Background
Identifiers and status | First posted | Design | Participants | Interventions | Follow-up | Primary outcomes |
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NCT03962647; not yet recruiting | 24 May 2019 | Single-group assignment, clinical trial | 30 patients, ER+ breast cancer | Experimental: 2-week ketogenic diet | After 2 weeks of a ketogenic diet | Patients who complete the dietary intervention |
NCT03535701; recruiting | 24 May 2018 | Non-randomized, clinical trial | 15 patients with stage IV breast cancer (KETO-CARE) | Active comparator:aArm I (standard of care); Experimental: arm II (standard of care, ketogenic diet) | Baseline up to 26 weeks | Adherence and compliance to the ketogenic diet; Changes in psychosocial measures; Changes in physiological outcomes |
NCT02092753; completed | 20 March 2014 | Non-randomized, clinical trial | 150 patients with breast cancer during the rehabilitation phase | Placebo comparator: standard diet; Experimental: ketogenic diet; Experimental: logi diet | 20 weeks spanning 3 phases: 3 weeks of stationary intervention, 16 weeks of outhouse phase, and 1 final week of stationary intervention | Quality of life. This will be assessed by comparing the results of the EORTC QLQ-30 and the QLQ-BR23 questionnaires |
Methods/design
Study design and setting
Eligibility criteria
Inclusion criteria
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Female patients with histologically or cytologically confirmed locally recurrent or metastatic breast cancer. The Her-2 testing criteria are based on the 2006 American Society of Clinical Oncology (ASCO)/American College of Pathologists (CAP)-approved Her-2 testing guidelines for breast cancer
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Aged 18–70 years
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Body mass index ≥ 24 kg/m2, or body fat percentage ≥ 28%
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Tumor tissues with a large amount of tumor cells will be extracted, and TOP1 immunohistochemical testing will be performed in the central laboratory before enrollment, with a TOP1 expression rate ≥ 10%
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Patients with locally recurrent or metastatic breast cancer who are unable to receive radical surgery and have been treated with at least two chemotherapy regimens(a)The regimens must include any anthracycline and any taxane (as adjuvant therapy or/and metastatic therapy) in any combination; if these drugs are contraindicated in the intended patients, they are not required to be used in previous treatments, but they must be recorded in the medical history of the intended patients(b)The disease was not controlled in the latest chemotherapy treatment, i.e., disease progression must have occurred during the last chemotherapy treatment or less than 6 months after the last chemotherapy treatment(c)The use of hormone therapy is allowed in neoadjuvant and/or adjuvant therapy and the treatment of advanced diseases; however, this treatment must be terminated 2 weeks before randomization
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Estimated overall survival ≥ 3 months
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Measurable lesions defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 within 2 weeks before enrollment (note: a measurable lesion is confirmed if there has been a previously defined disease progression in the target lesion during radiotherapy) [14]
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Eastern Cooperative Oncology Group (ECOG) Performance Status Scale score 0–2
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Blood routine examinations: white blood cell count ≥ 3.0 × 109/L, absolute neutrophil count ≥ 1.5 × 109/L, and platelet count ≥ 100 × 109/L
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Liver and kidney function tests: total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (a patient with known Gilbert syndrome is eligible if their serum bilirubin level is ≤ 3 × ULN), alanine transaminases ≤ 1.5 times the ULN, aspartate aminotransferase ≤ 1.5 times the ULN, urea nitrogen and serum creatinine ≤ 1.5 times the ULN, and a creatinine removal rate ≥ 50 mL/min (Cockcroft-Gault formula)
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Coagulation function test: international normalized ratio and activated partial thromboplastin time ≤ 1.5 times the ULN
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Intended subjects of childbearing age are negative for serum pregnancy test during screening (within 7 days prior to the first dose) and require effective contraception before enrollment, throughout the study, and 6 months after the last dose
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Provision of informed consent
Exclusion criteria
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Patients with homozygous mutations in UGT1A1*6 and/or UGT1A1*28 (such patients are susceptible to irinotecan-induced diarrhea)
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Patients who have received chemotherapy, surgery (such as a major surgery for breast cancer), or molecular-targeted therapy within 4 weeks prior to randomization or who have received hormone therapy or radiotherapy within 2 weeks prior to randomization
