IBI343 Combined With Chemotherapy in Advanced Pancreatic Cancer

A Phase Ib/II Study to Evaluate the Safety, Tolerability and Efficacy of IBI343 in Combination With Chemotherapy in Subjects With Advanced Pancreatic Cancer

This is a Phase Ib/II study to evaluate the safety, tolerability and efficacy of IBI343 in combination with chemotherapy in patients with advanced pancreatic cancer, including a Phase Ib safety introduction and Phase II expansion phase.

In phase Ib (safe introduction phase), participants with CLDN18.2-positive advanced pancreatic adenocarcinoma (PAC) who had previously received first-line gemcitabine-based systemic therapy were enrolled to receive IBI343 in combination with chemotherapy.A classic "3+3" dose-escalation design was used to determine the dose of the combination therapy, including the following two cohorts:

Cohort A: received IBI343+ capecitabine TBD mg/m2 BID PO×14d Q3W; Cohort B: received IBI343+ capecitabine TBD mg/m2 BID PO×14d Q3W+ oxaliplatin TBD mg/m2 IV Q3W (each subject received up to 8 cycles of oxaliplatin).

In cohort A, 3 subjects were enrolled in Intravenous (IV) Q3W, and the starting dose of IBI343 was 6 mg/kg.The preset starting dose of capecitabine was 750mg/m2 BID PO, D1-14, Q3W. The observation period of safe introduction of DLT was 21 days (3 weeks) after the first administration, and IBI343 was administered only once during the DLT observation period.If the first 3 subjects did not develop DLT during the DLT observation period, 3-6 subjects were allowed to receive IBI343 6mg/kg combined with capecitabine 1000mg/m2 BID PO, D1-14, Q3W;If DLT occurs in 1 of these 3 subjects, the other 3 subjects will be included in the same dose group.If no DLT occurred in the three additional subjects, 3-6 subjects were allowed to receive IBI343 6mg/kg combined with capecitabine 1000mg/m2BID PO, D1-14, Q3W;If DLT occurred in ≥1 of the 3 subjects included in the supplement, or ≥2 of the 6 subjects in total, or ≥2 of the first 3 subjects, 3 to 6 subjects were allowed to receive IBI343 4.5mg/kg Q3W;If intolerance remains, the mode and dose of administration will be further discussed.

If the dose level of 1000mg/m2 in combination with capecitabine is confirmed to be safe, subjects in combination with capecitabine 750mg/m2 are allowed to increase the dose of capecitabine to 1000mg/m2 in subsequent cycles.

If IBI343 combined with capecitabine is tolerated according to the above safety introduction rules, the safe introduction of IBI343 in cohort B (IBI343 combined with oxaliplatin and capecitabine) is initiated after the dose of IBI343 combined with capecitabine is determined.The preset starting dose of oxaliplatin in cohort B was 75mg/m2 IV D1 Q3W, and A preset climbing dose level of 100mg/m2 IV D1 Q3W was introduced in the same way as in cohort A.If both dose levels of oxaliplatin are not tolerated, the administration mode and dose will be further discussed, such as downregulating the administration dose of IBI343.

The sponsor is allowed to adjust the safe dose of IBI343 based on the results of the preliminary study.

To allow sponsors to further explore the dose of combination chemotherapy based on the observed safety during the Phase Ib safety introduction phase.

Each cohort will enter the Phase II expansion phase of the cohort after safety introduction, determination of the combination dose and safety of IBI343.

Participants enrolled in the expansion phase are consistent with those enrolled in the safety introduction phase, i.e., CLDN18.2-positive advanced PAC subjects who have previously received first-line gemcitabine-based systemic therapy:

Phase II Cohort A: Approximately 32 subjects (including Phase Ib Cohort A dosing subjects) were scheduled to receive IBI343+ capecitabine Q3W.

Phase II Cohort B: Approximately 24 subjects (including Phase Ib Cohort B dosing subjects) were scheduled to receive IBI343+ capecitabine + oxaliplatin Q3W.Each subject received a maximum of 8 cycles of oxaliplatin therapy.

Queue A and queue B are expanded sequentially. Queue A is expanded first. After queue A is expanded, queue B is expanded.The investigator may also terminate the expansion of a cohort based on early efficacy and safety data, in which case only one of the cohorts should be expanded.

Sponsors and funders are allowed to adjust the CLDN18.2 expression level requirements of enrolled subjects based on the results of other trials of IBI343.

Subjects will continue to receive treatment until disease progression, toxicity intolerance, withdrawal of informed consent, loss of follow-up, death, or any other reason for discontinuation of study therapy (whichever occurs first).

After discontinuation of study treatment, participants will be followed up for safety and survival.

During the study, participants were evaluated by imaging according to RECIST v1.1.

In the oxaliplatin combination cohort, oxaliplatin was used for a maximum of 8 cycles, and subjects in this cohort could continue maintenance therapy with IBI343+ capecitabine after oxaliplatin withdrawal.

