2025-524691-33-00招募中2 期
A multicenter, Phase Ib/II study to evaluate the safety, tolerability, pharmacokinetics and preliminary clinical activity of TUB-040, in combination with standard ovarian cancer drugs in patients with high-grade epithelial serous or endometrioid epithelial ovarian cancer (OC) (NAPISTAR 1-02)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Tubulis GmbH
- 入组人数
- 42
- 试验地点
- 4
- 主要终点
- • Occurrence and severity of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
To determine the safety and tolerability of TUB-040 + XXX + XXX in patients with XXOC To determine the maximum tolerated dose (MTD), if observed of TUB-040 + XXX + XXX in patients with XXOC
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female ≥ 18 years of age at the time of the first screening visit
- •Female patients will be considered post-menopausal if they have undergone bilateral salpingectomy, and/or bilateral oophorectomy, and/or hysterectomy or have been amenorrheic for 12 months without an alternative medical cause (treatment with anti-hormonal therapies is considered an alternative medical cause). The following age-specific requirements apply: a) Women <50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all hormonal replacement therapy and/or if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution. b) Women ≥50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all hormonal replacement therapy or had radiation-induced menopause with most recent menses >1 year ago or had chemotherapy-induced menopause with most recent menses >1 year ago.
- •In the opinion of the INV, the patient must be able to understand, must be willing to sign informed consent form (ICF) and comply with all study-related procedures, medication use, and evaluations.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or
- •Patients must have 1-2 prior lines of systemic XXX therapy and have not progressed within 182 days after the date of the last dose of XXX.
- •Prior treatment with PARPi is required (for patients who were previously documented to be HRD positive or have a germline or somatic BRCA 1/2 mutation), if PARPi therapy was locally approved at the time of testing.
- •3.Histologically confirmed advanced high-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer.
- •Have XXX ovarian cancer (XXOC) defined as: Patients who had recurrences (radiologically confirmed) to XXX-based therapy and have responded to the last XXX therapy received before study entry and did not progress within 6 months (182 days) of the date of the last dose of XXX-based systemic treatment.
- •5.Radiologically measurable disease in at least 1 lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, that can include a lesion in an irradiated field and that shows progression according to RECIST v1.
- •Patients must have progressed radiographically on or after their most recent line of anti-cancer therapy.
- •Adequate hematologic function as indicated by: a) Platelet counts 100,000/mm3 (no transfusion or growth factors e.g. eltrombopag, romiplostim, or IL-11 within 4 weeks before first dose) b) Hemoglobin ≥9.0 g/dL (no transfusion or growth factors e.g. erythropoietin [EPO], darbepoetin within 4 weeks before first dose or long-acting white blood cell growth factors within 20 days before first dose) c) Absolute neutrophil count (ANC) ≥1500/μL (no growth factors, e.g., granulocyte colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF] within 4 weeks before first dose) d) International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (aPTT) ≤1.5 × upper limit of normal (ULN) in the absence of anticoagulation therapy. If patients are on anticoagulation therapy with a specific INR goal, INR should be within the therapeutic range for the medical indication.
- •Adequate renal function defined by glomerular filtration rate ≥60 mL/min (according to the Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI, formula).
- •Adequate hepatic function defined as total bilirubin level ≤1.5 × ULN, an aspartate aminotransferase (AST) level ≤2.5 × ULN, and an alanine aminotransferase (ALT) level ≤2.5 × ULN a) For documented Gilbert's Syndrome, a total bilirubin <3 × ULN is accepted b) For patients with liver metastases, AST and ALT <5 × ULN is accepted.
- •Alkaline phosphatase < 2.5 x ULN, except if there is an alternative explanation for ALP elevation rather than hepatic failure, such as the presence of bone metastasis.
