A Study of BL-B01D1, SI-B003 and BL-B01D1+SI-B003 in Patients With Recurrent or Metastatic Cervical Cancer and Other Gynecological Malignancies

Study Overview
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Brief Summary
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Objective: To explore the efficacy, safety and tolerability of BL-B01D1, SI-B003 and BL-B01D1+SI-B003 in patients with recurrent or metastatic cervical cancer and other gynecological malignancies, and to further explore the optimal dose and mode of combination.

Detailed Description
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Objective: To explore the efficacy of BL-B01D1 monotherapy, SI-B003 monotherapy, and BL-B01D1+SI-B003 combination therapy in patients with recurrent or metastatic cervical cancer. To explore the safety and tolerability of BL-B01D1 monotherapy, SI-B003 monotherapy and BL-B01D1+SI-B003 combination therapy in patients with recurrent or metastatic cervical cancer and other gynecological malignancies, and to further explore the optimal dose and mode of combination therapy.

Official Title
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A Phase II Clinical Study to Evaluate the Efficacy and Safety of BL-B01D1 Monotherapy, SI-B003 Monotherapy and BL-B01D1+SI-B003 Combination Therapy (BL-B01D1+SI-B003) in Patients With Recurrent or Metastatic Cervical Cancer and Other Gynecological Malignancies

