Combination Therapy with Liposomal Doxorubicin and Withaferin a (Ashwagandha, ASWD) in Recurrent Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 72
- 试验地点
- 1
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
The proposed study "combination therapy with liposomal doxorubicin and withaferin A (Ashwagandha, ASWD) in recurrent ovarian cancer" is focused to determine the feasibility and maximum tolerance dose of Ashwagandha with liposomal doxorubicin (DOXIL) in recurrent ovarian cancer patients. The study contains two parts. In part 1 (phase I), 18 patients with recurrent ovarian cancer eligible for DOXIL therapy will be recruited and three doses of Ashwagandha (2.0 g, 4.0 g and 8.0 g) in the form of tablets along with DOXIL will be evaluated for feasibility and tolerance of ASWD. In part 2 (phase II), 54 patients with recurrent ovarian cancer will be recruited and treated with DOXIL and Ashwagandha (dose determined from part 1) to evaluate the complete response (CR), partial response (PR), and stable disease (SD).
详细描述
Study Design Overview:
This is a two-part open-label clinical trial of ASWD (Ashwagandha) administered to patients with recurrent ovarian cancer in combination with liposomal doxorubicin, (DOXIL) following at least one previous line of chemotherapy. Patients will initially be enrolled in part 1 of the study, which is the feasibility/tolerability evaluation. Once the part 1 enrollment is completed, the patients will be enrolled in part 2 of the study.
In both parts, ASWD will be administered orally daily whereas liposomal doxorubicin will be administered intravenously (IV) every 4 weeks for at least 4 cycles or until disease progression and/or unacceptable toxicity, whichever comes first. If disease progression and/or unacceptable toxicity is not encountered, study treatment will be for a maximum of 10 cycles, or until a total cumulative dose of anthracycline therapy exceeds 450 mg/m2. Continued treatment with liposomal doxorubicin and/or ASWD will be determined by the provider. Once there is a completion of 10 cycles, ASWD will be continued in a daily regimen as maintenance, without continued liposomal doxorubicin, until disease progression and/or unacceptable toxicity.
Part 1 Part 1 (Phase I) is a feasibility/tolerability evaluation in which approximately 18 patients with recurrent ovarian cancer will be enrolled. The enrolled patients will be treated with 3 doses of ASWD [1.0 g, 2.0 g or 4.0 g/twice daily (total 2.0 g, 4.0 g or 8.0 g/day) taken orally with water in the form of capsule (500 mg/capsule, containing 500 mg of active ashwagandha)] in combination with set dosage of DOXIL (40 mg/m2 over 60 min, every 4 weeks). DOXIL will be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, infusion rate will be increased to complete administration over 1 hour. Bolus injection or undiluted solution will not be administered.
Dose Escalation:
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients with recurrent ovarian/fallopian tube/primary peritoneal cancer for whom liposomal Doxorubicin would be an acceptable therapeutic option will be recruited. Patients are eligible if they have received first line chemotherapy containing platinum and have become platinum resistance or have refractory disease. The patient must also meet all the following criteria:
- •Signed approved informed consent document stating that they understand the investigational nature of the treatment program before entering study
- •Female patients, age ≥ 18 years
- •Pathological confirmed ovarian, fallopian tube, or primary peritoneal carcinoma with the one of the following histologic types: high grade papillary serous carcinoma, low grade papillary serous carcinoma, high grade mucinous carcinoma, low grade mucinous carcinoma, clear cell carcinoma, high grade endometrioid carcinoma.
- •Received at least one line chemotherapy, which must be a platinum containing regimen and develop platinum resistance. Patients may have not received previous liposomal doxorubicin therapy, and must be considered to be eligible for single agent liposomal doxorubicin treatment.
- •Patients may have undergone surgical cytoreduction at the time of primary diagnosis or following neoadjuvant chemotherapy. Patients who had optimal (<1 cm residual disease) or suboptimal (>1 cm residual disease) following surgical cytoreduction will be included.
- •Patients who did not undergo surgical cytoreduction will also be included.
