| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult female patients with breast cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult female patients with breast cancer. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To characterize the pharmacokinetic profile and to compare bioavailability of cyclophosphamide powder relative to cyclophosphamide tablet. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate taste/palatability of cyclophosphamide powder
- To compare the safety of cyclophosphamide powder relative to cyclophosphamide tablet. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must sign an ICF indicating that she understands the purpose of, and procedures required for the study as described in this protocol and is willing to participate in the study.
2. Participant must be female of weight ≥40 kg, aged between 18 to 55 years of age inclusive, at the time of signing the informed consent.
3. Participants with documented medical history of histologically or cytologically confirmed breast cancer.
4. Participant must have of HER2 negative, ER/PR positive or negative breast cancer [as defined by American Society for Clinical Oncology (ASCO)- College of American Pathologists (CAP) guidelines] confirmed by local laboratory performed on primary tumor and/or metastatic lesion.
5. Patients who are
a. Neoadjuvant, adjuvant, recurrent, or metastatic setting
AND
b. To be initiated on cyclophosphamide 100 mg/m2 (rounded within 5% of the prescribed dose but always in multiples of 50 mg per day) daily for at least 14 days by oral route with established treatment regimen either as a monotherapy or as part of combination therapy as per independent clinical judgement of a treating physician based on standard medical care.
OR
Already receiving stable dose of cyclophosphamide 100 mg/m2 (rounded within 5% of the prescribed dose in multiples of 50 mg per day) daily for at least 14 days by oral route with established treatment regimen either as a monotherapy or as part of combination therapy as per independent clinical judgement of a treating physician based on standard medical care.
6. Documented disease progression (clinical or radiographic imaging) following most-recent anti-cancer systemic study intervention regimen before current cyclophosphamide therapy (not applicable for newly diagnosed patients/adjuvant patients).
7. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 at screening and baseline visit.
8. Body mass index (BMI) within the range 18.5 – 30 kg/m2 (inclusive) at screening and baseline.
9. Life expectancy of ≥12 weeks at screening and baseline. Patients are required to be in stable health status between the two periods of the study.
10. Patient must have recovered from acute toxicity of radiotherapy or previous cycle of chemotherapy before baseline visit. Patients if have received radiotherapy (regardless of site & dose), a gap of 28 days must be maintained between the last dose of radiotherapy and baseline visit.
11. Patient with adequate hematologic, liver and renal function at screening visit.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP)
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency when used consistently and correctly, as described in Appendix 10.4 during the intervention period and for at least 12 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for a period of at least 12 months. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive serum pregnancy test at screening; and urine pregnancy test before the first dose of study intervention at baseline visit.
• If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in Appendix 10.2.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
13. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
|
|
| E.4 | Principal exclusion criteria |
1. History of clinically significant medical condition including but not limited to liver insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances; any severe, acute, or chronic medical, psychiatric or social condition; or laboratory abnormality that as per Investigator's opinion may either (a) not be in the best interest of the participant, (b) interfere with the informed consent process and/or with compliance with the requirements of the trial, or (c) prevent, limit, or confound the protocol-specified assessments or (d) result in the variation of absorption or metabolism of drug, i.e., ulcerative colitis, or gastrointestinal disease.
2. Known allergies, hypersensitivity, or intolerance to cyclophosphamide powder or tablet or its excipients
3. Contraindications to the use of cyclophosphamide per SmPC at screening and at baseline.
• Participant with bladder/urinary toxicity of cyclophosphamide.
• Participant with urinary outflow obstructions or acute urothelial toxicity from cytotoxic chemotherapy or radiation therapy.
• Participant with bone marrow aplasia.
• Participant with severe infection within 4 weeks prior to randomization, bacteremia, or severe pneumonia OR Received oral or IV antibiotics within 2 weeks prior to Baseline visit. Patients receiving routine antibiotic prophylaxis are eligible.
4. Had of major surgery, within 12 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study or within 30 days after the last dose of study intervention administration.
5. History of hepatitis B surface antigen or hepatitis C antibody positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening Visit.
6. History of human immunodeficiency virus antibody positive, or tests positive for HIV at Screening Visit.
7. History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders criteria within 1 year before Screening or positive test result(s) for alcohol or drugs of abuse at Screening Visit.
8. Lymphoma, leukemia, or any malignancy within the past 5 years except for malignancy under study, basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years; carcinoma in situ of the cervix; or malignancy, which is considered cured with minimal risk of recurrence
9. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
10. QTc >470 msec or QTc >480 msec in participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to Bazett’s formula. It is either machine-read or manually over-read.
11. More than one prior line of chemotherapy for locally advanced or metastatic breast cancer. Radiation therapy or endocrine therapy for metastatic disease is permitted.
12. Patients unable to ingest oral medications.
13. Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met
• Only supratentorial metastases allowed.
• No evidence of interim progression or hemorrhage after completion of CNS-directed therapy.
• No ongoing requirement for corticosteroids as therapy for CNS disease
• No stereotactic radiation within 14 days or whole-brain radiation within 28 days prior to randomization.
14. Leptomeningeal disease.
15. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥4 weeks prior to Baseline.
16. History of any of the following clinically significant cardiac conditions at screening and/or at Baseline:
• Unstable angina
• Myocardial infarction within the past 6 months of Baseline
• Unstable arrhythmias
• Clinically significant pericardial disease
• Electrocardiographic evidence of acute ischemic or active conduction system abnormalities
• Any other cardiac illness that could lead to a safety risk to the patient in case of enrolment in the study
• Patients with a known left ventricular ejection fraction <40% will be excluded.
• Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
17. Received an investigational intervention or used an invasive investigational medical device within 30 days or 5 half-lives prior to Baseline, whichever is longer, before the signing the consent or is currently enrolled in an investigational study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To characterize the pharmacokinetic profile and to compare bioavailability of cyclophosphamide powder relative to cyclophosphamide tablet. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Following pharmacokinetic parameters will be evaluated:
- Primary Pharmacokinetic Parameters: Cmax,ss and AUC0-τ,ss
- Secondary Pharmacokinetic Parameters: Tmax,ss, Cav,ss, Cτ,ss, %Fluctuation and Cpd |
|
| E.5.2 | Secondary end point(s) |
- To evaluate taste/palatability of cyclophosphamide powder
- To compare the safety of cyclophosphamide powder relative to cyclophosphamide tablet. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Test product palatability will be evaluated using palatability evaluation scale in terms of taste, flavor and mouth feel assessment.
- Frequency and/or incidence of significant clinical signs and symptoms, and laboratory abnormalities during treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Comparative bioavailability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Comparative bioavailability |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Cyclophosphamide Tablets 50 mg |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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