A Phase 1/2, Open Label, Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 3
- 主要终点
- Estimate Overall Response Rate
研究概览
简要总结
This is an open label, multi-center, Phase 1/2 clinical trial in subjects with recurrent adenocarcinoma of the ovary who have been previously treated with a minimum of two courses of platinum-based chemotherapy, and up to two additional cytotoxic regimens that may also have included platinum (no more than four total lines of prior therapy), with or without bevacizumab, whose cancer has recurred within six months of the most recent platinum-based chemotherapy. All eligible subjects will receive VAL 083 i.v. in a once weekly cycle until disease progression, development of other unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or Sponsor ending the study, whichever occurs first.
详细描述
The basis of drug treatment for advanced-stage ovarian cancer in the first-line setting is platinum (cisplatin or carboplatin) plus taxane (paclitaxel or docetaxel), with or without bevacizumab. First line treatment regimens often result in high response rates, but most tumors will recur within 2 years and patients die within 3 to 4 years of diagnosis. If a patient progresses after 2 consecutive regimens without a response (refractory) or has recurrent ovarian cancer within 6 months from their last platinum-based regimen (platinum-resistant), prognosis is poor. The absence of an approved treatment or standard of care in the recurrent setting represents an unmet need.
Early NCI studies in the 1970s and 1980s support VAL-083 activity in ovarian cancer. Interest in this agent for ovarian cancer has recently re-emerged. The unique functional groups and cytotoxic mechanisms are hoped to provide a viable novel treatment option in patients with recurrent ovarian cancer that was resistant to platinum chemotherapies.
This is an open label, multi-center, Phase 1/2 clinical trial in subjects with recurrent adenocarcinoma of the ovary who have been previously treated with a minimum of two courses of platinum-based chemotherapy, and up to two additional cytotoxic regimens that may also have included platinum (no more than four total lines of prior therapy), with or without bevacizumab, whose cancer has recurred within six months of the most recent platinum-based chemotherapy.
Study subjects will initially receive VAL-083 60 mg/m2 i.v. once weekly. If this regimen is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 67 mg/m2 i.v. If the 67 mg/m2 dose is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 75 mg/m2 i.v. once weekly for the remainder of the study. Dosing will continue once weekly for 16 weeks or until disease progression, development of other unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or Sponsor ending the study, whichever occurs first. The treatment plan is to enroll a minimum number of 20 subjects in Phase 1, followed by expansion of enrollment in Phase 2 using the optimal dosing regimen determined in Phase 1.
Hematological safety assessments will be conducted at Screening and weekly before each treatment. Clinical evaluations for physical examination, vital signs, disease symptoms, quality of life measures (FOSI and opioid pain medication use), adverse events and concomitant medications will be completed while the subject remains on study treatment. Radiographic assessments (computed tomography [CT] or magnetic resonance imaging [MRI]) to obtain tumor measurements and CA-125 concentration will be conducted at Screening and every 8 weeks while on study treatment, independent of dose delays and/or dose interruptions, until progression of disease is suspected.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 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
- •Patient must willingly provide written consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. (Human protection committee approval of this protocol and consent form is required).
- •Must be ≥18 years old.
- •Histologically-confirmed initial diagnosis of adenocarcinoma of the ovary (AO), excluding clear cell, low grade serous, mucinous adenocarcinoma or carcinosarcoma.
- •Subjects must have completed and failed a minimum of 2 previous lines of platinum-containing therapy (e.g., carboplatin, oxaliplatin, or cisplatin).
- •Subjects may have failed up to 2 additional cytotoxic regimens that may have included platinum.
- •Subjects must have had no more than 4 lines of prior drug therapy.
- •If treated with bevazicumab, subjects should have completed and failed treatment.
- •Subjects with BRCA mutation (positive) should have completed and failed treatment with a PARP inhibitor, or have been ineligible for treatment with a PARP inhibitor.
- •Patient must have had documented best response, disease recurrence, and date of progression based on RECIST v1.1 or CGIG criteria within 6 months from the start of last prior platinum-based therapy.
- •Formalin fixed, paraffin-embedded archival tumor available from the primary or recurrent cancer required.
- •Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 and have been stable during wash-out period from prior therapy.