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Patients who have participated in other drug clinical trials within 4 weeks prior to randomization
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Uncontrolled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) or unstable angina; a history of chronic heart failure that meets the New York Heart Association (NYHA) criteria and severe arrhythmias (except for atrial fibrillation and paroxysmal supraventricular tachycardia) that require treatment; a history of myocardial infarction within 6 months prior to randomization
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Patients who have developed central nervous system (CNS) diseases, except for those with asymptomatic CNS metastases who have been treated and met all of the following conditions:(a)Measurable lesions outside the CNS(b)Only supratentorial and cerebellar metastases (i.e., no metastasis to the midbrain, pons, medulla, or spinal cord)(c)CNS diseases not requiring corticosteroid treatment (allowing the use of a stable dose of anticonvulsants)(d)No stereotactic or whole-brain radiotherapy within 2 weeks prior to randomization(e)No evidence of disease progression or bleeding after CNS-targeted therapy; (note: if a new, disease-free CNS metastasis is detected during a screening, the patient must receive radiotherapy and/or surgical treatment for the CNS metastases, and such patients will be excluded from the trial)
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Uncontrollable bone metastasis (i.e., patients who have fractures or have a recent risk of fracture, have a recent schedule for surgery or local radiotherapy, or have other critical conditions)
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Human immunodeficiency virus infection, chronic hepatitis B, hepatitis C, or other infections that have been clinically confirmed at the active phase
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Currently suffering from serious and uncontrollable systemic diseases (e.g., cardiovascular disease, lung disease, or clinically confirmed metabolic disease)
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Metastasis to the liver and kidneys
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Patients undergoing allogeneic organ transplantation who require immunosuppressive therapy
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Known or suspected allergy to the primary agent or any other drug administered during the study
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A history of another primary malignancy, except for bilateral breast cancer, in-situ cervical carcinoma, fully treated non-melanoma skin cancer, and malignant tumors that have been treated and have not relapsed in the past 5 years
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Patients with concurrent metabolic diseases such as carnitine deficiency, carnitine palmitoyl, basal transferase I or II deficiency, carnitine transferase II deficiency, beta-oxidase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, long-chain cyl-CoA dehydrogenase deficiency, short-chain cyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl coenzyme deficiency, medium-chain 3-hydroxyacyl coenzyme deficiency, pyruvate carboxylase deficiency, and porphyria
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Patients with concurrent urinary calculi, history of renal failure or severe renal insufficiency, familial dyslipidemia, severe liver disease, chronic metabolic acidosis, history of pancreatitis, severe diabetes, active gallbladder disease, fat digestive disorder, epilepsy, and severe cardio-cerebrovascular diseases
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Lactating women
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Patients who are unable to cooperate with a ketogenic diet because they have trouble eating
Withdrawal criteria
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Failure to recover from treatment-related toxicity to baseline or grade-1 AEs (except for grade-2 hair loss and grade-2 fatigue) within the scheduled 3 weeks (i.e., the inception of each new cycle is over 21 days behind schedule)
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Loss to follow-up
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The patients are randomized to the intervention but do not adhere to the intervention
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Patients for whom the trial medication regimen must be altered
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Presence of concurrent diseases or deterioration of patient’s conditions, or if the investigator believes that the patient cannot continue the study
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Patients with a body mass index ≤ 21 kg/m2 are unable to continue the trial
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Patients who have not adhered to the ketogenic diet as prescribed during the treatment, or those who have poor tolerance to the ketogenic diet
Interventions
Ketogenic diet
Dietary regimen
Ketogenic-diet monitoring
Assessment of ketogenic-diet compliance
Criteria for ketogenic-diet termination
Drug administration
Irinotecan monotherapy
Drug-dose adjustment
Hematological toxicity
Minimal value | Dose in the next cycle | |
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Neutrophil count (× 109/L) | Platelet count (× 109/L) | |
≥ 0.5 | … and ≥ 50 | No change |
