Study of Combination Therapy in The Treatment of Recurrent Breast Cancer
Breast cancer is a disease in which cells in the breast grow out of control. There are different kinds of breast cancer. The kind of breast cancer depends on which cells in the breast turn into cancer. Breast cancer can begin in different parts of the breast. A breast is made up of three main parts: lobules, ducts, and connective tissue. The lobules are the glands that produce milk. The ducts are tubes that carry milk to the nipple. The connective tissue (which consists of fibrous and fatty tissue) surrounds and holds everything together. Most breast cancers begin in the ducts or lobules. Breast cancer can spread outside the breast through blood vessels and lymph vessels. When breast cancer spreads to other parts of the body, it is said to have metastasized.
Kinds of Breast Cancer
The most common kinds of breast cancer are: Invasive ductal carcinoma. The cancer cells grow outside the ducts into other parts of the breast tissue. Invasive cancer cells can also spread, or metastasize, to other parts of the body. Invasive lobular carcinoma. Cancer cells spread from the lobules to the breast tissues that are close by. These invasive cancer cells can also spread to other parts of the body. There are several other less common kinds of breast cancer, such as Paget’s disease, medullary, mucinous, and inflammatory breast cancer. Ductal carcinoma in situ (DCIS) is a breast disease that may lead to breast cancer. The cancer cells are only in the lining of the ducts and have not spread to other tissues in the breast.
Breast cancer is treated in several ways. It depends on the kind of breast cancer and how far it has spread. People with breast cancer often get more than one kind of treatment such as surgery, biological therapy, hormonal therapy, radiation therapy but our clinical trial concern is Chemotherapy which is Using special medicines to shrink or kill the cancer cells. The drugs can be pills you take or medicines given in your veins, or sometimes both. The study purpose is to evaluate the efficacy and safety of Cabozantinib+Lynparzal for the treatment of breast cancer using Chemotherapy.
Based on phase II clinical trial results showing that 250mg/kg Cabozantinib and Lynparzal were safe and effective in the treatment of breast cancer, the phase III the clinical study is to further verify the efficacy and safety of Chemotherapy using Cabozantinib and Lynparzal for Breast cancer
The study primary objective is to evaluate the efficacy and safety of Cabozantinib+Lynparzal for the treatment of breast Cancer compared tousing placebo plus Lynparzal as the control. The evaluation of the therapeutic effect of the chemotherapy will be done by a comparison between the participants that received Cabozantinib and Lynparzal and the participants that received the placebo plus Lynparzal. At baseline, measurable tumor lesions will accurately be measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 10 mm) per RECIST 1.1 10 mm caliper measurement by clinical exam (when superficial) per RECIST 1.120 mm by chest X-ray (if clearly defined and surrounded by aerated lung) per RECIST 1.1
Change from baseline in tumor lesions measured at Week 12 of combination therapy with Cabozantinib (administered once a day) and Lynparzal vs. placebo plus Lynparzal per RECIST 1.1
Clinical Benefit Rate: [ Time Frame: 12 weeks]CBR will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 12 weeks, per RECIST 1.1
Time to clinical worsening during combination therapy with Cabozantinib and Lynparzal vs. placebo plus Lynparzal where clinical worsening is defined by liver cirrhosis due to breast cancer, death due to breast cancer, hospitalization for breast cancer worsening, any early discontinuation from study due to Chemotherapy.
Overall Response Rate per Immune Criteria: [ Time Frame: 12 weeks]. ORR will be determined according to immune-related response criteria (IRRC). Number of participants with adverse events [ Time Frame: ] Toxicities will be defined according to NCI CTCAE,
This is a parallel, placebo-controlled, double-blinded and multicenter clinical trial. The subjects are randomized into trial group and control group at 3:1 ratio in this phase III clinical trial. The subjects will be assigned to a trial group or control group by stratified block randomization to receive not more than 2 courses of treatment. The control group receivesd placebo during the first course of treatment followed by a trial drug during the second course of treatment. Based on phase II clinical trial results, the trial drug dose is set at 250mg.
3.2 Sample Size
Statistical estimation of the sample size: using two-sided test of the efficacy, ?=0.05 and ?=0.1(power=90%) based on phase II clinical trial results, the expert estimates the total clinical efficacy rate of Cabozantinib+Lynparzal to be 65% in the treatment of Breast Cancer and expects a 30% difference from the placebo group; consequently, the estimated number of participants 625, we approximated to 640 . Taking into account a dropout rate of 20% as per another study, the sample size of this clinical trial was determined to be 600 subjects for the trial group and 200 subjects for the control group, giving a total of 800 subjects.
Trial arm and number of Participants Dosage of Cabozantinib+Lynparzal Trial period Randomized, double-blinded, placebo and parallel-controlled (multicenter) 600 participants in trial arm 250mg
The first courseof treatment
Randomized, double-blinded, placebo and parallel-controlled (multicenter) 200 participants in control arm 0mg The first course of treatment Randomized, double-blinded(multicenter) 600 participants in the trial arm250mg
The second course of treatment
Randomized, double-blinded(multicenter) 200 participants in control arm 250mg The second course of treatment
In this randomized and double-blinded trial, each subject should be assigned a drug serial number strictly in accordance with the inclusion time sequence to determine the treatment group. Stratified block randomization was performed, and a software analysis system is used to generate continuously serial numbers corresponding to the sample size. The randomization numbers for each study center are generated at the same time.
3.4 Subject selection
The participant is capable of understanding and complying with the protocol and has signed the informed consent document. The study population will consists of female patients 25 years and older.
3.4.1 Inclusion Criteria
- Participants must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease with Lynparzal.
- Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
- Participants must have measurable disease by RECIST version 1.1
- Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to registration. Participants should also be adequately recovered from acute toxicities of prior treatment.
- Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days prior to registration.
- In all cases, there must be complete recovery and no ongoing complications from prior radiotherapy.
3.4.2 Exclusion Criteria
Those who have recent health conditions like surgery which involves wound healing. No clinically relevant ongoing complications from prior surgery are not eligible.
- The participant has a tumour in contact with, invading, or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions.
- The subject has pathologic evidence of a tumour invading the GI tract (oesophagus, stomach, small or large bowel, rectum or anus), or any evidence of an endotracheal or an endobronchial tumour within 28 days before the first dose of the trial drug.
- Concurrent administration of other anti-cancer therapy within 14 days of starting protocol therapy and during the course of this study.
- The participant has received another investigational agent within 14 days of the first dose of study drug.
- The participant has received a prior c-Met inhibitor Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
- Cardiovascular disorders including:
- The participant is unable to swallow oral dosage forms.
- The participant is pregnant or breastfeeding
4.0 Treatment Administration
Lynparzal is given to participants given every 2 weeks intravenously the dosage as determined by the phase II trial is 150mg. Cabozantinib is administered orally once daily to all participant in the treatment group the dosage is 250mg The Control Placebo is designed in the same way as Cabozantinib and the Lynparzal with the same dosage and same administration method.
4.1 Concomitant drugs
The participants are not allowed to use the drugs listed in the exclusion criteria during this trial. If concomitant drugs are indeed needed to treat other diseases, the name, dosage, indication, the beginning and ending date, and other relevant information should be recorded in the case report form (CRF)
4.2 Multi-Center and the number of participants
The total number of subjects, grouping, randomization method and the tasks undertaken by each centre .The total number of subjects planned to include is 800 and the distribution of these subjects among the centres are listed in the following table.