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PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial (PETREMAC)

Primary Purpose

Breast Cancer

Status

Active

Phase

Phase 2

Locations

Norway

Study Type

Interventional

Intervention

Neoadjuvant tamoxifen + goserelin (premenopausal women)

Neoadjuvant letrozole (postmenopausal women)

Neoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone)

Neoadjuvant docetaxel + cyclophosphamide

Neoadjuvant docetaxel

Neoadjuvant docetaxel + trastuzumab + pertuzumab

Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab

Neoadjuvant olaparib

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

Breast conserving surgery or mastectomy + SNB/axillary dissection

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Adjuvant trastuzumab

Adjuvant letrozole (postmenopausal women)

Adjuvant tamoxifen + goserelin (premenopausal women)

Adjuvant palbociclib (if palbociclib given neoadjuvant)

Adjuvant Epirubicin+ Cyclophosphamide

About this trial

This is an interventional basic science trial for Breast Cancer focused on measuring neoadjuvant treatment, personalized medicine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Previously untreated, histologically confirmed non-inflammatory breast cancer, >4 cm in diameter and /or metastatic ipsilateral axillary deposits for which the smallest diameter of the largest node >2 cm by CT or ultrasound scan.
WHO performance status 0-1
Known tumor ER, PGR, HER2 and TP53 status.
Known tumor Ki67 percentage (if ER/PGR>50% and TP53 wt status).
Distant metastasis not suspected. Patients will undergo radiology exams during screening phase, after signing the informed consent.
Age >18 years
Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST.
Radiology studies (CT thorax/abdomen and bone scintigraphy/bone scan) must be performed within 28 days prior to registration.
Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Before patient registration/randomization, written informed consent must be given according to national and local regulations.
For arms B-H:
- Neutrophils > 1.5 x 109/L
- Platelets > 100 x 109/L
- Bilirubin < 2 x upper limit normal (ULN). For patients with Gilbert´s syndrome bilirubin >2 x ULN is accepted if there is no evidence of biliary obstruction.
- Serum creatinine < 1.5 x ULN
- ALT and Alk Phos (ALP) <2.5 x ULN
- INR < 1.5

Exclusion Criteria:

Unstable angina pectoris or heart failure
Other co-morbidity that, based on the assessment of the treating physician, may preclude the use of chemotherapy at actual doses.
Pregnant or lactating patients can not be included.
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.
Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.
Active cystitis (to be treated upfront)
Active bacterial infections
Urinary obstruction

Sites / Locations

Akershus University Hospital
Haukeland University Hospital
Helse Fonna
Helse Stavanger
Helse Førde
St. Olavs Hospital
Helse Nord/UNN

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Arm Label

Arm Description

ER/PGR>50% TP53 wt

ER/PGR>50% TP53 mutated

ER/PGR<50% TP53 wt

ER/PGR<50% TP53 mutated

HER2+ TP53 wt

HER2+ TP53 mutated

Triple negative breast cancer TP53 wt

Triple negative breast cancer TP53 mutated

Outcomes

Primary Outcome Measures

Predictive and prognostic value of mutations in 300 cancer-related genes assessed in breast cancer tissue by next generation sequencing before starting neoadjuvant therapy.

Primary endpoint

Secondary Outcome Measures

To assess genetic/epigenetic changes within the tumor tissue during therapy

Secondary endpoint

The objective response rate (ORR) of personalized medicine, compared to ORR for best standard-of-care using historical data for comparison

Secondary endpoint

Tumor Ki67 reduction after 2 and 5 weeks of treatment in Arm A

Secondary endpoint

To estimate recurrence-free and overall survival when patients are treated with the optimal personalized treatment available as of 2015, using historical data for comparison

Secondary endpoint

To evaluate the percentage of patients completing neoadjuvant treatment and completing surgery

Secondary endpoint

Breast conserving surgery rate (potential to avoid mastectomy)

Secondary endpoint

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Secondary endpoint

Full Information

NCT ID

NCT02624973

First Posted

November 30, 2015

Last Updated

August 24, 2021

Sponsor

Haukeland University Hospital

Collaborators

Helse Vest, Pfizer, AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT02624973

