Retrospective registration

A Multicenter, Open-Label, Phase 1a/b First-in-Human Study to Investigate the Safety, Tolerability,Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of BG-C477 in Patients with Selected Advanced Solid Tumors

A Multicenter, Open-Label, Phase 1a/b First-in-Human Study to Investigate the Safety, Tolerability,Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of BG-C477 in Patients with Selected Advanced Solid Tumors

Zhang Xujuan 

Xu Ruihua 

288 South Xizang Road, Huangpu District, Shanghai, China

651 Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China

BeiGene Guangzhou Biologics Manufacturing Co., Ltd.

Sun Yat-sen University Cancer Center (Sun Yat-sen University Cancer Hospital, Sun Yat-sen University Cancer Institute)

Yes

Ethics Committee of Sun Yat-sen University Cancer Center

Pan Xuzhi

651 Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China

Sun Yat-sen University Cancer Center (Sun Yat-sen University Cancer Hospital, Sun Yat-sen University Cancer Institute)

651 Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China

BeiGene Guangzhou Biologics Manufacturing Co., Ltd.

Advanced Solid Tumors

Interventional study

1

Single arm 

1a Main Purpose: To assess the safety and tolerability for BG-C477 monotherapy in patients with selected advanced solid tumors. To determine the MTD or MAD and RDFE[s] of BG-C477 monotherap Secondary purpose: To assess the preliminary antitumor activity of BG-C477 monotherap To characterize the pharmacokinetics of BG-C477 monotherapy To assess host immunogenicity to BG-C477 Exploratory purpose: To further assess the preliminary antitumor activity of BG-C477 monotherapy. To assess the predictive, prognostic, and other biomarkers, including any association with clinical outcome to study treatment and mechanism(s) of resistance. 1b Main purpose: To determine RP2D of BG-C477 alone and in combination with capecitabine with or without bevacizumab To assess the antitumor activity of BG-C477 alone and in combination with capecitabine with or without bevacizumab in patients with selected advanced solid tumors Secondary purpose: To further assess the safety and tolerability of BG-C477 alone and in combination with capecitabine with or without bevacizumab To further evaluate the antitumor activity of BG-C477 alone and in combination with capecitabine with or without bevacizumab To further characterize the PK of BG-C477 alone and in combination with capecitabine with or without bevacizumab To further assess the host immunogenicity to BG-C477 exploratory To assess OS To assess predictive, prognostic, and other biomarkers associated with response to study treatment and

1. Patients must sign the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 2. Patients must be >= 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), inclusive, at the time of signing the informed consent. 3. Phase 1a (Monotherapy Dose Escalation and Safety Expansion): Patients with histologically or cytologically confirmed advanced, metastatic, or unresectable solid tumors, limited to CRC, GC/GEJC, NSCLC, SCLC or pancreatic cancer, who were previously treated with at least 2 lines of standard systemic therapy or for whom no standard treatment is available in the medical judgment of the investigator. Patients with molecular aberrations or a highly expressed tumor associated antigen for which an appropriate molecular targeted therapy exists, must be adequately treated with that therapy. (1) For CRC: Patients with known MSI-high/deficient mismatch repair status must have received at least one line of treatment with an immune checkpoint inhibitor if available as locally approved treatment. (2) For non-CRC: Patients should have a test result of serum CEA >= 5 ng/ml or documented tumor tissue CEA positivity by immunohistochemistry testing per local laboratory. Phase 1b (Dose Expansion): (1) Part A (Dose Optimization): Patients with histologically or cytologically confirmed advanced, metastatic, or unresectable CRC, GC/GEJC, or other selected tumor types as described in Section 4.1.1.6. Patients must have been previously treated with 1 or 2 lines of standard systemic therapy. For non-CRC, patients should have a test result of serum CEA >= 5 ng/ml or documented tumor tissue CEA positivity by immunohistochemistry testing per local laboratory. (2) Part B (Combination Therapy Expansion): Patients with histologically confirmed CRC who have only received 1 line of systemic therapy for the advanced, metastatic, or unresectable disease. 4. Patients must provide agreement for collection of archival tumor tissue (FFPE block or approximately 10-15 freshly cut unstained FFPE slides) for Phase 1a and Phase 1b. For Phase 1a Safety Expansion and Phase 1b cohorts, archival tumor tissues should be <= 1 year of age but preferably obtained after the most recent systemic therapy. Acceptance of tumor tissue older than 1 year will be decided by the sponsor. Patients without tissues meeting the aforementioned archived tissue criteria can undergo a fresh biopsy as deemed fit by the investigator. Fine needle aspirates and biopsies from sites of bone lesions are not acceptable. 5. Patients must have >= 1 measurable lesion as assessed by RECIST v1.1. 6. Patients must have a stable ECOG Performance Status of <= 1. 7. Patients must have adequate organ function as indicated by the following laboratory values during screening or <= 7 days before the first dose of study drug(s): (1) Patients must not have required blood transfusion or growth factor support <= 14 days before sample collection at screening for the following: 1) ANC >= 1.5 × 10^9/L 2) Platelets >= 100 × 10^9/L 3) Hemoglobin >= 90 g/L (2) Creatinine clearance >= 60 mL/min, as determined by CKD-EPI equation (Appendix 7) (3) Serum total bilirubin <= 1.5 × ULN (total bilirubin must be < 3 × ULN and direct bilirubin <= 1.5 × ULN for patients with Gilbert syndrome) (4) Albumin >= 2.0 g/dL (5) AST and ALT <= 2.5 × ULN or < 5 × ULN if hepatic metastases are present (6) In Phase 1b Part B, for patients receiving combination therapy with bevacizumab, additional inclusion criteria are listed below: 1) Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study treatment). Patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours. 2) Coagulation parameters: INR <= 1.5 (or an in-range INR <= 3, if a patient is on a stable dose of therapeutic warfarin) and a PTT < 1.2 × ULN; 8. Female patients of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for >= 8 months after the last dose of BG-C477 and for >= 6 months after the last dose of capecitabine and bevacizumab, whichever comes later. They must also have a negative urine or serum pregnancy test result <= 2 days before the first dose of study drug(s). Note: a woman is considered of childbearing potential (ie, fertile, following menarche and until becoming postmenopausal) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy; 9. Nonsterile male patients must be willing to use a highly effective method of birth control and refrain from sperm donation for the duration of the study and for >= 5 months after the last dose of BG-C477, and for >= 3 months after capecitabine, whichever comes later. A sterile man is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. For EU: A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

