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The p53 Breast Cancer Trial (p53b)

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ClinicalTrials.gov Identifier: NCT02965950
Recruitment Status : Recruiting
First Posted : November 17, 2016
Last Update Posted : July 29, 2020
Sponsor:
Information provided by (Responsible Party):
Haukeland University Hospital

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.


Condition or disease Intervention/treatment Phase
Locally Advanced Breast Cancer Metastatic Breast Carcinoma Drug: Cyclophosphamide Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 190 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Patients With Advanced Breast Cancer Harboring TP53 Mutations With Dose-dense Cyclophosphamide - the p53 Breast Cancer Trial
Actual Study Start Date : October 2016
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2030

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: TP53 mutated, LABC
Patients with locally advanced breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide
Drug: Cyclophosphamide
I.v. infusion
Other Name: ATC-number: L01A A01

Experimental: TP53 mutated, MBC
Patients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide
Drug: Cyclophosphamide
I.v. infusion
Other Name: ATC-number: L01A A01

Experimental: TP53 wt, LABC
Patients with locally advanced breast cancer, TP53 wt disease. Dose-dense cyclophosphamide
Drug: Cyclophosphamide
I.v. infusion
Other Name: ATC-number: L01A A01

Experimental: TP53 wt, MBC
Patients with metastatic breast cancer, TP53 wt disease. Dose-dense cyclophosphamide
Drug: Cyclophosphamide
I.v. infusion
Other Name: ATC-number: L01A A01




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Number of patients harboring the same molecular aberration or set of aberrations, and which are associated with either response to treatment or survival. [ Time Frame: Four years ]
    These are genomic and proteomic aberrations beyond TP53 mutations.

  2. Number of patients harboring the same TP53 mutation subtype [ Time Frame: Four years ]
    Assess whether responses are recorded among patients harbouring TP53 mutations belonging to particular mutation subgroups.

  3. Number of patients achieving pathological complete response (pCR) [ Time Frame: Four years ]
    Patients achieving pathological complete response (pCR), measured as no remaining infiltrative carcinoma in the breast and axillary nodes by histology, in TP53 wt and mutated subgroups, after dose-dense cyclophosphamide.

  4. Recurrence-free survival [ Time Frame: 14 years ]
    Recurrence-free survival after dose-dense cyclophosphamide.

  5. Overall survival [ Time Frame: 14 years ]
    Recurrence-free and overall survival after dose-dense cyclophosphamide.

  6. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Four years ]
    Safety and tolerability of dose-dense cyclophosphamide



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

LABC:

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.

* Only for patients with TP53 mutated disease. Previous adjuvant chemotherapy, including alkylating agents (cyclophosphamide a.o.) and/or platinum, is allowed if completed >12 months prior to inclusion in the trial.

** In metastatic breast cancer resistance to taxanes/anthracyclines is defined as progressive disease (PD). In LABC lack of response is defined as stable disease (SD) after 4 courses of chemotherapy or PD. 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 (CT thorax/abdomen and bone scintigraphy/bone scan) and ecco cor must be performed within 28 days prior to start of treatment.
  • 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.
  • Amendment 2018: Patients with HER2 positive, metastatic breast cancer in the first line setting (Arm C).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02965950


Contacts
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Contact: Hans Petter Eikesdal, MD PhD +4755972010 hans.eikesdal@uib.no
Contact: Per Eystein Lønning, Professor +4755972010 per.lonning@helse-bergen.no

Locations
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Norway
Haukeland University Hospital Recruiting
Bergen, Hordaland, Norway, 5021
Contact: Hans Petter Eikesdal, MD PhD    +4755972010      
Contact: Per Eystein Lønning, MD PhD    +4755972010      
Sub-Investigator: Sindre Molvær, MD         
Principal Investigator: Hans Petter Eikesdal, MD PhD         
Sub-Investigator: Stian Knappskog, PhD         
Sub-Investigator: Turid Aas, MD PhD         
St. Olavs Hospital Not yet recruiting
Trondheim, Sør Trøndelag, Norway
Contact: Steinar Lundgren, Professor         
Principal Investigator: Steinar Lundgren, MD PhD         
Sub-Investigator: Sunil Raj, MD PhD         
Akershus University Hospital Not yet recruiting
Lørenskog, Norway
Contact: Jürgen Geisler, MD PhD       jurgen.geisler@medisin.uio.no   
Principal Investigator: Jürgen Geisler, MD PhD         
Stavanger University Hospital Not yet recruiting
Stavanger, Norway
Contact: Bjørnar Gilje, MD PhD       bjornar.gilje@sus.no   
Principal Investigator: Bjørnar Gilje, MD PhD         
University Hospital of Northern Norway Recruiting
Tromsø, Norway
Contact: Egil S. Blix, MD PhD       Egil.Store.Blix@unn.no   
Principal Investigator: Egil S. Blix, MD PhD         
Sponsors and Collaborators
Haukeland University Hospital
Investigators
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Principal Investigator: Hans Petter Eikesdal, MD PhD Haukeland University Hospital
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Responsible Party: Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT02965950    
Other Study ID Numbers: 2016/816
2016-003459-31 ( EudraCT Number )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: July 29, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Plan to share with collaborators
Keywords provided by Haukeland University Hospital:
breast cancer
TP53
cyclophosphamide
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists