2024-511074-80-01招募中2 期
A multicenter, first-in-human, dose escalation and optimization phase I/IIa study to investigate safety, tolerability, pharmacokinetics, and efficacy of the NaPi2b antibody-drug conjugate TUB-040 in patients with platinum-resistant high-grade ovarian cancer (PROC) or relapsed/refractory adenocarcinoma non-small cell lung cancer (NSCLC) (NAPISTAR 1-01).
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Tubulis GmbH
- 入组人数
- 66
- 试验地点
- 5
- 主要终点
- Phase I: Incidence of dose-limiting toxicities (DLTs) at different dose levels
研究概览
简要总结
Phase I dose escalation • To determine the safety and tolerability of TUB-040 • To determine the maximum tolerated dose (MTD) or the identified dose for optimization (IDO)
Phase IIa: dose optimization: • To assess safety of TUB-040 • To assess the preliminary efficacy of TUB-040 • To assess selected IDOs to take forward in future development of TUB-040
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Patients with OC: Histologically confirmed high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer
- •All patients: In the opinion of the INV, the patient must be able to understand, give their written informed consent, and comply with all study-related procedures, medication use and evaluations.
- •All patients: The patient must not have a history of non-compliance with medical regimens or be considered potentially unreliable and/or uncooperative.
- •Patients with OC: Have platinum-resistant disease defined as: a) Patients who have only received one line of platinum-based therapy must have received at least three cycles of platinum and then progressed between 30 and 183 days after the date of the last dose of platinum. b) Patients who have received two to five lines of prior platinum therapy must have progressed during or within 183 days after the date of the last dose of platinum.
- •All patients: The patient must be willing to sign and date the informed consent form (ICF).
- •Patients with OC: Have received no more than 5 lines of platinum-based therapy and 2 lines of non-platinum-based therapy in platinum resistant disease.
- •Patients with NSCLC: Histologically confirmed NSCLC of adenocarcinoma subtype, including its mixed histologies
- •Patients with NSCLC: Have progressed after previous treatment for locally advanced/metastatic disease that includes a platinum-based doublet if indicated* and/or a checkpoint inhibitor if indicated. *Patients who received indicated first-line checkpoint-inhibitor monotherapy are allowed in the study in the US
- •Patients with NSCLC: Not a candidate for an existing alternative standard therapy, including KRAS G12C, epidermal growth factor receptor (EGFR), ALK, ROS1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, human epidermal growth factor receptor 2 alterations, and NTRK fusions.
- •All patients: Male or non-pregnant, non-breastfeeding female aged 18 years or older at the date of consent
- •All patients: Disease not amenable to curative intent treatment
- •All patients: Radiologically measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, that can include a lesion in an irradiated field that shows progression according to RECIST v1.1 after irradiation
- •All patients: Patients have exhausted the standard of care treatment (SoC) with expected clinical benefit and are not denied SoC with expected clinical benefit by participating in the trial.
- •All patients: Patients with previous systemic topoisomerase 1 inhibitor treatment ( e.g Topotecan) are allowed in the study
- •All patients: For patients with known brain metastases evidence of clinically stable disease post radiation therapy is required prior to enrollment. The final dose of stereotactic radiation must have been administered ≥ 7 days, or the final dose of whole brain radiation must have been administered ≥ 14 days prior to C1D
- •All patients: Eastern Cooperative Oncology Group (ECOG) 0-1; see Appendix A of protocol.
- •All patients: Have a life expectancy of more than 12 weeks for disease-related mortality, as evaluated by the INV.
- •All patients: 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 newly acquired biopsy specimen must be taken.
- •All patients: Patients must be willing to undergo a non-contrast high-resolution HRCT of the thorax scan and pulmonary function testing (PFT) at screening.
- •All patients: Adequate organ function, as defined by the following criteria assessed during the screening period: a) Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvate transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN). b) Total serum bilirubin ≤ 1.5 x ULN (CTCAE Grade ≤ 1) unless secondary to Gilbert´s syndrome. Patients with Gilbert´s syndrome may be included if their unconjugated bilirubin is ≤ 3 x ULN. c) Creatinine clearance (eGFR) >60 ml/min/1.73m2 either measured by 24h urine collection or calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. d) Alkaline phosphatase (ALP) < 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. e) Hemoglobin ≥9.0 g/dL (without support by red blood cell transfusion or growth factors). f) Absolute neutrophil count ≥1500/mm3 (without G-CSF support). g) Platelet count ≥100,000 mm3 (=100 G/l) (without support by platelet transfusions). h) International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN in the absence of anticoagulation therapy. If patients are on anticoagulation therapy, INR should be within the therapeutic range for the medical indication.
- •All patients: Resolution of all acute toxic effects of prior therapy or surgical procedures to ≤Grade 1 (except alopecia, hyperpigmentation, or discoloration (incl. vitiligo) of the skin and nails, stable immune-related toxicity such as hypothyroidism on hormone replacement, corticosteroid treatmenton ≤10 mg daily prednisone [or equivalent], chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy).
