Prospective registration

An open, multi-center, first human dose escalation and early dose expansion phase I clinical study, aimed at evaluating the safety, tolerability and preliminary effectiveness of IMM2902 in the treatment of advanced solid tumors expressing HER2

An open, multi-center, first human dose escalation and early dose expansion phase I clinical study, aimed at evaluating the safety, tolerability and preliminary effectiveness of IMM2902 in the treatment of advanced solid tumors expressing HER2

Dong Fangfang 

Tian Wenzhi 

15 Building, 1000 Lane, Zhangheng Road, Pudong New Area, Shanghai

15 Building, 1000 Lane, Zhangheng Road, Pudong New Area, Shanghai

ImmuneOnco Biopharmaceuticals (Shanghai) Co., Ltd

ImmuneOnco Biopharmaceuticals (Shanghai) Co., Ltd

Yes

Ethics Committee of Chinese PLA General Hospital

Cao Jiang

28 Fuxing Road, Haidian District, Beijing

Chinese PLA General Hospital

28 Fuxing Road, Haidian District, Beijing

Self-funded

Advanced solid tumors expressing HER2

Observational study

1

Single arm 

To observe the safety, tolerability, the preliminary anti-tumor efficacy, PK, and the immunogenicity of IMM2902 in patients with advanced solid tumors expressing HER2, so as to determine the maximum tolerated dose (MTD) and the recommended dose for expension(RDE) of IMM2902 monotherapy (Phase Ia). To further observe the safety and tolerability of IMM2902 in patients with unresectable locally advanced or metastatic solid tumors with overexpression or underexpression of HER2 (stage Ib).

