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

NCT ID: NCT02624973

Last Updated: 2021-08-27

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-15
• Study Completion Date: 2030-06-30

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

A

ER/PGR\>50% TP53 wt

Group Type: EXPERIMENTAL

Neoadjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

Neoadjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

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

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

Adjuvant palbociclib (if palbociclib given neoadjuvant)

Intervention Type: DRUG

Adjuvant Epirubicin+ Cyclophosphamide

Intervention Type: DRUG

B

ER/PGR\>50% TP53 mutated

Group Type: EXPERIMENTAL

Neoadjuvant docetaxel + cyclophosphamide

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

C

ER/PGR\<50% TP53 wt

Group Type: EXPERIMENTAL

Neoadjuvant docetaxel

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

D

ER/PGR\<50% TP53 mutated

Group Type: EXPERIMENTAL

Neoadjuvant docetaxel + cyclophosphamide

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

E

HER2+ TP53 wt

Group Type: EXPERIMENTAL

Neoadjuvant docetaxel + trastuzumab + pertuzumab

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant trastuzumab

Intervention Type: DRUG

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

F

HER2+ TP53 mutated

Group Type: EXPERIMENTAL

Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant trastuzumab

Intervention Type: DRUG

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

G

Triple negative breast cancer TP53 wt

Group Type: EXPERIMENTAL

Neoadjuvant olaparib

Intervention Type: DRUG

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

H

Triple negative breast cancer TP53 mutated

Group Type: EXPERIMENTAL

Neoadjuvant olaparib

Intervention Type: DRUG

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

Intervention Type: PROCEDURE

After response to neoadjuvant treatment

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Interventions

Neoadjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

Neoadjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

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

Intervention Type: DRUG

Neoadjuvant docetaxel + cyclophosphamide

Intervention Type: DRUG

Neoadjuvant docetaxel

Intervention Type: DRUG

Neoadjuvant docetaxel + trastuzumab + pertuzumab

Intervention Type: DRUG

Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab

Intervention Type: DRUG

Neoadjuvant olaparib

Intervention Type: DRUG

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone)

Intervention Type: DRUG

Breast conserving surgery or mastectomy + SNB/axillary dissection

After response to neoadjuvant treatment

Intervention Type: PROCEDURE

Postoperative radiotherapy breast/chest wall + regional lymph nodes

Intervention Type: RADIATION

Adjuvant trastuzumab

Intervention Type: DRUG

Adjuvant letrozole (postmenopausal women)

Intervention Type: DRUG

Adjuvant tamoxifen + goserelin (premenopausal women)

Intervention Type: DRUG

Adjuvant palbociclib (if palbociclib given neoadjuvant)

Intervention Type: DRUG

Adjuvant Epirubicin+ Cyclophosphamide

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Helse Vest

OTHER

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Haukeland University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hans Petter Eikesdal, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Consultant oncologist

Locations

Akershus University Hospital

Lørenskog, Akershus, Norway

Haukeland University Hospital

Bergen, Hordaland, Norway

Helse Fonna

Haugesund, Rogaland, Norway

Helse Stavanger

Stavanger, Rogaland, Norway

Helse Førde

Førde, Sogn Og Fjordande, Norway

St. Olavs Hospital

Trondheim, Sør Trøndelag, Norway

Helse Nord/UNN

Tromsø, Troms, Norway

Countries

Norway

References

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.

Reference Type: RESULT

PMID: 33242536 (View on PubMed)

Yndestad S, Engebrethsen C, Herencia-Ropero A, Nikolaienko O, Vintermyr OK, Lillestol RK, Minsaas L, Leirvaag B, Iversen GT, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Aase HS, Aas T, Gudlaugsson EG, Llop-Guevara A, Serra V, Janssen EAM, Lonning PE, Knappskog S, Eikesdal HP. Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. JCO Precis Oncol. 2023 Sep;7:e2300338. doi: 10.1200/PO.23.00338.

Reference Type: DERIVED

PMID: 38039432 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36223740 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36048535 (View on PubMed)

Other Identifiers

2015/8463

Identifier Type: -

Identifier Source: org_study_id