< 0.5 or ≥ 0.5 accompanied by fever and lack of granulocytes | … or < 50 | Irinotecan dose decreased by 20% |
Non-hematological toxicity
Liver toxicity
AST/ALT | Alkaline phosphatase level | Dose adjustment |
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< 1.5 × ULN | < 5 × ULN | No dose adjustment |
1.5 × ULN to < 2.5 × ULN | < 2.5 × ULN | No dose adjustment |
2.5 × ULN to < 5 × ULN | < 2.5 × ULN | The irinotecan dose will be reduced by 20%. |
> 1.5 × ULN to < 5 × ULN | > 2.5 × ULN to < 5 × ULN | |
> 5 × ULN and/or > 5 × ULN (except for bone metastases without any liver damage) | If recovery is not achieved within 3 weeks, the patient will be withdrawn from the trial |
Peripheral neurotoxicity
Chemotherapeutic drug sensitivity
Criteria for re-treatment or treatment delay
- Their absolute neutrophil count is > 1500/mm3
- Their platelet count is > 100,000/mm3
- Any treatment-related non-hematological toxicity has resolved to level ≤ 1 or baseline (the exceptions are grade-2 hair loss and grade-2 fatigue)
- Patients who respond well to the medication can continue their therapy with the consent of the study sponsor
Medication-cycle delay
Drug withdrawal
Outcome measures
Primary outcome measures
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Sensitivity to irinotecan is determined by various indicators, including the tumor-growth inhibition rate (TGI), chemosensitivity index (CSI), half inhibitory concentration (IC50), and 90% inhibitory concentration (IC90). These indicators are calculated as follows:1.TGI = (1 – average fluorescence value in drug treatment group/average fluorescence value in control group) × 100%2.CSI-500 indicates the sum of the inhibition rates of the respective drug concentrations. A smaller value indicates a higher inhibition rate of the chemotherapy drug on tumor cells3.IC50 indicates a test-drug concentration (TDC) that allows 50% growth inhibition4.IC90 indicates a TDC that allows 90% growth inhibition5.The sensitivity of chemotherapeutic drugs can be determined according to the TDC, CSI, IC50, and IC90: sensitive, IC50 ≤ 25% TDC; mildly sensitive, IC90 ≤ 100% TDC and IC50 > 25% TDC, or CSI ≤ 300; resistant, IC90 > 100% TDC, IC50 > 25% TDC, and CSI > 300 [19]
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The ORR of the target lesions will be evaluated using the RECIST version 1.1 [14]. The study’s primary endpoint is the ORR, which is defined as the percentage of patients who experience complete or partial cancer shrinkage or disappearance after treatment. The ORR will be calculated by dividing the number of patients who achieve a complete or partial response by the total sample size according the formula:
Secondary outcome measures
Other outcome measures
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The patients’ general health will be evaluated using the Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) [22]
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Laboratory testing will acquire hematological data (hemoglobin, white blood cell count, blood glucose, blood ketones, blood lipids, neutrophil count, and platelet count), biochemical data (total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum creatinine, total protein, sodium ions, potassium ions, magnesium ions, chloride, calcium, urea, and thyroid function), pregnancy status (if applicable), tumor-marker data (CA153 and carcino-embryonic antigen), routine urinary data (urinary glucose, urinary ketones, urinary protein), and imaging data (computed tomography/magnetic resonance imaging of target lesions). The biological samples collected in this trial will only be used in the present trial and will not be used in other studies
Sample size estimation
Recruitment
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The patients will be mainly recruited from the Department of Medical Oncology, Liaoning Cancer Hospital and Institute, China. This facility focuses on treating advanced breast cancer. This department houses the Liaoning Breast Cancer Clinic, which treats patients from across the entire province
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Recruitment will be performed using leafleting that advertises to advanced breast cancer inpatients and outpatients. After being informed of the trial’s objective and procedures, potentially interested patients or relatives will contact the project manager via their attending physicians, or by telephone, e-mail, or Wechat
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Patients must provide written informed consent if they wish to participate
Randomization and blinding
Data collection and management
Statistical analysis
Data description
Intergroup comparison
Survival analysis
Economic analysis
Statistical analysis dataset
Safety assessment
Adverse events (AEs)
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Patients included in the clinical trial will be monitored and followed-up and may undergo close examinations in our hospital without charge. Each patient will be able to receive transportation and registration fees for admission examination
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The investigator will determine the relevance of any AEs, and claims will be covered for AEs that are considered “relevant” to the study. There is no anticipated harm and compensation for trial participation