1. Previous ADCs targeting CEA or ADCs containing TOP1 inhibitors as payloads. 2. History of severe allergic reactions, severe reaction to infusion, or hypersensitivity to the active ingredient and excipients of the study drug(s) or protein-based therapeutics. 3. Patients with active leptomeningeal disease or uncontrolled, untreated brain metastasis. Patients with a history of treated and, at the time of screening, stable CNS metastases are eligible, provided they meet all the following criteria: (1) Show no evidence of interim progression during brain imaging at screening, and there is no evidence of new brain metastases. (2) Are clinically stable for >= 6 weeks. (3) Have measurable disease outside the CNS. (4) Have no ongoing requirement for corticosteroids as therapy for CNS disease, off corticosteroids for at least 2 weeks before the first dose of study drug(s); anticonvulsants at a stable dose are allowed. (5) Have no stereotactic radiation or whole-brain radiation <= 14 days before the first dose of study treatment. 4. Patients with any malignancy <= 2 years before the first dose of study drug(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast). Patients with concurrent tumor types under investigation in this study (eg, patients with concurrent NSCLC and CRC or concurrent NSCLC and GC/GEJC) are excluded. 5. Patients with uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention). 6. History of ILD, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc. Patients with significantly impaired pulmonary function or who require supplemental oxygen at baseline > 2 L/min by nasal cannula are excluded. 7. Clinically significant infections (including tuberculosis infection, etc) requiring systemic (oral or intravenous) antibacterial, antifungal, or antiviral therapy <= 14 days before the first dose of study drug(s). Patients receiving prophylactic antibiotics (eg, for prevention of urinary tract infection, chronic obstructive pulmonary disease, or for dental extraction) are eligible. 8. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA >= 500 IU/mL (or >= 2500 copies/mL) at screening. Note: Inactive hepatitis B surface antigen carriers, with treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable hepatitis B surface antigen or detectable HBV DNA should be managed per treatment guidelines. 9. Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. 10. Patients with known HIV infection. In Phase 1b, patients with treated HIV infection may be included only if they meet all the following criteria: (1) Agree to adhere to antiretroviral therapy per WHO guidelines. (2) Have no documented multidrug resistance that would prevent effective antiretroviral therapy. (3) Have CD4+ T-cell (CD4+) counts >= 350 cells/μL at screening. (4) Have viral load of < 400 copies per mL before enrollment. (5) Have no opportunistic infection reported within 12 months before enrollment. (6) Are stable on antiretroviral therapy for >= 4 weeks, before enrollment. (7) If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon agreement with the medical monitor; 11. Patients with any of the following cardiovascular risk factors: (1) Cardiac chest pain, defined as moderate pain that limits ADL, <= 28 days before the first dose of study drug(s). (2) Symptomatic or life-threatening pulmonary embolism <= 3 months prior to the first dose of study drug(s). (3) Any history of acute myocardial infarction <= 6 months before the first dose of study drug(s). (4) Any history of heart failure meeting NYHA Classification III or IV <= 6 months before the first dose of study drug(s). (5) Any event of ventricular arrhythmia >= Grade 2 in severity <= 6 months before the first dose of study drug(s). (6) Any history of cerebrovascular accident <= 6 months before the first dose of study drug(s). (7) Uncontrolled hypertension that cannot be managed by standard antihypertension medications <= 28 days before the first dose of study drug(s). Systolic pressure >= 140 mmHg or diastolic pressure >= 90 mmHg on repeated measurements. (8) Any episode of syncope or seizure <= 28 days before the first dose of study drug(s). (9) Baseline QTcF > 470 milliseconds based on the screening triplicate 12-lead ECG records. 