- •Adequate recovery from all recent surgery is required; at least 1 week must have elapsed from the time of a minor surgery; at least 21 days must have elapsed from the time of a major surgery. Must have recovered from all surgery-related toxicities to Grade 1 or less.
- •A minimum of 28 days between termination of the investigational drug and administration of VAL
- •Must have recovered from all prior treatment-related toxicities to Grade 1 or less.
- •Laboratory values as follows at screening and within 3 days of planned first dose of therapy:
- •Absolute neutrophil count (ANC) ≥ 1500/μL
- •Hemoglobin (HgB) ≥ 9 g/dL
- •Platelets ≥ 100,000/μL ( > 150,000/μL if prior nitrosureas)
- •Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance > 60 mL/min (measured or calculated by the Cockcroft-Gault formula) (Cockcroft & Gault, 1976)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 2 × ULN unless liver metastases are present, in which case they must be ≤ 5 × ULN.
- •Total bilirubin < 1.5 × the institutional ULN, unless the patient has documented conjugated bilirubin disorder such as Gilbert's syndrome. Subjects with known Gilbert's disease who have serum bilirubin ≤ 3 × ULN (NCI CTCAE v4.03 Grade 2) may be enrolled.
- •International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
- •Heart-rate corrected QT interval (QTc) < 450 msec on screening EKG.
- •No clinically significant cardiac conduction disorder on screening.
- •Subjects must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and be accessible for follow-up.
排除标准
- •Subjects with clear cell, low grade serous or mucinous adenocarcinoma, or carcinosarcoma.
- •Current history of neoplasm other than the entry diagnosis. Subjects with previous cancers treated and cured with local therapy alone may be considered with approval of the Medical Monitor.
- •Persistent Grade ≥2 toxicity from prior cancer therapy.
- •Subjects with declining ECOG performance status, defined by 1 point over a 28-day period, will be excluded.
- •Concurrent severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Any of the following cardiac conditions:
- •History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting up to 12 weeks before initiation of treatment with VAL-083
- •Class III or IV heart failure as defined by the New York Heart Association functional classification system up to 6 months before initiation of treatment with VAL-083
- •Subjects with known active hepatic disease (i.e., hepatitis B or C).
- •Subjects known to be HIV positive and not on stable medication or have an AIDS-related illness.
- •Subjects with a known sensitivity to any of the products to be administered during treatment and assessments.
研究组 & 干预措施
VAL-083, Dianhydrogalactitol
VAL-083 given by intravenous infusion with a starting dose of 60 mg/m2 once weekly. If this regimen is well tolerated for at least three sequential weekly treatments the patient's dose may be escalated to 67 mg/m2 i.v. If the 67 mg/m2 dose is well tolerated for at least three sequential weekly treatments the patient's dose may be escalated to 75 mg/m2 i.v. once weekly for the remainder of the study. Dosing will be conducted once per week for a total of 16 weeks.
干预措施: VAL-083, Dianhydrogalactitol (Drug)
结局指标
主要结局
Estimate Overall Response Rate
时间窗: Every 8 weeks from Screening to achievement of either complete response (CR) or partial response (PR) for at least 6 months
Overall number of tumor complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or GCIG criteria using computed tomography (CT) or magnetic resonance imaging (MRI)
次要结局
- Progression-free Survival(Every 30 days from Screening until disease progression or patient death, whichever occurs first, for at least 6 months)
- Duration of Response(Every 8 weeks from Screening to achievement of either complete response (CR) or partial response (PR) for at least 6 months)
- Safety evaluation of VAL-083 for adverse events(From Screening up to 28 days following last study treatment with VAL-083)
- Efficacy evaluation of VAL-083 against CA-125 biomarker(From Screening to achievement of either complete response (CR) or partial response (PR) for at least 6 months)
- Overall Survival(Every 30 days from Screening until patient death or for at least 6 months, whichever occurs first)
- Tmax(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- AUClast(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- AUCinf(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- Lambda z(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- Comparative Progression-free Survival(Every 30 days from Screening until disease progression or patient death, whichever occurs first, for at least 6 months)
- Cmax(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- T 1/2(Treatment Day 1 pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of i.v. infusion of VAL-083)
- Quality of Life(Every 4 weeks from Screening until disease progression, for at least 6 months)