Brief Title

PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

Acronym

PETREMAC

Official Title

PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Active, not recruiting

Study Start Date

April 15, 2016 (Actual)

Primary Completion Date

June 1, 2020 (Actual)

Study Completion Date

June 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Haukeland University Hospital

Collaborators

Helse Vest, Pfizer, AstraZeneca

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Breast cancer is an optimal "model disease" for studying personalized medicine. Breast cancer was the first malignancy for which a predictive factor forecasting response to therapy was identified nearly 50 years ago; the expression of the estrogen receptor (ER). Furthermore, breast cancer is by far the malignancy in which prognostic and predictive factors have been most extensively studied. Primary medical treatment (pre-surgical medical therapy) offers a unique setting to explore predictive factors due to the fact that primary breast cancers are easily accessible to repeated tissue sampling and evaluation of therapy response both clinically and radiologically. For many years, the investigators have studied predictive factors in primary medical treatment of breast cancer. In the present project, the investigators will implement a new trial concept where the current knowledge from previous trials with respect to predictive markers (hormone receptors, HER2; TP53, CHEK2 and RB1), will be combined with massive parallel sequencing (MPS). Thereby, the investigators aim to design the "next-generation" primary medical treatment where 1) therapy regimens are individualized based on a limited number of known predictive factors and, 2) MPS is used to explore additional predictive factors and their co-regulators in order to fully identify the mechanisms of drug sensitivity / resistance across individual tumours and pave the way for further personalized breast cancer therapy in the future. As for the new era of "genomic medicine", the current trial concept will allow individual tumours to be characterized by their unique gene mutation / epigenetic modification profile upfront, to allocate patients to their optimal personalized medicine as compared to "classical" drug testing through phase II/III trials.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer

Keywords

neoadjuvant treatment, personalized medicine

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

200 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

ER/PGR>50% TP53 wt

Arm Title

Arm Type

Experimental

Arm Description

ER/PGR>50% TP53 mutated

Arm Title

Arm Type

Experimental

Arm Description

ER/PGR<50% TP53 wt

Arm Title

Arm Type

Experimental

Arm Description

ER/PGR<50% TP53 mutated

Arm Title

Arm Type

Experimental

Arm Description

HER2+ TP53 wt

Arm Title

Arm Type

Experimental

Arm Description

HER2+ TP53 mutated

Arm Title

Arm Type

Experimental

Arm Description

Triple negative breast cancer TP53 wt

Arm Title

Arm Type

Experimental

Arm Description

Triple negative breast cancer TP53 mutated

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant letrozole (postmenopausal women)

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone)

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant docetaxel + cyclophosphamide

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant docetaxel

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant docetaxel + trastuzumab + pertuzumab

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant olaparib

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

Intervention Type

Procedure

Intervention Name(s)

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Description

After response to neoadjuvant treatment

Intervention Type

Radiation

Intervention Name(s)

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type

Drug

Intervention Name(s)

Adjuvant trastuzumab

Intervention Type

Drug

Intervention Name(s)

Adjuvant letrozole (postmenopausal women)

Intervention Type

Drug

Intervention Name(s)

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type

Drug

Intervention Name(s)

Adjuvant palbociclib (if palbociclib given neoadjuvant)

Intervention Type

Drug

Intervention Name(s)

Adjuvant Epirubicin+ Cyclophosphamide

Primary Outcome Measure Information:

Title

Predictive and prognostic value of mutations in 300 cancer-related genes assessed in breast cancer tissue by next generation sequencing before starting neoadjuvant therapy.

Description

Primary endpoint

Time Frame

Ten years

Secondary Outcome Measure Information:

Title

To assess genetic/epigenetic changes within the tumor tissue during therapy

Description

Secondary endpoint

Time Frame

Before vs. 16-24 wks after treatment start. Four years: summary of all patients treated.

Title

The objective response rate (ORR) of personalized medicine, compared to ORR for best standard-of-care using historical data for comparison

Description

Secondary endpoint

Time Frame

Four years

Title

Tumor Ki67 reduction after 2 and 5 weeks of treatment in Arm A

Description

Secondary endpoint

Time Frame

Assessment for each patient after 2 and 5 weeks of treatment. Four years - summary of all patients in arm A.