- •Recurrent disease confirmed by biopsy, radiologic imaging, and/or elevated CA 125
- •Patients may have received radiation therapy
- •Life expectancy > 6 months
- •Part 1: Have evaluable disease by radiologic measurements (See 11) or CA 125
- •Part 2: Have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as > 1 cm on cross-sectional imaging (where the CT slice thickness is no greater than 5 mm) or at least 2 cm by standard techniques; positron emissions tomography (PET] and ultrasound are not permitted methods for tumor measurements under this protocol. Consult RECIST 1.1 guidance for additional information (Appendix C and Eisenhauer et al., 2009; Ref 61).
- •Adequate organ function within 14 days prior to first WFA/ASWD dose or liposomal doxorubicin whichever occurs first, including the following: absolute neutrophil count (ANC) ≥ 1.5 x 103/L, platelet count ≥ 100 x 103/L, hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L), patients may receive packed RBC transfusion to achieve this level at the discretion of the investigator, total bilirubin < 1.5 x upper limit of normal (ULN) unless elevated secondary to conditions such as Gilbert's Disease, aspartate aminotransferase (AST) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases), alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases), alkaline phosphatase < 3.0 x ULN, calculated creatinine clearance ≥ 60 mL/min per Cockcroft and Gault formula
- •Satisfy one of the following:
- •Females: non-pregnant and non-lactating; surgically sterile, post- menopausal, or patient/partner compliant with a reliable contraceptive regimen, as determined by the investigator, for 4 weeks prior to screening.
- •Patients of reproductive potential must test negative for pregnancy at screening, prior to each cycle, and must agree to use a reliable method of birth control during the study period and 6 months following completion of treatment.
- •The patient is willing and able to comply with the study visit schedule and procedures and has geographical proximity (Investigator's discretion) that allows follow-up specified by the protocol
- •For Part 1: Patients have discontinued all prior chemotherapies, biological therapies, and other investigational therapies for cancer for at least 4 weeks prior to study treatment and have recovered from the acute effects of therapy
- •ECOG performance status of 0, 1, or 2
- •Adequate ejection fraction determined by transthoracic echo or MUGA of at least 55%
- •Patients may have received prior anthracycline or anthracenedione therapy. In this scenario, the use of prior treatments will be incorporated into the cumulative dose calculations when applicable, given a known increased risk of cardiomyopathy to 11% when the cumulative dose of liposomal doxorubicin was between 450 mg/m2 to 550 mg/m
排除标准
- •Patients will be excluded from the study if they meet any of the following criteria:
- •ECOG performance status 3 or 4
- •Pregnant or breastfeeding
- •Treatment with another investigational drug, biological agent, or device within 4 weeks (6 weeks for biological agents) before screening or 5 half-lives of study agent, whichever is longer
- •Patients with treated or untreated parenchymal brain metastases or leptomeningeal disease. Brain imaging is required for symptomatic patients to rule out brain metastases, but is not required in asymptomatic patients
- •Patients with known pericardial effusion
- •Patients with active infection or serious concomitant systemic disorder (for example, heart failure) incompatible with the study (at the discretion of the Investigator)
- •Presence or history of malignancy other than ovarian cancer that does not include carcinoma in situ of the cervix, or non-melanoma skin cancer. In the case of other malignancies, patients may be considered for participation if the prior malignancies were diagnosed and definitively treated at least two years previously with no subsequent evidence of recurrence
- •Presence of an underlying disease state associated with active bleeding
- •Concurrent treatment with other anticancer drugs
- •Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device
- •Patients with any other medical conditions that, in the opinion of the Investigator, would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study
- •Patients with known septicemia, severe infection, or acute hepatitis
- •Patients with known congestive heart failure or unstable angina or those who had a myocardial infarction within the past 6 months
- •Patients with known clinically significant pericardial disease
- •Patients taking medications known to affect the cardiac conduction system
- •Allergy to WFA/ASWD
- •Previous treatment with liposomal doxorubicin
- •Prior use of other anthracyclines or anthracenediones -
研究组 & 干预措施
Combination of DOXIL and Ashwagandha
The study contains two parts. In part 1 (Phase I), 18 patients with recurrent ovarian cancer will be recruited and administered IV with liposomal doxorubicin (DOXIL) 40 mg/m2 on day 1 of 28 days cycle for 4 cycles. Ashwagandha will be administered on daily basis for 2 years. Three doses of Ashwagandha (2 g, 4 g or 8.0 g) will be administered orally with water every day for two years to evaluate a tolerable dose of Ashwagandha. Six patients will be recruited for each dose.