12. Patients with any of the following treatments before the first dose of study drug(s), including but not limited to: (1) Prior systemic anticancer therapy (including targeted therapy and immunotherapy [eg, interleukin, interferon, thymosin, etc]) <= 14 days, <= 28 days for immuno-oncological antibody, <= 14 days or 5 half-lives (whichever is shorter) for chemotherapy, ADCs, or investigational therapy. (2) Palliative radiation therapy to the chest <= 4 weeks; <= 2 weeks for palliative radiation therapy to other areas (ie, limited field and 10 or fewer days or fractions) including whole brain radiotherapy. (3) Chinese patent medicine with anticancer activity approved by the China NMPA (regardless of the type of cancer) <= 14 days. (4) Ongoing treatment with a strong CYP3A4 inhibitor, or strong CYP3A4 inducer, or drugs with a risk of prolonged QT/QTc, except for capecitabine in combination cohorts <= 14 days or 5 half-lives, whichever is shorter or known. (5) Herbal remedies that are known to potentially interfere with liver or other major organ functions (eg, hypericin) <= 14 days or 5 half-lives, whichever is shorter or known. (6) Major surgical procedure <= 28 days (or <= 14 days for low-invasive cases [eg, colostomy]). 13. Patients with toxicities (because of prior anticancer therapy) that have not recovered to baseline or stabilized, except for adverse events not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory abnormalities). 14. Patients with underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug(s), will affect the explanation of drug toxicity or adverse events, or will result in insufficient or impaired compliance with study conduct. 15. Female patients who are pregnant or are breastfeeding. 16. Concurrent participation in another therapeutic clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. 17. Patients with significant gastrointestinal dysfunction or pathology, including: (1) Grade >= 2 diarrhea (liquid stool) or ileus. (2) Active Grade >= 3 anorexia, nausea, or vomiting. (3) GC/GEJC patients with clinically significant bleeding (CTCAE >= Grade 2) from the gastrointestinal tract within 1 month prior to first dose of study treatment or history of >= Grade 2 (CTCAE) GI perforation and/or fistulae (including prior gastric fistula operation) within 6 months prior to first dose of study treatment. 18. In Phase 1b Part B, for all patients: (1) Patients who have known partial or complete DPD deficiency are ineligible. (2) History of severe hypersensitivity reactions to fluorouracil or capecitabine. (3) Patients who are unable to swallow capsules or with disease/procedure significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastrointestinal perforation or fistulae. 19. In Phase 1b Part B, for patients undergoing treatment with bevacizumab: (1) A history of abdominal or tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of the first dose of study treatment. (2) History of intestinal obstruction and/or clinical signs or symptoms of gastrointestinal obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months of the first dose of study treatment. Note: Patients with signs/symptoms of sub-occlusive syndrome/intestinal obstruction at the time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution. (3) Evidence of abdominal free air that is not explained by paracentesis. (4) Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture. (5) NYHA Class II or greater cardiac disease. (6) Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other hemorrhage/bleeding event CTCAE grade >= 3 within 4 weeks prior to first dose of study drug. (7) Deep venous thromboembolic event <= 4 weeks or deep arterial thromboembolic event <= 6 months before the first dose of bevacizumab;

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It is expected that the research will be completed within half a year. Resman (http://www.medresman.org.cn/)

Data required per the protocol will be entered into an EDC system. All study-related data collected or received by the investigator or study team shall be promptly entered into the eCRFs. Data collection in the eCRF should follow the instructions described in the eCRF Completion Guidelines.