1. Phase Ia (dose escalation phase): The study will include 20 to 42 patients with advanced solid tumors with HER2 expression [immunohistochemistry (IHC) 1+, 2+ or 3+] who have progressed on standard therapy, failed therapy, or no standard therapy, including but not limited to breast cancer, gastric cancer (including gastroesophageal junction adenocarcinoma), bladder cancer, biliary tract cancer, ovarian cancer, colon cancer and non-small cell lung cancer, etc., aiming to determine MTD and RDE by evaluating the safety and tolerability of IMM2902 monotherapy. The trial will use a modified 3+3 design method for dose escalation. The initial dose of IMM2902 is set to 0.03 mg/kg, and the maximum dose is tentatively set to 2.0 mg/kg. There are 7 dose levels designed in the dose escalation phase: 0.03, 0.1, 0.25, 0.5, 1.0, 1.5 and 2.0 mg/kg, of which the first 2 dose groups (0.03 mg/kg and 0.1 mg/kg) are using rapid titration approach to reduce the number of subjects exposed to potentially ineffective doses who may not benefit from treatment; dose exploration for subsequent dose groups (>= 0.25 mg/kg) starting with the 3rd dose uses traditional 3+3 mode to determine MTD and RDE. Each subject in each dose group underwent dose escalation according to the dose escalation rule, and the observation period for dose-limiting toxicity (DLT) was set within 28 days after the first dose of the first cycle. Eligible subjects will be treated with IMM2902 for injection, intravenous infusion, once a week (7±1 days) (D1, D8, D15, D22) for 4 consecutive doses. During the DLT observation period, if the subject does not observe DLT and the investigator believes that continued treatment can bring clinical benefit to the subject, the subject will continue to receive IMM2902 treatment, administered once a week (7±1 day), 4 weeks as a treatment cycle, until intolerable toxicity, disease progression or death, the subject withdraws informed consent, the investigator considers that it is in the best interests of the subject to terminate the treatment, and the subject receives other anti-tumor treatments or the cumulative treatment for 12 treatment cycles (whichever occurs first). Among subjects enrolled with accelerated titration (dose groups 1 to 2), 1 patient will be enrolled in each group. During the DLT observation period, if no DLT occurred or no grade >=2 AEs related to study drug occurred, escalation to the next dose group. If the subject has >= grade 2 AEs related to the study drug, the dose group will be expanded to 3 subjects to further observe the safety of the drug, and the "3+3" rule escalation will be started from this dose group. Among subjects enrolled in the 3+3 design, 3 to 6 patients will be included in each group. The subjects in each dose group are enrolled in a case-by-case manner. The first and second subjects should be enrolled at least 1 week apart, and the subsequent subjects should be enrolled at least 24 hours apart. At least 3 subjects who have completed 4 weeks of treatment should be evaluated for safety before proceeding to the next dose level. If no DLT occurred in 3 subjects in a dose group, escalation to the next dose group was performed. When 1 out of 3 subjects in a dose group observes DLT, 3 more patients in the same dose group need to be added (a total of 6 subjects in this dose group completed 4 weeks of treatment); if no DLT occurred in any of the additional 3 patients, proceed to the next level of dose escalation; if patient >= 1 of the additional 3 patients observed DLT, the dose escalation was stopped, and the safety monitoring committee (SMC, composed of the sponsor and investigator) to discuss whether a dose reduction (at least 6 subjects) is required to proceed with the DLT evaluation. When > 1 case of 3 subjects in a dose group developed DLT, the dose escalation was stopped, and the SMC discussed whether it was necessary to reduce a dose (at least 6 subjects) to continue the DLT evaluation. During this study, if 3 patients in the first dose group (0.03 mg/kg) had > 1 case of DLT, the SMC suggested whether to reduce the dose based on the first dose group for DLT evaluation. If no DLT was observed in the set of 7 dose groups, the SMC discussed whether to increase the dose or explore the frequency of dosing (eg, once every 2 weeks) until the MTD occurred. In order to find a more accurate MTD, at the pre-set dose, the decision to increase the intermediate dose group can be made based on the obtained safety and PK data based on the results discussed by the investigator and the sponsor. At least 6 subjects in the MTD dose group must complete the DLT assessment. Even if the MTD has been achieved, the selection of RDE still requires reference to the MTD and available information on: grade 1-2 AEs, AEs occurring in subsequent treatment cycles, PK, and efficacy data. The RDE may be the MTD or an evaluable dose lower than the MTD, and the determined RDE may be used as the study dose in the dose expansion phase. 2. Phase Ib (dose expansion phase): The study will enroll 92 patients with unresectable locally advanced or metastatic breast cancer, gastric cancer (including gastroesophageal esophagus) with overexpression of HER2 [IHC3+ or IHC2+/fluorescence in situ hybridization (FISH+)] or low expression of HER2 (IHC1+ or IHC2+/FISH-) and HER2 overexpressing (IHC3+ or IHC2+) patients with other types of solid tumors to further evaluate the safety, efficacy, PK characteristics and immunogenicity by IMM2902 monotherapy. Eligible subjects will be treated by IMM2902 of RDE, intravenous infusion, once a week (7±1 day), 4 consecutive doses, 4 weeks as a treatment cycle, until intolerance Subject to toxicity, disease progression or death, subject withdraws informed consent, researcher believes that it is in the best interests of subject to terminate treatment, subject receives other anti-tumor therapy or accumulated treatment for 12 treatment cycles (whichever occurs first). Taking the first dose as day 1, tumor imaging assessments were performed every 8 weeks (±7 days) for the first 6 treatment cycles, and tumor imaging assessments were performed every 12 weeks (±7 days) after 6 treatment cycles until Subject has disease progression, initiation of other anti-tumor therapy, withdrawal from the study, loss to follow-up, death, or termination of the study (whichever occurs first). In the event of a dosing delay or a visit delay occurring during treatment, tumor assessments should still be performed on the scheduled date after the first dose. Subjects withdrew/terminated study treatment for any reason, with withdrawal/termination of treatment follow-up within 7 days after learning/determination of the end of treatment, safety follow-up 30 days (± 7 days) after the last dose, and every subsequent 90 days (± 7 days) days) for a survival follow-up until the end of the study. In the study, the concentration of IMM2902 in the serum of the subjects will be measured, and the PK parameters will be analyzed according to the drug-time curve. In addition, the production of anti-drug antibodies (ADA) in the serum of the subjects should be detected, and the biomarkers (HER2 protein expression level) and pharmacodynamic indicators (cytokine levels and distribution characteristics of lymphocyte subsets) that predict efficacy should be tested. explore. SMC is responsible for safety supervision, dose escalation design, MTD/RDE, and other important research decisions. When the investigator and the sponsor propose to adjust the dose escalation range, dosing frequency or new dose group in the adjustment plan, the SMC makes an evaluation and recommendation based on the previous safety data. The specific content of the composition and responsibilities of the SMC can be found in the Regulations of the Safety Monitoring Committee. 

1. Sign the ICF voluntarily and follow the requirements of the plan;

2. Age ≥18 years old, and ≤75 years old, no gender limit;

3. Expected survival time ≥ 12 weeks;

4. HER2 expression:
HER2 protein expression or HER2 gene amplification in primary or metastatic tumor tissues was detected by IHC or FISH.

Phase Ia (dose escalation phase): HER2 expression is defined as IHC1+, IHC2+ or IHC3+, FISH testing is not required, and the results of local qualified medical institutions can be accepted.
Phase Ib (dose expansion phase): HER2 overexpression is defined as IHC3+ or IHC2+/FISH+; HER2 low expression is defined as IHC1+ or IHC2+/FISH-, and the results must be confirmed by the pathology laboratory of the research center during the screening period;

5. Clinical diagnosis:
Phase Ia (dose escalation phase): Patients with advanced solid tumors with HER2 expression (IHC1+, IHC2+ or IHC3+) confirmed by histology or cytology, who have received advances in standard treatment, have failed to treat or have no standard treatment plan, Including but not limited to breast cancer, gastric cancer (including gastroesophageal junction adenocarcinoma), urothelial cancer, biliary tract cancer, ovarian cancer, colon cancer and non-small cell lung cancer.