- •All patients: Patients of childbearing potential (FCBP) who are sexually active with a non-sterilized partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions until the end of exposure, plus 5 half-lives and 6 months add-on in the case of patients assigned female at birth. Abstinence is acceptable only as true abstinence 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, symptothermal, post-ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception. Patients must refrain from egg cell donation and breastfeeding while on study treatment and for at least 7 months after the last dose of study treatment.
排除标准
- •Patients with OC: Patients with low-grade OC or any grade non-serous OC.
- •All patients: History of hypersensitivity to exatecan or excipients of the TUB-040 formulation.
- •All patients: Progression on treatment with ADCs with deruxtecan, exatecan, or camptothecan as a payload. ADCs with the topoisomerase 1 inhibitor SN-38 and all other payloads are allowed (e.g MMAE, MMAF and others).
- •All patients: Patients with spinal cord compression, active central nervous system disease and/or carcinomatous meningitis.
- •All patients: Patients are not allowed to participate in interventional clinical studies either concurrently or within the previous 28 days or within 5 half-lives of any investigational pharmacologic agents or imaging materials, including dyes, investigational surgical techniques, or devices.
- •All patients: Prior radiotherapy < 2 weeks from trial inclusion except in the case of stereotactic radiation to the brain, in which case the required interval is 7d.
- •All patients: Major surgery within 21 days prior to signing the ICF, unless the patient is recovered at that time.
- •All patients: Has a history of non-infectious ILD/pneumonitis/radiation pneumonitis that required steroids or has current ILD/pneumonitis.
- •All patients: Has an oxygen saturation of <93% on room air at rest.
- •All patients: Has a forced vital capacity <60% and diffusing capacity of the lung for carbon monoxide <70%.
- •All patients: Has a QTcF >470 ms
- •Patients with OC: Patients with primary platinum refractory OC
- •All patients: History of nephrotic syndrome
- •All patients: Active corneal disease, or history of corneal disease within 12 months prior to enrollment.
- •All patients: Active, uncontrolled or severe impairment of the urogenital, renal, hepatobiliary, 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.
- •All patients: 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.
- •All patients: Documented other concurrent non-malignant comorbidities such as unstable or uncontrolled pectoral angina, myocardial infarction during the last 6 months, valvular heart disease that requires treatment, acute myocarditis, or congestive heart failure (CHF) (New York Heart Association III or IV).
- •All patients: 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.
- •All patients: Live vaccines within 30 days prior to study entry.
- •All patients: Patients with acute or chronic infections such as: a) Patients who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Note: Patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post-completion of study intervention. b)Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Patients must have completed curative anti-viral therapy at least 4 weeks prior to enrollment. c) HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined in Section 7.2.3 of the protocol. d) Any other known unresolved and active bacterial, viral, fungal, mycobacterial, or other infection at screening. e) History of severe and recurrent infections per INV’s judgment. f) History of progressive multifocal leukoencephalopathy.
- •Patients with OC: Patients with unresolved malignant bowel obstruction, including patients with radiological findings indicating bowel obstruction on CT scans such as the presence of elevated air-fluid levels.
- •Patients with OC: Prior thoracocentesis for therapeutic drainage of malignant effusion < 2 weeks from trial inclusion (only for dose escalation).
- •Patients with OC: Repeated paracentesis for therapeutic drainage of malignant effusion < 2 weeks before trial inclusion (only for dose escalation)
- •Patients with OC: Patients on total parental nutrition (TPN)
- •Patients with OC: Patients with serum albumin level <2 g/dL (subjects should not have received i.v. albumin within 2 weeks of the test)
- •Patients with NSCLC: Prior pneumectomy.
- •All patients: The patient is pregnant, lactating or breastfeeding or has a positive serum pregnancy test during the screening period.
结局指标
主要结局
Phase I: Incidence of dose-limiting toxicities (DLTs) at different dose levels
Phase I: Incidence of dose-limiting toxicities (DLTs) at different dose levels
Phase I: Incidence and severity of treatment-emergent adverse events (TEAEs)
Phase I: Incidence and severity of treatment-emergent adverse events (TEAEs)
Phase II: Incidence and severity of TEAEs
Phase II: Incidence and severity of TEAEs
Phase II: Overall response rate (ORR) as assessed by investigator (INV)
Phase II: Overall response rate (ORR) as assessed by investigator (INV)
次要结局
- PK parameters of TUB-040, total mAb and free exatecan, including Cmax, Cmin, Tmax, and as far as collected data allow for a calculated estimation of t1/2, and area under the curve (AUC)
- Number and percentage of patients developing anti-TUB-040 antibodies, and semiquantitative titer assessments
- Assessed by INV and by BICR (for the dose optimization part of the trial): • ORR • Duration of response (DoR) • Response rate at the end of Cycle 4 and 6 • Overall survival (OS) • Incidence of Grade ≥3 lab abnormalities • Incidence of serious adverse events (SAEs)
研究者
Mary Ann A. Lumiqued
Scientific
Tubulis GmbH
研究点 (5)
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