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

NCT02624973 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 2015/8463
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 7

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

Keywords

neoadjuvant treatment; personalized medicine

Outcome Measures

Primary Outcomes (1)

• 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

  Ten years

Secondary Outcomes (7)

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

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

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

  Four years

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

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

• 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

  Ten years

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

  Four years

Study Arms (8)

A

EXPERIMENTAL

ER/PGR\>50% TP53 wt

Drug: Neoadjuvant tamoxifen + goserelin (premenopausal women); Drug: Neoadjuvant letrozole (postmenopausal women); Drug: Neoadjuvant endocrine therapy + palbociclib (if lack of response to endocrine therapy alone); Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women); Drug: Adjuvant palbociclib (if palbociclib given neoadjuvant); Drug: Adjuvant Epirubicin+ Cyclophosphamide

B

EXPERIMENTAL

ER/PGR\>50% TP53 mutated

Drug: Neoadjuvant docetaxel + cyclophosphamide; Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women)

C

EXPERIMENTAL

ER/PGR\<50% TP53 wt

Drug: Neoadjuvant docetaxel; Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women)

D

EXPERIMENTAL

ER/PGR\<50% TP53 mutated

Drug: Neoadjuvant docetaxel + cyclophosphamide; Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women)

E

EXPERIMENTAL

HER2+ TP53 wt

Drug: Neoadjuvant docetaxel + trastuzumab + pertuzumab; Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant trastuzumab; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women)

F

EXPERIMENTAL

HER2+ TP53 mutated

Drug: Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab; Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes; Drug: Adjuvant trastuzumab; Drug: Adjuvant letrozole (postmenopausal women); Drug: Adjuvant tamoxifen + goserelin (premenopausal women)

G

EXPERIMENTAL

Triple negative breast cancer TP53 wt

Drug: Neoadjuvant olaparib; Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone); Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes

H

EXPERIMENTAL

Triple negative breast cancer TP53 mutated

Drug: Neoadjuvant olaparib; Drug: Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone); Procedure: Breast conserving surgery or mastectomy + SNB/axillary dissection; Radiation: Postoperative radiotherapy breast/chest wall + regional lymph nodes

Interventions

Neoadjuvant tamoxifen + goserelin (premenopausal women) DRUG

A

Neoadjuvant letrozole (postmenopausal women) DRUG

A

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

A

Neoadjuvant docetaxel + cyclophosphamide DRUG

B; D

Neoadjuvant docetaxel DRUG

C

Neoadjuvant docetaxel + trastuzumab + pertuzumab DRUG

E

Neoadjuvant docetaxel + cyclophosphamide + trastuzumab + pertuzumab DRUG

F

Neoadjuvant olaparib DRUG

G; H

Neoadjuvant cyclophosphamide (after 10 weeks of olaparib alone) DRUG

G; H

Breast conserving surgery or mastectomy + SNB/axillary dissection PROCEDURE

After response to neoadjuvant treatment

A; B; C; D; E; F; G; H

Postoperative radiotherapy breast/chest wall + regional lymph nodes RADIATION

A; B; C; D; E; F; G; H

Adjuvant trastuzumab DRUG

E; F

Adjuvant letrozole (postmenopausal women) DRUG

A; B; C; D; E; F

Adjuvant tamoxifen + goserelin (premenopausal women) DRUG

A; B; C; D; E; F

Adjuvant palbociclib (if palbociclib given neoadjuvant) DRUG

A

Adjuvant Epirubicin+ Cyclophosphamide DRUG

A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Haukeland University Hospital: lead
• Helse Vest: collaborator
• Pfizer: collaborator
• AstraZeneca: collaborator

Study Sites (7)

Akershus University Hospital

Lørenskog, Akershus, Norway

Location

Haukeland University Hospital

Bergen, Hordaland, 5021, Norway

Location

Helse Fonna

Haugesund, Rogaland, Norway

Location

Helse Stavanger

Stavanger, Rogaland, Norway

Location

Helse Førde

Førde, Sogn Og Fjordande, Norway

Location

St. Olavs Hospital

Trondheim, Sør Trøndelag, Norway

Location

Helse Nord/UNN

Tromsø, Troms, Norway

Location

Related Publications (4)

• 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.

  PMID: 33242536 RESULT

• 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.

  PMID: 38039432 DERIVED

• 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.

  PMID: 36223740 DERIVED

• 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.

  PMID: 36048535 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Goserelin; palbociclib; Cyclophosphamide; Trastuzumab; pertuzumab; olaparib; Mastectomy, Segmental; Mastectomy

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Surgical Procedures, Operative

Study Officials

• Hans Petter Eikesdal, MD PhD

  Consultant oncologist

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2015
• First Posted: December 9, 2015
• Study Start: April 15, 2016
• Primary Completion: June 1, 2020
• Study Completion (Estimated): June 1, 2030
• Last Updated: February 12, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

NO (7)