Phase Ib (dose expansion stage), including 3 cohorts:
Cohort 1: Unresectable locally advanced or metastatic breast cancer with HER2 expression confirmed by histology or cytology, including 2 subgroups:
HER2 overexpression (IHC3+ or IHC2+) /FISH+) group: Recurrence or disease progression after receiving at least second-line anti-HER2 therapy (including but not limited to trastuzumab);
HER2 low expression (IHC1+ or IHC2+/FISH-) group: previous second-line or higher system therapy Failure (including standard chemotherapy regimens, PD-1/PD-L1 inhibitor therapy, etc.).

Cohort 2: Unresectable locally advanced or metastatic gastric cancer with HER2 expression confirmed by histology or cytology (including gastroesophageal junction adenocarcinoma), including 2 subgroups:
HER2 overexpression (IHC3+ or IHC2+/FISH+) group: Recurrence or disease progression after receiving first-line anti-HER2 therapy (including but not limited to trastuzumab combined with platinum and 5-fluorouracil);
HER2 low expression (IHC1+ or IHC2+/FISH-) group: previous second-line or above system Treatment failure (including standard chemotherapy regimens, PD-1/PD-L1 inhibitor treatment, etc.);

Cohort 3:
HER2 overexpression (IHC3+ or IHC2+) confirmed by histology or cytology and other types of advanced solid tumors (excluding breast cancer and gastric cancer), recurrence or disease progression after receiving standard treatment in the past, including but not limited to urothelial cancer, bile duct cancer, ovarian cancer, cervical cancer, colon cancer, non-small cell lung cancer, etc.;

6. Patients enrolled in the Phase Ib study were required to provide fresh or recently archived tumor tissue and its pathology report to detect HER2 expression status. If tissue samples are not available, the patient is advised to undergo a new tumor biopsy;

7. Measurable lesions according to Evaluation Criteria for Solid Tumors (RECIST v1.1) (longest diameter ≥10 mm on helical CT scan and ≥15 mm short diameter if the lesion is a lymph node; and the lesion has not received radiotherapy unless the lesion has clearly progressed );
Phase Ia (dose escalation phase): Evaluable lesions (target or non-target lesions);
Phase Ib (dose expansion phase): Measurable lesions (target lesions) according to RECIST v1.1 criteria

8. Physical fitness score ECOG 0 or 1 point;

9. Organ function level must meet the following requirements:
bone marrow: absolute value of neutrophil count (ANC) ≥1.5×109/L, platelet count ≥85×109/L, hemoglobin ≥90g/L, and not received within 14 days Blood transfusion or biological response modifier (such as granulocyte, red blood cell growth factor, etc.) treatment;
liver: total bilirubin (TBIL) ≤ 1.5 × ULN, aspartate aminotransferase (AST) And alanine aminotransferase (ALT) are both ≤2.5×ULN; if there is liver metastasis, TBIL≤3.0×ULN, AST and ALT are both ≤5.0×ULN;
heart: left ventricular ejection fraction (LVEF) ≥50% (ECHO confirmed );
Kidney: creatinine (Cr)≤1.5×ULN, or creatinine clearance (Ccr)≥50mL/min (according to the Cockcroft-Gault formula);
10. Coagulation function: International normalized ratio (INR) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (except for receiving therapeutic anticoagulant drugs);

11. Previous systemic chemotherapy, radical/extensive radiotherapy or other anti-tumor drug treatment related adverse events recovered to (NCICTCAEv5.0) ≤ grade 1 ( Except for non-clinically significant or asymptomatic laboratory abnormalities);

12. The cumulative dose of anthracycline doxorubicin≤360mg/m2 or its equivalent, epirubicin≤720mg/m2;

13. Patients of childbearing age must take effective contraceptive measures during the study to 6 months after the last dose.