In part 2 Phase II), 54 additional patients with recurrent ovarian cancer will be recruited and administered with DOXIL IV (40 mg/m2) and maximum tolerable dose of Ashwagandha (determined from part 1) in the form tables orally with water on daily basis for two years. The survival rate (SR), complete response (CR) and partial response (PR) will be evaluated.
干预措施: DOXIL (Drug)
Combination of DOXIL and Ashwagandha
The study contains two parts. In part 1 (Phase I), 18 patients with recurrent ovarian cancer will be recruited and administered IV with liposomal doxorubicin (DOXIL) 40 mg/m2 on day 1 of 28 days cycle for 4 cycles. Ashwagandha will be administered on daily basis for 2 years. Three doses of Ashwagandha (2 g, 4 g or 8.0 g) will be administered orally with water every day for two years to evaluate a tolerable dose of Ashwagandha. Six patients will be recruited for each dose.
In part 2 Phase II), 54 additional patients with recurrent ovarian cancer will be recruited and administered with DOXIL IV (40 mg/m2) and maximum tolerable dose of Ashwagandha (determined from part 1) in the form tables orally with water on daily basis for two years. The survival rate (SR), complete response (CR) and partial response (PR) will be evaluated.
干预措施: Withaferin A (Drug)
Combination of DOXIL and Ashwagandha
The study contains two parts. In part 1 (Phase I), 18 patients with recurrent ovarian cancer will be recruited and administered IV with liposomal doxorubicin (DOXIL) 40 mg/m2 on day 1 of 28 days cycle for 4 cycles. Ashwagandha will be administered on daily basis for 2 years. Three doses of Ashwagandha (2 g, 4 g or 8.0 g) will be administered orally with water every day for two years to evaluate a tolerable dose of Ashwagandha. Six patients will be recruited for each dose.
In part 2 Phase II), 54 additional patients with recurrent ovarian cancer will be recruited and administered with DOXIL IV (40 mg/m2) and maximum tolerable dose of Ashwagandha (determined from part 1) in the form tables orally with water on daily basis for two years. The survival rate (SR), complete response (CR) and partial response (PR) will be evaluated.
干预措施: Ashwagandha (Drug)
Combination of DOXIL and Ashwagandha
The study contains two parts. In part 1 (Phase I), 18 patients with recurrent ovarian cancer will be recruited and administered IV with liposomal doxorubicin (DOXIL) 40 mg/m2 on day 1 of 28 days cycle for 4 cycles. Ashwagandha will be administered on daily basis for 2 years. Three doses of Ashwagandha (2 g, 4 g or 8.0 g) will be administered orally with water every day for two years to evaluate a tolerable dose of Ashwagandha. Six patients will be recruited for each dose.
In part 2 Phase II), 54 additional patients with recurrent ovarian cancer will be recruited and administered with DOXIL IV (40 mg/m2) and maximum tolerable dose of Ashwagandha (determined from part 1) in the form tables orally with water on daily basis for two years. The survival rate (SR), complete response (CR) and partial response (PR) will be evaluated.
干预措施: Combination of ASWD and DOXIL (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: From study entry to time of progression or death, whichever occurs first, assessed up to 4 years.
Will be presented by Kaplan Meier methods.
次要结局
- Overall survival(Time from study entry to date of death from any cause, assessed up to 4 years)
- Incidence of adverse events (AE)(From study entry, up to 4 years.)
- Objective response rate (ORR)(From the start of the treatment until disease progression/recurrence, assessed up to 4 years)
- Duration of response(From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 4 years.)
研究者
Sham Sunder Kakar
Professor
University of Louisville