- •Patients must be willing to sign an archival tissue release form for research purposes and determination of biomarker (e.g., NaPi2b) expression. The patient must have an adequate tumor tissue sample available for biomarker assessment by the central laboratory. Mandatory is either a tissue (FFPE) block or a minimum of 6 freshly cut unstained sections based on the most recently available tumor sample. If no archival specimens are available, a new biopsy must be performed. For patients in which a fresh biopsy poses unacceptable clinical risk in the judgment of the treating investigator, enrollment may be considered on a case-by-case basis only after discussion with the Sponsor Medical Monitor.
- •Resolution of all acute toxic effects of prior therapy or surgical procedures to Grade ≤1 including peripheral neuropathy (except alopecia, hyperpigmentation, or discoloration (incl. vitiligo) of the skin and nails, stable immune-related toxicity such as hypothyroidism on hormone) replacement, corticosteroid treatment on ≤10 mg daily prednisone (or equivalent).
- •Patients with previous systemic topoisomerase 1 inhibitor treatment (e.g., Topotecan) or patients that are previously treated with ADCs are allowed (except for ADCs with a topoisomerase 1 inhibitor, such as SN38 or other camptothecin derivatives as payload or any ADC targeting NaPi2b)
- •Completed washout of prior therapy: a. Systemic anti-neoplastic therapy: five half-lives or 4 weeks, whichever is shorter prior to first dose of study drug. Hormonal therapy is not considered anti-neoplastic therapy. b. Radiotherapy: last dose ≥ 2 weeks from first dose of study drug c. Completed major surgery at least 4 weeks prior from first dose of study drug and recovered from side effects to Grade ≤
- •Viral infections: a) Patients who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B (HBV) anti-viral therapy for at least 4 weeks and have undetectable HBV viral load b) Patients with history of hepatitis C viral (HCV) infection are eligible if HCV viral load is undetectable at screening.
- •Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized partner must use at least 1 highly effective method of contraception (with a failure rate of ≤1% per year) from the time of screening and must agree to continue using such precautions until the end of exposure, plus at minimum 5 half-lives and 6 months after last dose of either TUB-040, carboplatin, or bevacizumab, whichever is later, in the case of patients of childbearing potential. Abstinence is acceptable only when this is in line with the preferred and usual lifestyle of the patient for the duration of the study treatment and the above-referred period after the end of the exposure. Periodic abstinence (e.g. calendar ovulation, symptom-thermal, post-ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception. Notes see protocol.
- •Patients must agree to continue a highly effective contraceptive method, refrain from egg cell donation and breastfeeding while on study treatment and for 5 half-lives plus 6 months after the last dose of study treatment.
排除标准
- •Patients with clear-cell, mucinous histology, mixed histology with mucinous component, sarcoma, sarcomatous component, or low-grade ovarian cancer.
- •Clinically significant proteinuria: urine-protein (UPC) ratio ≥ 1.0 or urine dipstick result ≥ 2+; patients with UPC ratio ≥ 1.0 or ≥ 2+ proteinuria should undergo 24-hour urine collection and must show result < 1 gram of protein in 24-hour period.
- •Patient pregnant, lactating or breastfeeding or having a positive serum pregnancy test during the screening period.
- •Patients with untreated spinal cord compression or cerebrovascular accident/stroke within <6 months of enrollment.
- •History of hypersensitivity to exatecan or excipients of the TUB-040 formulation.
- •Patients with unresolved malignant bowel obstruction (including patients with radiological findings indicating possible bowel obstruction on CT scans), history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess or Patients on total parenteral nutrition (TPN).
- •Prior thoracocentesis for therapeutic drainage of malignant effusion < 4 weeks from trial inclusion and repeated paracentesis for therapeutic drainage of malignant effusion < 4 weeks before trial inclusion.
- •Prior radiotherapy to the pelvis or abdomen (Dose Escalation phase only).
- •Patients with serum albumin level <2,5 g/dL (subjects should not have received IV albumin within 4 weeks of the test).
- •Participation in interventional clinical studies either concurrently or within the previous 28 days or within 5 half-lives (whichever is shorter) of any investigational pharmacologic agents before study treatment
- •Previous systemic topoisomerase-1 inhibitor treatment (except Topotecan).
