement of
systemic ports, core needle biopsy, and prostate biopsy, provided the surgery
is completed at least 24 hours before the first dose of study intervention);
2. receipt of live vaccine or live attenuated vaccine within 4 weeks prior to
first dose of study intervention;
3. use of modulating drugs within 14 days prior to first dose of study
intervention, including but not limited to thymosin peptide, interleukin-2,
interferon, etc.;
4. history of allogeneic organ transplant, allogeneic hematopoietic stem cell
transplant, or bone marrow transplant.
7. Prior use of drugs with the same mechanism of action as the study drug (e.g.,
anti-PD1 antibody in combination with anti-TIM3 antibody, PD1/TIM3 bispecific
antibody, or IL-10-containing drug).
8. Active infection including syphilis, hepatitis B (HBsAg positive and HBV-DNA > 200
IU/mL or 1000 cps/mL or HBV DNA above the lower limit of detection if the lower
limit of the study center is above 200 IU/mL), hepatitis C (Patients with HCV
antibody positive but HCV-RNA < lower limit of the study center were admitted).
9. History of other malignant tumors within the past 3 years.
10. Subjects with meningeal metastasis, spinal cord compression, or symptomatic unstable
brain metastases or requiring steroids and/or antiepileptic drugs within 4 weeks
before enrollment.
11. Severe infection requiring systemic antibiotic therapy within 14 days prior to first
dose, or active infection requiring systemic treatment.
12. Uncontrolled or poorly controlled diabetes (glycated hemoglobin ≥ 7.5 at screening),
asthma, chronic obstructive pulmonary disease, or other diseases that pose a risk to
study participants.
13. Any syncope or seizure within 28 days prior to first dose of the study intervention.
14. Known gastric bleeding lesions or patients considered to be at high risk of gastric
bleeding by the investigator.
15. Known presence of diseases such as symptomatic irritable bowel syndrome (such as
chronic nausea, persistent recurrent vomiting or diarrhea) and gastric bleeding or
intestinal obstruction.
16. Known history of serious cardiovascular and cerebrovascular diseases, including but
not limited to:
1. uncontrolled cardiovascular diseases within 3 months before the study,
including but not limited to congestive heart failure required treatment (NYHA
> II), uncontrolled hypertension (resting blood pressure ≥ 160/100 mmHg),
uncontrolled arrhythmia;
2. myocardial infarction, unstable angina, viral myocarditis, pericarditis,
cerebrovascular accident, or other acute uncontrolled heart disease within the
recent 6 months;
3. Electrocardiogram: Female QTcF > 470 milliseconds (ms), Male QTcF > 450 ms
(QTcF = QT/RR1/3), or congenital long QT syndrome;
4. Echocardiographic assessment: Left ventricular ejection fraction (LVEF) ≤ 50%
measured by multiple-gated acquisition (MUGA) or echocardiography.
17. Known evidence of interstitial lung disease, symptomatic or may interfere with
suspicious findings or management of drug-related pulmonary toxicity.
18. Active tuberculosis (TB).
19. Positive human immunodeficiency virus (HIV).
20. Diseases involving the central nervous system (except for patients with prior brain
metastases treated at least 4 weeks before first dose, clinically stable, and not
requiring long-term corticosteroid therapy) or history of NCI CTCAE 5.0 Grade 3 or
higher drug-related central nervous system toxicity.
21. Venous/arterial thrombotic events occurred within 6 months, including
cerebrovascular accidents (such as transient ischemic attacks, cerebral hemorrhage,
cerebral infarction such as lacunar infarcts), deep venous thrombosis, and pulmonary
embolism.
22. Uncontrolled pleural effusion, pericardial effusion, or ascites (clinically
significant recurrence requiring additional intervention every 2 weeks or more
frequently).
23. History of severe psychiatric disorders, substance abuse, alcoholism, or drug abuse.
24. Have experienced ≥ grade 3 infusion-related reactions to protein therapeutics.
25. Any other disease (including severe medical or psychiatric conditions) or
significant clinical laboratory abnormalities judged by the investigator to
potentially affect subject safety, study integrity, or subject's willing in the
study.
26. All known MSI-H/dMMR patients.
27. All known HER-2 positive (IHC 3+ or IHC 2+, Fish amplification) patients.
28. Urine protein ≥ 2+, and 24-hour urine protein quantification ≥ 1.0g.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Shanghai East Hospital
Address:
City:
Shanghai
Zip:
201114
Country:
China
Status:
Recruiting
Contact:
Last name:
Wei Li
Phone:
+8613817918714
Email:
leewluck@gmail.com
Start date:
June 19, 2024
Completion date:
December 30, 2027
Lead sponsor:
Agency:
L & L biopharma Co., Ltd., Shanghai China
Agency class:
Industry
Collaborator:
Agency:
Shanghai East Hospital
Agency class:
Other
Source:
L & L biopharma Co., Ltd., Shanghai China
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06468358