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: BL-B01D1
* Drug: SI-B003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects voluntarily participated in the study and signed informed consent; Women aged ≥18 years and ≤75 years; Expected survival time ≥3 months; ECOG 0-1; Recurrent or metastatic cervical cancer and other gynecologic malignancies (including but not limited to cervical cancer, endometrial cancer, ovarian cancer, fallopian tube cancer) confirmed by histopathology and/or cytology after failure or intolerance to standard treatment or for which no standard treatment is currently available: Cohort_A, Cohort_C patients who have previously failed or are intolerant to standard therapy or who currently have no standard therapy: 1) cervical or endometrial cancer (or PD-1/PD-L1 immunotherapy for eligible patients such as MSI-H) and ineligible for surgery or radiotherapy; 2) epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; Patients with platinum-resistant relapse (< 6 months between relapse or progression and the last (at least 4 cycles) of a previous platinum-based regimen) who had failed standard therapy after at least two lines of treatment (which could include patients with a BRCA mutation or HRD-positive who had failed PARP inhibitor therapy) met any one of the following criteria. Or patients with platinum-sensitive relapse who had failed standard therapy (≥6 months between relapse or progression and the last platinum-based chemotherapy of at least four previous cycles) after at least three lines of treatment (which could include patients with a BRCA mutation or HRD-positive who had failed PARP inhibitor therapy). Note: Disease progression or recurrence requires evidence of radiographic or clinical progression (e.g., cytological report of new ascites or pleural effusion). An increase in CA125 alone cannot be used as a criterion for disease progression or recurrence. Cohort_B patients with failure to receive or intolerance to at least one previous standard therapy or no current standard therapy; Treatment failure was defined as disease progression during or after systemic antitumor therapy. Intolerance refers to the refusal of patients to continue the original regimen due to grade 3-4 adverse reactions after receiving standard treatment. Note: Recurrence or disease progression within 6 months after the last chemotherapy of multimodal therapy was considered as the first line of treatment. Consent to provide archival tumor tissue specimens (10 unstained sections (anti-slip) surgical specimens (thickness 4-5μm)) or fresh tissue samples from primary or metastatic lesions within 3 years. If participants cannot provide tumor tissue samples, they can be enrolled if they meet other inclusion and exclusion criteria, after the evaluation of the investigator; Must have at least one measurable lesion according to RECIST v1.1 definition; Lesions that had been previously treated with radiation could be included in a measurable lesion only if there was definite disease progression after radiation therapy; Organ function level must meet the following criteria: Blood routine: hemoglobin (HGB) ≥ 90g/L; Absolute neutrophil count (NEUT) ≥ 1.5×10 9 /L; Platelet count (PLT) ≥ 100×10 9 /L; Renal function: creatinine (Cr) ≤1.5 ULN, or creatinine clearance (Ccr) ≥50 mL/min (according to Cockcroft and Gault formula). Liver function: total bilirubin (TBIL≤1.5 ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were all ≤2.5 ULN, and AST and ALT were both ≤5.0 ULN when liver metastasis was present; coagulation function: international normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5ULN; no severe cardiac dysfunction with left ventricular ejection fraction ≥50%; proteinuria ≤2+ or ≤1000mg/24h. Toxicity of previous antineoplastic therapy has returned to ≤ grade 1 as defined by NCI-CTCAE v5.0 (except for asymptomatic laboratory abnormalities such as ALP elevation, hyperuricemia, and hyperglycemia, as judged by the investigator, and toxicity without safety risk, such as alopecia, grade 2 peripheral neurotoxicity, or decreased hemoglobin ≥90g/L, as judged by the investigator); For premenopausal women with childbearing potential, a pregnancy test must be performed within 7 days before the start of treatment, the serum or urine pregnancy test must be negative, and the patient must not be lactating; All enrolled patients should take adequate barrier contraception during the whole treatment cycle and for 6 months after the end of treatment. Exclusion Criteria: Previous treatment with an ADC drug with a topoisomerase I inhibitor as a toxin; Antineoplastic therapy, including chemotherapy, biologic therapy, immunotherapy, definitive radiotherapy, major surgery (investigator-defined), or targeted therapy (including small-molecule tyrosine kinase inhibitors), has been administered within 4 weeks or 5 half-life cycles (whichever is shorter) before the first dose; Mitomycin and nitrosoureas were administered within 6 weeks before the first dose; Oral fluorouracil drugs such as S-1, capecitabine, or palliative radiotherapy within 2 weeks before the first dose; Cohort_B and Cohort_C patients with a history of immunotherapy and grade ≥3 irAE or grade ≥2 immune-related myocarditis were excluded; Cohort_B and Cohort_C patients who have used immunomedulators (including but not limited to thymosin, interleukin-2, interferon, etc.) within 14 days before the first dose of study drug should be excluded; A history of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias or Ⅲ degree atrioventricular block requiring clinical intervention; prolonged QT interval at rest (QTc > 450 msec in men or QTc > 470 msec in women); myocardial infarction, unstable angina, cardiac angioplasty or stent implantation, coronary artery/peripheral artery bypass grafting, New York Heart Association (NYHA) class III or IV congestive heart failure, cerebrovascular accident, or transient ischemic attack within 6 months before the first dose; Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory intestinal diseases and Hashimoto's thyroiditis, etc., excluding type I diabetes mellitus, hypothyroidism that can only be controlled by replacement therapy, and skin diseases without systemic treatment (such as vitiligo and psoriasis); Other malignant tumors that have progressed or require treatment within 5 years before the first dose, except for radical basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, radical resection of carcinoma in situ, such as carcinoma in situ of the breast, and prostate cancer; Notes: Patients with localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and PSA < 10ng/mL at prostate cancer diagnosis (as measured) who had received radical treatment and no biochemical recurrence of prostate specific antigen (PSA) were eligible to participate in this study); A history of (non-infectious) interstitial lung disease (ILD)/pneumonitis requiring steroid treatment, current ILD/ pneumonitis, or suspected ILD/ pneumonitis that cannot be ruled out by imaging at screening; Prior to the initiation of study treatment, present: Poorly controlled diabetes (fasting blood glucose ≥ 13.3 mmol/L) Poorly controlled hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) History of hypertensive crisis or hypertensive encephalopathy Unstable deep vein thrombosis, arterial thrombosis, and pulmonary embolism requiring medical intervention within 6 months before screening; Infusion-related thrombosis was excluded; Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastases). Patients who had received treatment for brain metastases (radiotherapy or surgery; Patients with stable brain metastases who had stopped radiotherapy or surgery 28 days before the first dose were eligible. Patients with cancerous meningitis (meningeal metastases) were excluded even if they were treated and judged to be stable. Stable was defined as being asymptomatic, stable, and not requiring steroid medication for a full 4 weeks before starting study treatment; Patients with clinical symptoms or repeated drainage of pleural, abdominal, pelvic effusion, pericardial effusion; Patients with a history of allergy to recombinant humanized antibody or human-mouse chimeric antibody or to any excipients of BL-B01D1; Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT); Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number > 103 IU/ml) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > detection limit); Active infection requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc; Participated in another clinical trial within 4 weeks before the first dose (calculated from the time of the last dose); Persons with a history of psychotropic drug abuse and inability to quit or mental disorders; Other circumstances that the investigator deemed inappropriate for participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>Participants received BL-B01D1, SI-B003 or BL-B01D1 + SI-B003 therapy in the first cycle (3 weeks). Participants who had a clinical benefit could receive additional cycles of additional treatment. Administration will be discontinued because of disease progression or intolerable toxicity or for other reasons. | Drug: BL-B01D1<br>* BL-B01D1 was administered by intravenous infusion on D1 and D8 in a 3-week cycle.<br>Drug: SI-B003<br>* SI-B003 was administered by intravenous infusion every 3 weeks (Q3W).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the percentage of participants, who has a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experiences a confirmed CR or PR is according to RECIST 1.1. | Up to approximately 24 months | 
| Recommended Phase II Dose (RP2D) | The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for phase II study, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study . | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The PFS is defined as the time from the first dose of medication to disease progression or death, whichever occurred first. | Up to approximately 24 months | 
| Disease control rate (DCR) | The DCR is defined as the percentage of participants who has a CR, PR, or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD]). | Up to approximately 24 months | 
| Duration of response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Treatment-Emergent Adverse Event (TEAE) | TEAE is defined as any adverse and unexpected change in body structure, function, or chemistry or any exacerbation of an existing condition (i.e., any clinically significant adverse change in frequency and/or intensity) during treatment. The type, frequency, and severity of TEAE will be assessed during treatment. | Up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gynecological malignancies