Evaluation of Dose-Dense Cyclophosphamide in Patients with TP53 Mutated or Wild-Type Advanced Breast Cancer
- Trial ID
- 2024-515135-29-00
- Protocol
- P53
- Sponsor
- Helse Bergen HF
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this trial is to prospectively evaluate the **objective response rate (ORR)** of dose-dense cyclophosphamide in patients with **TP53** mutated breast cancer or TP53 wild-type breast cancer. This is clinically relevant as it aims to determine the efficacy of cyclophosphamide in a specific genetic subset of breast cancer patients, potentially guiding personalized treatment strategies.
The secondary objectives of this trial include:
- Identifying molecular markers of therapy response/resistance and survival outcomes beyond TP53 mutations.
- Assessing responses among patients with TP53 mutations in specific subgroups, such as "Gain of Function" mutations, mutations in the DNA-binding domain of the p53 protein, mutations with loss of heterozygosity (LOH), and mutations in other genes within the p53 pathway.
- Determining the percentage of patients with T2 tumors or locally advanced breast cancer achieving pathological complete response (pCR).
- Evaluating the clinical benefit rate (CBR) in patients with metastatic breast cancer.
- Comparing recurrence-free and overall survival to historical data.
- Assessing the safety and tolerability of the study treatment.
Participants
The clinical trial focuses on evaluating the objective response rate of dose-dense cyclophosphamide in patients with **breast cancer**, specifically those with TP53 mutated or TP53 wild-type tumors. The study population comprises adult females over the age of 18, with no male participants included. Participants are required to have a WHO performance status of 0-1, indicating they are in relatively good health, and must have clinically or radiographically documented measurable breast cancer according to RECIST criteria. The trial does not include a vulnerable population. Participants must have a primary tumor or at least one metastatic lesion available for biopsy collection at protocol inclusion. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. Key inclusion criteria include the need for pre-surgical chemotherapy for primary or locally advanced breast cancers, or chemotherapy for metastatic breast cancer. Participants must have known tumor ER, PGR, and HER2 status, and radiology studies for tumor measurements and cardiac function must be performed within 28 days of commencing treatment per protocol.
Plans and Procedures
The clinical trial is designed to evaluate the **objective response rate** of dose-dense **cyclophosphamide** in patients with **TP53** mutated or wild-type breast cancer. This is a randomized, double-blind, controlled trial, categorized as a Phase II therapeutic exploratory and confirmatory study. The trial is expected to span from November 2016 to June 2028, with participant involvement lasting up to 24 months. The study includes a series of visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as tumor type, prior cancer therapy, and blood test results. Participants must have a **WHO performance status** of 0-1 and be over 18 years of age. The primary tumor or a metastatic lesion must be available for biopsy at protocol inclusion.
Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include radiology studies for tumor measurements and assessments of cardiac function. The end-of-study visit will evaluate the overall treatment efficacy and safety, with endpoints including **pCR**, clinical benefit rate, recurrence-free survival, and tolerability. Participants may be terminated early from the study if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of cyclophosphamide in this patient population, contributing to the understanding of treatment options for advanced breast cancer.