Inclusion Criteria:

1. Sign a written Informed Consent Form (ICF) and be willing and able to comply with the visit and related procedures stipulated by the program.

2. Histopathologically confirmed unresectable locally advanced, recurrent, or metastatic PAC.

3. Progression or intolerance following first-line gemcitabine-based systemic therapy at locally advanced or recurrent/metastatic stages.If the time from the last neoadjuvant/adjuvant therapy to disease recurrence/metastasis is less than 6 months, the treatment is considered first-line therapy.

4. The subject must not be suitable for radical treatment methods such as radical chemoradiotherapy and/or surgery.

5. According to RECIST v1.1, at least 1 measurable lesion had not received prior radiotherapy.(At baseline, an intravenous contrast agent is preferred by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) to accurately measure nodes with a long diameter ≥10 mm except for the short axis of the lymph nodes≥15 mm Target lesion diameter ≥2 times image layer thickness and lesions suitable for repeated accurate measurement.If a lesion located in a previously irradiated area clearly demonstrates progression to RECIST V1.1 criteria, it can be considered a measurable lesion).

6. Age ≥18 years old, gender is not limited.

7. Score of 0 or 1 according to the Eastern Cooperative Oncology Group Performance Status (ECOG PS).

8. BMI 17 kg/m2.

9. Expected survival ≥12 weeks.

10. With full bone marrow and organ function:

    A. routine blood ANC acuity 1.5 x 109 / L platelet count 100 x 109 or higher acuity 9.0 g/dL/L hemoglobin content subjects in blood sampling may not be received within 7 days before losing blood products (including red suspension, single mining platelet and cryoprecipitate, etc.), Erythropoietin,Granulocyte-colony Stimulating Factor or Granulocyte-Macrophage Colony-Stimulating Factor treatment b. Liver function TBIL≤1.5×ULN Subjects with Gilbert syndrome allowed TBIL≤3×ULN Subjects without liver metastasis ALT and AST≤2.5×ULN Subjects with liver metastasis ALT and AST≤5×ULN albumin ≥30 g/L c. Renal creatinine clearance ≥60 mL/min Urinary protein < 2+ by Cockcroft-Gault formula or total urinary protein < 1 g in 24h d. Coagulation function: International Normalized Ratio≤1.5 and Activated Partial Thromboplastin Time≤1.5×ULN (subjects who are allowed to receive anticoagulation therapy and whose coagulation function is in the above range).

11. Female subjects of childbearing age or male subjects whose partners are women of childbearing age are required to take effective contraceptive measures throughout the treatment period and for 6 months after the treatment period.

12. The histopathological test confirmed that *CLDN18.2 was positive.For subjects who have previously received any anti-CLDN18.2 treatment, tumor samples should be collected again after the relevant anti-CLDN18.2 treatment has ended.

Note:

*CLDN18.2 positive was defined as Claudin18.2 immunohistochemical membrane staining intensity ≥ acceptance of previous test results, center test results, and laboratory test results in ≥40% of tumor cells.The proportion of CLDN18.2 expression can be dynamically adjusted by sponsors and funders during the study based on newly generated data.

Exclusion Criteria:

1. Participating in another interventional clinical study, other than an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study.

2. Cytochrome P450 3A4 CYP3A4 (cytochrome P450 3A4) suppressant treatment within 2 weeks or 5 half-lives (whichever is longer) prior to the first administration of the study drug.

3. Receive the last anti-tumor treatment 4 weeks before the first administration of the study drug or within 5 half-lives of the anti-tumor therapy drug (whichever is shorter) (drugs without an exact half-life need to be eluted for 2 weeks).

4. Received therapeutic or palliative radiotherapy within 2 weeks prior to the first administration of the study drug.

5. Biliary stenting or PTCD was performed within 7 days prior to the first use of the study drug.

6. Plan to receive other anti-tumor therapy during the study drug treatment period [allowing palliative radiotherapy for the purpose of relieving symptoms (such as pain) without compromising the evaluation of efficacy].

7. Receive any live vaccines within 4 weeks prior to the first administration of the study drug or during the study period.

8. Had a major surgical procedure (craniotomy, thoracotomy, or laparotomy, or other procedure as defined by the investigator, excluding needle biopsy) or had an unhealed wound, ulcer, or fracture within 4 weeks prior to the first administration of the study drug;Or plan to require major surgery during the study.For the purpose of palliative care, local surgical treatment of isolated lesions is acceptable.

9. Toxicity from prior treatment that did not return to NCI CTCAE v5.0 before first administration of the investigational drug (excluding alopecia, weakness, pigmentation, and other conditions deemed by the investigator to be of no safety risk).

10. A history of gastrointestinal perforation and/or fistula within the 6 months prior to the first administration of the study drug that has not been cured by surgical treatment.

11. Presence of pyloric obstruction and/or persistent recurrent vomiting (vomiting ≥ 3 times within 24 hours).

12. Digestive tract [refers to the muscular duct from the mouth to the anal canal, including the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum) and anal canal, etc.] or after endotracheal stent implantation.