- •Live vaccines within 30 days prior to study entry or any known unresolved and active bacterial, viral (e.g. Hep B, Hep C, Varicella or CMV), fungal, mycobacterial, or other infection at screening.
- •Major surgery within 21 days prior to signing the ICF, unless the patient is recovered at that time.
- •History of non-infectious ILD/pneumonitis/radiation pneumonitis that required steroids or has current ILD/pneumonitis.
- •Documented cardiac comorbidities: Corrected QT interval > 470 msec on the screening ECG, unstable or uncontrolled pectoral angina, myocardial infarction during the last 6 months, valvular heart disease that requires treatment, uncontrollable hypertension (≥Grade 3), uncontrollable arrhythmias, acute myocarditis, or congestive heart failure (CHF) (New York Heart Association III or IV).
- •Active, uncontrolled or severe impairment of the urogenital, renal, hepatobiliary (including liver cirrhosis), cardiovascular, respiratory, gastrointestinal, neurologic, or hematopoietic systems which, in the opinion of the INV, would predispose the patient to the development of complications from the administration of protocol therapy.
- •Demyelinating diseases: History of multiple sclerosis or of progressive multifocal leukoencephalopathy.
- •History of another malignancy with ongoing treatment or not yet free from disease for 2 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with a similar expected curative outcome.
- •Any concurrent anti-cancer chemotherapy, radiotherapy (except for local radiation therapy of lesions that may cause imminent complications), hormonal therapy, immunotherapy, or corticosteroid therapy,other than that permitted in Section 8.8 in protocol.
- •Any patient who is required to take strong CYP3A4 inhibitors or inducers (see also Prohibited Medication and Guidance for Potential Use section).
- •History of hypersensitivity to XXX and risk of further cumulative toxicity with additional XXX, including but not limited to myelosuppression, with febrile neutropenia, Grade 4 hematotoxicity, neuropathy Grade ≥2, renal insufficiency during prior XXX-based therapy.
- •Patients with XXX refractory OC (XXX refractory is defined as disease that has not responded to a primary XXX-based regimen or progressed within 30 days after primary XXX-based therapy )or XXX resistant ovarian cancer.
- •Non-healing wounds, ulcers, or bone fractures.
- •History of posterior reversible encephalopathy syndrome.
- •Recent history of hemoptysis of ≥1/2 teaspoon of red blood within 4 weeks before first study treatment.
- •History of Grade 4 thromboembolic events.
- •Hypertension ≥ Grade 3 that is not controlled with medical management.
结局指标
主要结局
• Occurrence and severity of treatment-emergent adverse events (TEAEs)
• Occurrence and severity of treatment-emergent adverse events (TEAEs)
• Occurrence of DLTs (Dose limiting toxicities) at different dose levels (during first treatment cycle)
• Occurrence of DLTs (Dose limiting toxicities) at different dose levels (during first treatment cycle)
次要结局
- •PK parameters of TUB-040 ADC, total mAb and free exatecan, including but not limited to maximum concentration Cmax, time to Cmax (Tmax), area under the curve (AUC) and as far as collected data allow an estimation of half-life (t1/2)
- • Duration of response (DoR) by RECIST v1.1 assessed by INV
- • Incidence and titers of anti-drug antibodies (ADA) against TUB-040
- • Objective response rate (ORR) by RECIST v1.1 assessed by Investigator (INV)
- • Time to first response (TTR) by RECIST v1.1 assessed by INV
- • Progression-free survival (PFS) by RECIST v1.1 assessed by INV
- • Number of patients with Gynecologic Cancer Intergroup (GCIG) CA-125 criteria clinical responses
- • Incidence of serious adverse events (SAEs)
- • Incidence of ≥Grade 3 laboratory abnormalities
研究者
Ramola Bhandarkar
Scientific
Tubulis GmbH
研究点 (4)
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