1. Received the last systemic or local anti-tumor therapy within 4 weeks before the first dose, including chemotherapy, immunotherapy, biological agents, etc. within 4 weeks before the first administration; received hormone anti-tumor therapy, small molecule targeted therapy within 2 weeks before the first administration; Palliative local treatment for non-target lesions within 2 weeks before administration; non-specific immunomodulatory therapy (such as interleukin, interferon, thymosin, tumor necrosis factor, etc.) within 2 weeks before the first administration, excluding platelets Reduced IL11); receive Chinese herbal medicines or Chinese patent medicines with anti-tumor indications within 1 week before the first administration;

2. 4 weeks before the first administration, receive therapeutic drugs that target the SIRPα-CD47 signal axis, such as CD47 antibody, SIRPα fusion protein, SIRPα antibody and SIRPγ fusion protein;

3. Patients with primary central nervous system (CNS) malignant tumors or active CNS metastases who have failed local treatment (radiotherapy or surgery), but the following patients are allowed to be included in the group: a. Asymptomatic brain metastases; b. Clinical symptoms are stable ( That is, no imaging progress is seen 4 weeks before the first administration, and any neurological symptoms have returned to baseline levels), and corticosteroids and other treatments for brain metastases are not required for ≥ 4 weeks;

4. Hypertension not controlled by drugs (systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg) or pulmonary hypertension or unstable angina pectoris; myocardial infarction or bypass or stent surgery within 6 months before administration; New York Heart History of chronic heart failure with NYHA standard grade 3-4; clinically significant valvular disease; severe arrhythmia requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia), including QTc males ≥450ms , Female ≥470ms (calculated by Fridericia formula); Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 12 months before enrollment;

5. History of arterial thrombosis, deep vein thrombosis and pulmonary embolism within 3 months before the administration;

6. Have a history of moderate or severe dyspnea at rest due to advanced malignant tumors or their complications or severe primary lung diseases, or currently require continuous oxygen therapy, or currently suffer from interstitial lung disease (ILD) Or history of pneumonia, severe chronic obstructive pulmonary disease, severe pulmonary insufficiency, symptomatic bronchospasm, etc.;

7. Suffered from other malignant tumors within 5 years before the first administration. Except:
a. Cervical carcinoma in situ or non-melanoma skin cancer that has been cured;
b. The second primary cancer that has been cured and has no recurrence within five years;
c. Researchers believe that both primary cancers can be obtained from this study Benefit;
d. The investigator has clearly excluded the source of the primary tumor from the metastasis;

8. Diseases that may cause gastrointestinal bleeding or perforation (such as duodenal ulcer, intestinal obstruction, acute Crohns disease, ulcerative colitis, extensive gastric and small bowel resection, etc.); suffering from chronic Crohns disease and Patients with ulcerative colitis (except for total colon and rectal resection) should be excluded even in the inactive period; patients with hereditary non-polyposis colorectal cancer or familial adenomatous polyposis syndrome; previous bowel History of perforation, intestinal fistula, but not cured after surgical treatment; esophageal and gastric varices;

9. Thoracic and abdominal cavity and pericardial effusions that require puncture and drainage treatment that cannot be controlled, require repeated drainage or have obvious symptoms;

10. Have active hepatitis B [positive hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus antibody (HBcAb) positive, and HBV DNA ≥ 2000 IU/ml, and exclude drug or other causes of hepatitis], or active hepatitis C [anti-hepatitis C virus (HCV) antibody positive, and HCV RNA above the lower limit of detection, and excluding drug or other causes of hepatitis];

11. A history of immunodeficiency, including human immunodeficiency virus (HIV) infection, or other immune defective disease, or a history of organ transplantation

12. A history of autoimmune diseases, including but not limited to systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis, autoimmune thyroid disease, multiple sclerosis, etc. patient. Except:
a. Hypothyroidism that can be controlled only by hormone replacement therapy;
b. Skin diseases that do not require systemic treatment (such as vitiligo, psoriasis);
c. Controlled celiac disease.
However, patients who are using immunosuppressive agents or systemic hormone therapy (dose ≥10mg/day of prednisone or other equivalent hormones) and continue to use them within 2 weeks before enrollment cannot be enrolled;

13. There is evidence of uncontrollable serious active infection (such as sepsis, bacteremia, viremia, etc.);

14. A history of grade 3 or higher allergy to any component or excipient of the study drug; or a previous grade 3 or higher allergic reaction to trastuzumab or other anti-HER2 targeted drugs (CTCAE v5.0 classification);

15. Receiving anti-tumor vaccine treatment or planning to accept anti-tumor vaccine trials 4 weeks before the first administration;

16. Major surgery has been performed within 4 weeks before the first administration and has not fully recovered, or major surgery is planned to be performed in the first 12 weeks after receiving the study drug; minor surgery (including catheterization) has been received 2 days before enrollment , Except for central venous catheterization via peripheral venipuncture);

17. Those who have a clear history of neurological or mental disorders, such as epilepsy, dementia, and poor compliance;
18. A history of alcohol or drug abuse in the past year;

19. Positive serum pregnancy test or breastfeeding women; do not agree to use adequate contraception during the study and for 6 months after receiving the study drug;

20. Patients who have participated in other clinical studies in the past must meet the requirements of the original clinical study group and be more than 4 weeks away from the first administration of this study;

21. Other situations that the researcher thinks are not suitable for participating in this research;

NA

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Within 6 months after completing the trial

EDC