Treatment of Patients With Advanced Breast Cancer Harboring TP53 Mutations With Dose-dense Cyclophosphamide - the p53 Breast Cancer Trial
Overview
- Phase
- Phase 2
- Intervention
- Cyclophosphamide
- Conditions
- Locally Advanced Breast Cancer
- Sponsor
- Haukeland University Hospital
- Enrollment
- 190
- Locations
- 5
- Primary Endpoint
- Objective response rate (ORR) measured clinically (with calipers) or radiologically per RECIST guidelines.
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a multicenter, open labeled, phase 2 clinical trial, where patients are stratified to one of two treatment groups based on upfront TP53 mutation status; i.e. TP53 mutated vs. TP53 wt disease, and treated with dose-dense cyclphosphamide. Furthermore, patients included are stratified based on tumor stage; i.e. locally advanced breast cancer (M0 disease) or metastatic breast cancer (M1 disease). All participating cancer centers will prospectively include patients with breast cancer fulfilling the inclusion criteria.
If patients do not respond to the experimental treatment as outlined in the protocol, treatment with dose-dense cyclophosphamide will be terminated, and further cancer treatment will continue at the treating oncologist's discretion. The response data for all patients who have received at least one chemotherapy course will be included in the final efficacy analysis.
Tumor tissue, blood samples and radiology data will be collected before therapy starts, if therapy needs to be changed, and for patients with locally advanced breast cancer: at surgery. Response data will be evaluated closely during treatment, with clinical assessment of tumor size every two weeks for patients with locally advanced breast cancer and by radiology every eight weeks for patients with metastatic breast cancer. Evaluation of side effects/tolerance will be performed at every clinical visit, i.e. every two weeks for all patients included in the p53 trial.
Detailed Description
Stage IV breast cancer (distant metastases) remains a non-curable condition; thus, treatment is considered palliative. However, many patients may live for years with their metastatic disease with a reasonably good quality of life. As for locally advanced primary breast cancers in need of primary medical therapy, lack of responsiveness to regular chemotherapy is associated with a poor prognosis, with a high risk of relapse and, subsequent, breast cancer death. TP53 mutations have been shown to predict a poor response to anthracyclines, a group of cytotoxic agents which is extensively used and which is in general efficacious in breast cancer. Notably, dose-intensification with cyclophosphamide has been found to significantly improve the response rate in TP53 mutated primary breast cancers. Our preliminary experience indicates that the use of dose-dense cyclophosphamide monotherapy every 2nd week with G-CSF support is well tolerated. As for patients with metastatic disease for whom the alternative would be to receive continuous chemotherapy at 3-weekly intervals the hypothesis is that cyclophosphamide given at 2-weekly intervals over a limited time period, followed by a "treatment holiday" among responders should be associated with a non-inferior quality of life all-over. As for patients with TP53 mutated locally advanced breast cancers where standard chemotherapy fails, the hypothesis is that cyclophosphamide dose dense treatment may be an effective treatment option downstaging the tumor prior to surgery.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Locally advanced breast cancers in need of pre-surgical chemotherapy or metastatic breast cancer in need of chemotherapy.
- •Resistance to endocrine therapy:
- •Either i) estrogen and progesterone negative tumor, or ii) harboring an estrogen and / or progesterone positive tumor where regular endocrine therapies have failed or where the treating physician finds endocrine therapy not indicated.
- •Prior cancer therapy:
- •Metastatic disease:
- •First line treatment (amendment 2018):
- •No prior chemotherapy\*. Prior endocrine therapy +/- CDK4/6 inhibitor or mTOR inhibitors is allowed if hormone receptor positive, HER2 negative disease.
- •Late-stage disease (approved protocol):
- •i) Prior exposure to and resistance to a taxane regimen\*\*. ii) Prior exposure to and resistance to an anthracycline regimen\*\* -mandatory only for patients with TP53 wt tumors.
- •i) Prior exposure to and lack of response to to a taxane regimen\*\*. ii) Prior exposure to and lack of response to an anthracycline regimen\*\* - mandatory only for patients with TP53 wt tumors.
Exclusion Criteria
- •Co-morbidity that, based on the assessment of the treating physician, may preclude the use of cyclophosphamide at actual doses.
- •Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- •Pregnant or lactating patients.
- •Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist.
- •Active cystitis (to be treated upfront)
- •Active bacterial infections
- •Urinary obstruction
- •Known hypersensitivity towards cyclophosphamide or pegfilgrastim, their metabolites and other ingredients in the drug administration formulation.
- •Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.
- •Amendment 2018: Patients with HER2 positive, metastatic breast cancer in the first line setting (Arm C).
Arms & Interventions
TP53 mutated, LABC
Patients with locally advanced breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines.
Intervention: Cyclophosphamide
TP53 mutated, MBC, first line
Patients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide first line metastatic disease
Intervention: Cyclophosphamide
TP53 wt, LABC
Patients with locally advanced breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines.
Intervention: Cyclophosphamide
TP53 wt, MBC
Patients with metastatic breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines.
Intervention: Cyclophosphamide
TP53 mutated, MBC
Patients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines.
Intervention: Cyclophosphamide
Outcomes
Primary Outcomes
Objective response rate (ORR) measured clinically (with calipers) or radiologically per RECIST guidelines.
Time Frame: Four years
ORR of dose dense cyclophosphamide in patients with TP53 mutated breast cancer or TP53 wt breast cancer.
Secondary Outcomes
- Recurrence-free survival(14 years)
- Number of patients achieving pathological complete response (pCR)(Four years)
- Overall survival(14 years)
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(Four years)
- Number of patients harboring the same molecular aberration or set of aberrations, and which are associated with either response to treatment or survival.(Four years)
- Number of patients harboring the same TP53 mutation subtype(Four years)