Title

To estimate recurrence-free and overall survival when patients are treated with the optimal personalized treatment available as of 2015, using historical data for comparison

Description

Secondary endpoint

Time Frame

Ten years

Title

To evaluate the percentage of patients completing neoadjuvant treatment and completing surgery

Description

Secondary endpoint

Time Frame

Four years

Title

Breast conserving surgery rate (potential to avoid mastectomy)

Description

Secondary endpoint

Time Frame

Four years

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Description

Secondary endpoint

Time Frame

Ten years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Previously untreated, histologically confirmed non-inflammatory breast cancer, >4 cm in diameter and /or metastatic ipsilateral axillary deposits for which the smallest diameter of the largest node >2 cm by CT or ultrasound scan. WHO performance status 0-1 Known tumor ER, PGR, HER2 and TP53 status. Known tumor Ki67 percentage (if ER/PGR>50% and TP53 wt status). Distant metastasis not suspected. Patients will undergo radiology exams during screening phase, after signing the informed consent. Age >18 years Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST. Radiology studies (CT thorax/abdomen and bone scintigraphy/bone scan) must be performed within 28 days prior to registration. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial Before patient registration/randomization, written informed consent must be given according to national and local regulations. For arms B-H: Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L Bilirubin < 2 x upper limit normal (ULN). For patients with Gilbert´s syndrome bilirubin >2 x ULN is accepted if there is no evidence of biliary obstruction. Serum creatinine < 1.5 x ULN ALT and Alk Phos (ALP) <2.5 x ULN INR < 1.5 Exclusion Criteria: Unstable angina pectoris or heart failure Other co-morbidity that, based on the assessment of the treating physician, may preclude the use of chemotherapy at actual doses. Pregnant or lactating patients can not be included. 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. Patient not able to give an informed consent or comply with study regulations as deemed by study investigator. Active cystitis (to be treated upfront) Active bacterial infections Urinary obstruction

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hans Petter Eikesdal, MD PhD

Organizational Affiliation

Consultant oncologist

Official's Role

Principal Investigator

Facility Information:

Facility Name

Akershus University Hospital

City

Lørenskog

State/Province

Akershus

Country

Norway

Facility Name

Haukeland University Hospital

City

Bergen

State/Province

Hordaland

ZIP/Postal Code

5021

Country

Norway

Facility Name

Helse Fonna

City

Haugesund

State/Province

Rogaland

Country

Norway

Facility Name

Helse Stavanger

City

Stavanger

State/Province

Rogaland

Country

Norway

Facility Name

Helse Førde

City

Førde

State/Province

Sogn Og Fjordande

Country

Norway

Facility Name

St. Olavs Hospital

City

Trondheim

State/Province

Sør Trøndelag

Country

Norway

Facility Name

Helse Nord/UNN

City

Tromsø

State/Province

Troms

Country

Norway

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Tumor genomic data will be made available after publication.

Citations:

PubMed Identifier

33242536

Citation

Eikesdal HP, Yndestad S, Elzawahry A, Llop-Guevara A, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Vagstad G, Venizelos A, Minsaas L, Leirvaag B, Gudlaugsson EG, Vintermyr OK, Aase HS, Aas T, Balmana J, Serra V, Janssen EAM, Knappskog S, Lonning PE. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol. 2021 Feb;32(2):240-249. doi: 10.1016/j.annonc.2020.11.009. Epub 2020 Nov 24.

Results Reference

result

PubMed Identifier

36223740

Citation

Wang L, Wang D, Sonzogni O, Ke S, Wang Q, Thavamani A, Batalini F, Stopka SA, Regan MS, Vandal S, Tian S, Pinto J, Cyr AM, Bret-Mounet VC, Baquer G, Eikesdal HP, Yuan M, Asara JM, Heng YJ, Bai P, Agar NYR, Wulf GM. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype. Cell Rep. 2022 Oct 11;41(2):111462. doi: 10.1016/j.celrep.2022.111462.

Results Reference

derived

PubMed Identifier

36048535

Citation

Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lonning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, Wulf GM. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers. Clin Cancer Res. 2022 Nov 1;28(21):4714-4723. doi: 10.1158/1078-0432.CCR-22-0749.

Results Reference

derived

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PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

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