A Phase 1-2a, Multicenter, Open-Label, Multiple Dose, Safety, Tolerability, and Pharmacokinetic Study of Recombinant Human Hyaluronidase (Chemophase®) in Combination With Mitomycin in Patients With Non-Muscular-Invasive Bladder Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 5
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of this study is to explore a treatment that potentially enhances the delivery of chemotherapy to tumors in participants with superficial bladder cancer. The investigational medication to be studied is an enzyme called ChemophaseTM (recombinant human hyaluronidase, rHuPH20). Chemophase is being specifically developed for use with other anticancer drug to increase the local penetration of the anticancer drug for the treatment of superficial bladder cancer. In this study, Chemophase will be given in combination with mitomycin C directly into the bladder. Mitomycin C is an anti-tumor drug that is commonly used to treat superficial bladder cancer. It is envisioned that Chemophase with mitomycin C may potentially increase the local penetration of mitomycin C into remaining cancer cells following surgery to treat superficial bladder cancer.
详细描述
The primary objectives of this study are to:
- determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (mitomycin C, MMC) administered as weekly intravesical instillations for five weeks, and
- establish the dose of Chemophase with MMC recommended for future studies.
The secondary objectives of this study are to:
- assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase,
- for those participants treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations, and
- observe participants for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined.
Study participants will receive six weekly study treatments administered intravesically (at Weeks 1 through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 participants treated at MTD will continue to receive combination therapy every three months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. For other participants, long-term follow-up after Week 12 will consist of disease monitoring of participants by telephone and will be performed every three months beginning three months after last study treatment for two years and then every six months thereafter, until bladder tumor recurrence.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with initial presentation or recurrence of Stage Ta, T1 or Tis, any grade, bladder cancer after transurethral resection of bladder tumor (TURBT).
- •TURBT within 42 days prior to Day 1/Week 1
- •Karnofsky Performance Status greater than or equal to 80%
- •Life expectancy at least 3 years
- •18 years or older
- •A negative pregnancy test (if female of child-bearing potential)
- •Acceptable liver function within 7 days defined as: bilirubin less than or equal to 1.5 times upper limit of normal, and aspartate aminotransferase (AST) Glutamic-oxalacetic transaminase (SGOT), alanine aminotransferase (ALT), glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase <= 2.5 times upper limit of normal
- •Acceptable renal function within 7 days defined as: serum creatinine less than or equal to 1.5 times upper limit of normal, or calculated creatinine clearance greater than or equal to 40 milliliter (mL)/minute/1.73 meter^2
- •Acceptable hematologic status within 7 days defined as: absolute neutrophil count (ANC) greater than or equal to 2,500 cells/millimeter^3, platelet count greater than or equal to 150,000/millileter^3, and hemoglobin greater than or equal to 10.0 grams/deciliter.
- •Urinalysis showing no clinically significant abnormalities except those attributable to bladder cancer.
- •For men and women of child-producing potential, agreement to use an effective contraceptive method during the treatment period of the study.
- •Signed, written Institutional Review Board (IRB)-approved informed consent
排除标准
- •History or previous diagnosis of bladder fibrosis
- •Total bladder capacity estimated at cystoscopy to be less than 150 mL
- •Urinary incontinence of a severity that would compromise the ability of the participant to retain the study drug intravesical instillation for two hours.
- •Severe irritative voiding symptoms such as urgency, frequency, or nocturia
- •Known other malignant disease except squamous or basal cell skin cancer unless the malignancy has been in complete remission off therapy for at least 5 years.
- •Major surgery, other than TURBT and diagnostic surgery, within 28 days prior to Day 1/Week
- •Active, uncontrolled bacterial, viral, or fungal infections, including urinary tract infection.
- •Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one month prior to Day 1/Week 1 on study (two months for nitrosureas or MMC), unless given as standard treatment for bladder cancer and provided that patient is free of all treatment-related toxicities as of Day 1/Week
- •Known infection with human immunodeficiency virus (HIV)
- •Known active infection with hepatitis B or hepatitis C
- •Serious disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor (Halozyme).
- •History of a hypersensitivity or idiosyncratic reaction to, or other contraindication to, mitomycin.
- •Known allergy to bee or vespid venom
- •Known coagulation disorder or bleeding tendency
- •Treatment with heparin or anticipation of heparin treatment during the treatment period in this study.
- •Unwillingness or inability to comply with procedures required in this protocol.
研究组 & 干预措施
Cohort 1: MMC plus Chemophase 20,000 U
Participants will receive 40 milligrams (mg) MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 20,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Mitomycin C (Drug)
Cohort 1: MMC plus Chemophase 20,000 U
Participants will receive 40 milligrams (mg) MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 20,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Chemophase (Drug)
Cohort 2: MMC plus Chemophase 60,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 60,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Mitomycin C (Drug)
Cohort 2: MMC plus Chemophase 60,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 60,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Chemophase (Drug)
Cohort 3: MMC plus Chemophase 200,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 200,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Mitomycin C (Drug)
Cohort 3: MMC plus Chemophase 200,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 200,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Chemophase (Drug)
Cohort 4: MMC plus Chemophase 400,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 400,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Mitomycin C (Drug)
Cohort 4: MMC plus Chemophase 400,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 400,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Chemophase (Drug)
Cohort 5: MMC plus Chemophase 800,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 800,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Mitomycin C (Drug)
Cohort 5: MMC plus Chemophase 800,000 U
Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 800,000 U Chemophase intravesically once weekly from Weeks 2 through 6.
干预措施: Chemophase (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: 5 weeks (Week 2 to Week 6)
DLT was defined as any of the following: * Plasma MMC concentration \>= 100 ng/mL * AE with a CTC grade greater than or equal to 3 * New, treatment-emergent diagnosis of bladder fibrosis.
Maximum Tolerated Dose (MTD) of Chemophase in Combination With MMC
时间窗: 5 weeks (Week 2 to Week 6)
The MTD was defined as the maximum dose level at which no more than two of six participants experienced dose-limiting toxicities (DLT). DLT was defined as any of the following: * Plasma MMC concentration greater than or equal to (\>=) 100 nanograms (ng)/milliliter (mL) * Adverse event (AE) with a Common Toxicity Criteria (CTC) grade greater than or equal to 3 * New, treatment-emergent diagnosis of bladder fibrosis.
Recommended Dose of Chemophase With MMC For Future Studies
时间窗: 5 weeks (Week 2 to Week 6)
次要结局
- Number of Participants With a Quantifiable MMC Plasma Concentration Value(0 (predose), 1, 2, and 3 hours postdose at Weeks 1, 2, 5, and 6)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(Baseline up to 2 years)
- Number of Participants Who Remained Tumor Free at the End of the Study(Baseline up to 2 years)