Treatment
The clinical trial involves the administration of **cyclophosphamide**, a chemotherapeutic agent, as the experimental medication. The product used is "Cyclophosphamid beta 1000 mg/2 ml Konzentrat zur Herstellung einer Injektions-/Infusionslösung," which is a **solution for injection/infusion**. The active substance, cyclophosphamide, is of chemical origin and is classified under the ATC code L01AA01. The pharmaceutical form is a concentrate for the preparation of an injection or infusion solution, intended for **intravenous administration**. The dosing regimen involves a maximum daily dose of 1800 mg/m², with a total maximum dose of 40,000 mg over a treatment period of up to 24 weeks. The administration schedule is designed to be dose-dense, targeting patients with advanced breast cancer harboring TP53 mutations.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of dose-dense cyclophosphamide in the specified patient population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to prospectively evaluate the objective response rate (ORR) of the treatment in patients with TP53 mutated breast cancer or TP53 wild-type breast cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is the main endpoint. This trial focuses on evaluating the response of patients with TP53 mutated or TP53 wild-type breast cancer to dose-dense cyclophosphamide treatment. Secondary endpoints include pathological complete response (pCR), clinical benefit rate, recurrence-free survival, and assessments of safety and tolerability. These parameters will be measured and collected at specified intervals throughout the trial duration, with the objective of providing a comprehensive evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Primary (T2 tumors or Locally advanced breast cancers; LABC) 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: No prior chemotherapy*. Prior endocrine therapy +/- CDK4/6 inhibitor or mTOR inhibitors is allowed if hormone receptor positive, HER2 negative disease. * Only for patients with TP53 mutated disease. Previous adjuvant chemotherapy, including alkylating agents (cyclophosphamide a.o.) DocuSign Envelope ID: 00482556-BD7E-48A0-B3D5-54A7D3046AD9 Study protocol: The p53 breast cancer trial, version 1.9 24 and/or platinum, is allowed if completed >12 months prior to inclusion in the trial. 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*** - iii) Previous adjuvant chemotherapy, including alkylating agents (cyclophosphamide a.o.) and/or platinum, is allowed if completed >12 months prior to inclusion in the trial. Primary breast cancer (T2 tumors or LABC): i) Prior exposure to and lack of response to a taxane regimen**. ii) Prior exposure to and lack of response to an anthracycline regimen*** *** Mandatory only for patients with TP53 wt tumors. ** For HER2 positive breast cancer, previous taxane + anti-HER2 treatment is required. In metastatic breast cancer resistance to taxanes/anthracyclines is defined as progressive disease (PD). In primary breast tumors lack of response is defined as stable disease (SD) after 4 courses of chemotherapy or PD, or SD/PD after initial response, or further taxane/anthracyclines is not possible due to toxicity. Breast cancer relapsing within 12 months subsequent to adjuvant taxanes or anthracyclines is considered resistant and re-exposure is not required prior to inclusion in the trial. This relates also to patients who could not receive proper taxane or anthracycline therapy due to side effects or other medical reasons.
- The primary tumor or at least one metastatic lesion must be available for biopsy collection at protocol inclusion. Notably; for patients with primary metastatic breast cancer, TP53 status should be determined in a metastatic deposit; tissue from the primary tumor may not substitute (this relates both to patients with synchronous and metachronous metastatic disease).
- Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST.
- WHO performance status 0-1
- Known tumor ER, PGR and HER2 status in the current situation, i.e. archival and historic breast cancer tissue can not be used for patients with relapse of the disease. However, patients can be included regardless of hormone receptor and HER2 status; in case such information lacks at inclusion, it may be analysed on the biopsy retrospectively.
- Age >18 years
- Radiology studies for tumor measurements and ecco cor for cardiac function must be performed within 28 days of commencing treatment per protocol (MRI breast for primary breast cancer and CT thorax/abdomen/pelvis and/or MRI + bone scintigraphy/bone scan for metastatic disease).
- Before patient registration, written informed consent must be given according to national and local regulations.
- Blood test requirements: ▪ Neutrophils > 1.0 x 109/L ▪ Platelets > 75 x 109/L ▪ Bilirubin < 20 μmol/L. ▪ Serum creatinine < 1.5 x ULN
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.
- Patients with HER2 positive, metastatic breast cancer in the first line setting (Arm C).
- Amendment 2021: Previous platinum or cyclophosphamide chemotherapy (incl. EC90) if completed less than 12 months prior to inclusion in the trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Norway | Not Recruiting | 01 Nov 2016 | 63 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cyclophosphamid beta 1000 mg/2 ml Konzentrat zur Herstellung einer Injektions-/Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INJEKTIONS-/INFUSIONSLÖSUNG | INTRAVENOUS ADMINISTRATION | 1800 | 24 | PRD10049050 |