Locally Advanced Breast CancerPhase 2p53bNCT02965950
The p53 Breast Cancer Trial
A Phase 2 study testing Cyclophosphamide in people with Locally Advanced Breast Cancer and Metastatic Breast Carcinoma, run by Haukeland University Hospital at 5 sites in Norway.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Locally Advanced Breast Cancer, Metastatic Breast Carcinoma
- What is being tested?
- Cyclophosphamide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 190 participants
- Where
- 5 sitesNorway
- Study dates
- Oct 2016to May 2033
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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):
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- 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):
- 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:
- 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
Who cannot join
- 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
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- 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).
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Norway5 sites
Haukeland University Hospital
Bergen, Hordaland, 5021
Akershus University Hospital
Lørenskog
Stavanger University Hospital
Stavanger
University Hospital of Northern Norway
Tromsø
St. Olavs Hospital
Trondheim, Sør Trøndelag
About this study
Official title: Treatment of Patients With Advanced Breast Cancer Harboring TP53 Mutations With Dose-dense Cyclophosphamide - the p53 Breast Cancer Trial
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.
Read the 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.
- Being tested
- Cyclophosphamide
- Keywords
- breast cancer, TP53, cyclophosphamide
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CyclophosphamideDrug
Also called ATC-number: L01A A01
I.v. infusion
| Study group | Role | What they receive |
|---|---|---|
| TP53 mutated, LABC | Experimental | Patients with locally advanced breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines. Receives: Drug: Cyclophosphamide |
| TP53 mutated, MBC, first line | Experimental | Patients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide first line metastatic disease Receives: Drug: Cyclophosphamide |
| TP53 wt, LABC | Experimental | Patients with locally advanced breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines. Receives: Drug: Cyclophosphamide |
| TP53 wt, MBC | Experimental | Patients with metastatic breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines. Receives: Drug: Cyclophosphamide |
| TP53 mutated, MBC | Experimental | Patients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines. Receives: Drug: Cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective response rate (ORR) measured clinically (with calipers) or radiologically per RECIST guidelines.
ORR of dose dense cyclophosphamide in patients with TP53 mutated breast cancer or TP53 wt breast cancer.
Measured: Four years
Secondary outcomes (6)
Number of patients harboring the same molecular aberration or set of aberrations, and which are associated with either response to treatment or survival.
These are genomic and proteomic aberrations beyond TP53 mutations.
Measured: Four years
Number of patients harboring the same TP53 mutation subtype
Assess whether responses are recorded among patients harbouring TP53 mutations belonging to particular mutation subgroups.
Measured: Four years
Number of patients achieving pathological complete response (pCR)
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.
Measured: Four years
Recurrence-free survival
Recurrence-free survival after dose-dense cyclophosphamide.
Measured: 14 years
Overall survival
Recurrence-free and overall survival after dose-dense cyclophosphamide.
Measured: 14 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Safety and tolerability of dose-dense cyclophosphamide
Measured: Four years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Nov 2016 (estimated)
- Study startOct 2016
- Primary completionMay 2024 (estimated)
- Study completionMay 2033 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Locally Advanced Breast CancerStudies of the same condition, open and under way.
- More trials run by Haukeland University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 190 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Haukeland University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Hans Petter Eikesdal, MD PhD, Principal investigator, Haukeland University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02965950
- Sponsor's protocol ID
- 2016/816
- Other IDs
- 2016-003459-31, 2016
- Acronym
- p53b
- Status last verified
- Jan 2024
- First submitted
- 4 Nov 2016
- Last updated
- 12 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Plan to share with collaborators
Study at a glance
From the registry record, last updated by the sponsor on 12 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Patients With Advanced Breast Cancer Harboring TP53 Mutations With Dose-dense Cyclophosphamide - the p53 Breast Cancer Trial
- ClinicalTrials.gov ID
- NCT02965950
- Acronym / sponsor ID
- p53b / 2016/816
- Keywords
- breast cancer, TP53, cyclophosphamide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 190 participants (estimated)
- Lead sponsor
- Haukeland University HospitalUniversity, hospital or other
- Study start
- Oct 2016 (actual)
- Primary completion
- May 2024 (estimated)
- Study completion
- May 2033 (estimated)
- First posted
- 17 Nov 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| TP53 mutated, LABC | Experimental | Drug: CyclophosphamidePatients with locally advanced breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines. |
| TP53 mutated, MBC, first line | Experimental | Drug: CyclophosphamidePatients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide first line metastatic disease |
| TP53 wt, LABC | Experimental | Drug: CyclophosphamidePatients with locally advanced breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines. |
| TP53 wt, MBC | Experimental | Drug: CyclophosphamidePatients with metastatic breast cancer, TP53 wt disease. Dose-dense cyclophosphamide, after taxanes and anthracyclines. |
| TP53 mutated, MBC | Experimental | Drug: CyclophosphamidePatients with metastatic breast cancer, TP53 mutated disease. Dose-dense cyclophosphamide, after taxanes +/- anthracyclines. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- 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:
- No prior chemotherapy. Prior endocrine therapy +/- CDK4/6 inhibitor or mTOR inhibitors is allowed if hormone receptor positive, HER2 negative disease.
Key exclusion criteria (10 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CyclophosphamideAlso: ATC-number: L01A A01I.v. infusion | Drug | TP53 mutated, LABC, TP53 mutated, MBC, TP53 mutated, MBC, first line, TP53 wt, LABC, TP53 wt, MBC |
Primary outcome
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.
6 secondary outcomes
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
Number of patients harboring the same TP53 mutation subtype
Time frame: Four years
Number of patients achieving pathological complete response (pCR)
Time frame: Four years
Recurrence-free survival
Time frame: 14 years
Overall survival
Time frame: 14 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: Four years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jan 2024.
- Individual participant dataSharing planned: Yes. Plan to share with collaborators
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hans Petter Eikesdal, MD PhD principal investigator
Haukeland University Hospital
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cyclophosphamide in people with Locally Advanced Breast Cancer and Metastatic Breast Carcinoma, run by Haukeland University Hospital at 5 sites in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 12 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response rate (ORR) measured clinically (with calipers) or radiologically per RECIST guidelines. (time frame: Four years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jan 2024.