13. Symptomatic central nervous system metastasis.Participants with asymptomatic BMS (i.e., no neurological symptoms, no need for glucocorticoid therapy, all BMS ≤ 1.5 cm) or BMS with stable symptoms after treatment met all of the following criteria to be eligible for participation in this study: no midbrain, pontine, cerebellum, meninges, medulla bulbar, or spinal cord metastases;Clinical status remained stable for at least 4 weeks, clinical evidence confirmed no new or expanded brain metastases, and corticosteroids and anticonvulsants were discontinued for at least 2 weeks before first administration of the study drug.Note: The central nervous system is not a target lesion.

14. Bone metastases at risk of paraplegia.

15. Interstitial lung disease requiring steroid therapy, or a history of interstitial lung disease, non-infectious pneumonia, severely impaired lung function or uncontrolled lung disease, such as pulmonary fibrosis, severe radiation pneumonia, acute lung injury, etc., or suspected during screening.

16. There are uncontrolled diseases such as:

    1. Investigate the presence of poorly controlled infections that require treatment with systemic anti-infective drugs (antibiotics, antivirals, or antifungals) in the week prior to the first administration of the drug.
    2. HIV-1/2 antibody positive in people with human immunodeficiency virus (HIV).
    3. Acute or chronic active Hepatitis B (defined as Hepatitis B surface Antigen HBsAg) and/or hepatitis B Core Antibody HBcAb positive with hepatitis B virusDNA copy number ≥ 104 copies /mL or ≥ 2000 IU/mL or acute or chronic active Hepatitis C [Hepatitis C Virus antibody (HCVAb) positive HCV RNA 103 copies /mL].Subjects below the above criteria after nucleotide antiviral therapy and those with HCV antibody positive but RNA negative tests were admitted.
    4. Active tuberculosis, receiving antituberculosis therapy or receiving antituberculosis therapy within 1 year prior to the first administration of the investigational drug.
    5. Active plum poisoning or latent syphilis requires treatment.
    6. Symptomatic congestive heart failure (NYHA Class II to IV), symptomatic or poorly controlled arrhythmia, QTc interval 480 ms, or a personal or family history of congenital long/short QT syndrome.
    7. Standardized treatment of poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥100 mmHg).
    8. There is a risk of gastrointestinal/respiratory fistula.
    9. pleural effusion, ascites, or pericardial effusion that is symptomatic and requires intervention (e.g. drainage).
    10. Esophageal or gastric varices that require immediate intervention (e.g., lapping or sclerotherapy) or that are considered to have a high risk of bleeding in the opinion of the investigator or in consultation with a gastroenterologist or hepatologist,Subjects with evidence of portal hypertension (including splenomegaly on imaging) or a history of varicose bleeding must undergo endoscopic evaluation within 3 months prior to the first administration of the study drug.
    11. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal/varicose bleeding event requiring blood transfusion, endoscopic, or surgical treatment occurred in the 3 months prior to the first administration of the study drug.
    12. Study any arterial thromboembolic events, including myocardial infarction, unstable angina pectoris, cerebrovascular accident, and transient ischemic attack, within 6 months prior to the first administration of the drug.
    13. History of new or uncontrolled stable deep vein thrombosis, pulmonary embolism, or any other severe venous thromboembolism within the 3 months prior to the first administration of the investigational drug (implantable port of intravenous infusion or catheter-derived thrombosis or superficial venous thrombosis were not considered "severe" venous thromboembolism).
    14. hepatic encephalopathy, hepatorenal syndrome or Child-Pugh score > 7.
    15. Risk of intestinal obstruction or perforation (including, but not limited to, a history of acute diverticulitis, abdominal abscess) or a history of inflammatory bowel disease or extensive enterectomy (partial resection of the colon or extensive resection of the small intestine with chronic diarrhea), Crohn's disease, ulcerative colitis, etc.
    16. Other acute or chronic medical conditions or abnormalities in laboratory tests that may increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and, at the investigator's discretion, classify subjects as ineligible to participate in the study.
    17. Neurological, psychiatric, or social conditions that affect compliance with study requirements, significantly increase the risk of AE, or affect a subject's ability to provide a written ICF.

17. History of other primary malignancies, except the following:

    Cured malignancies with no known active disease ≥ 2 years prior to study inclusion and a very low risk of recurrence;Non-melanoma skin cancer or malignant lentigo with adequate treatment and no evidence of disease recurrence;Carcinoma in situ with adequate treatment and no evidence of disease recurrence.

18. Known history of immunodeficiency.

19. History of allogeneic organ transplantation and hematopoietic stem cell transplantation.

20. Previously received antibody drug conjugate therapy based on topoisomerase inhibitors.

21. For subjects receiving drug therapy, there is a history of prior allergy to the corresponding drug or preparation.

22. There are contraindications for subjects receiving medication.

23. For subjects receiving medication, there is a history of drug-related adverse reactions leading to permanent discontinuation.

24. Pregnant or lactating female subjects.

25. Other investigators did not consider themselves eligible to participate in the study.