A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)

NCT02125344 | Completed Phase 3 DMC

• 1 other identifier: GBG 84
• Study Type: interventional
• Target: 961
• Locations: 1 country
• Sites: 1

Brief Summary

Two regimen are currently considered to have highest efficacy for patients with high-risk early stage breast cancer: sequential treatment of high dose epirubicin, taxane, and cyclophosphamide concomitantly with a dual HER2-blockade, and weekly treatment with paclitaxel/non-pegylated liposomal doxorubicin with dual HER2-blockade or carboplatin. The aim of the GeparOcto study is to compare those two regimen/strategies. Both regimens are myelosuppressive with a significant incidence of chemotherapy induced anaemia. The second aim of the GeparOcto study is therefore to compare the use of parental ferric carboxymaltose versus physician's choice for the treatment of chemotherapy-induced anemia in patients with iron deficiency.

Conditions

Tubular Breast Cancer Stage II; Tubular Breast Cancer Stage III; Mucinous Breast Cancer Stage II; Breast Cancer Female NOS; Invasive Ductal Breast Cancer; HER2 Positive Breast Cancer; Inflammatory Breast Cancer

Outcome Measures

Primary Outcomes (2)

• pathological complete response (pCR= ypT0/is ypN0)

  To compare the pathological complete response (pCR= ypT0/is ypN0) rates of neoadjuvant treatment with sequential, dose-dense, dose-intensified ETC(+HP) vs. weekly PM(Cb)(+HP) in patients with high-risk operable or locally advanced breast cancer. Masked role for assessor.

  18 weeks (time window + 3 weeks)

• Only for those patients randomized for the supportive anemia treatment: frequency of patients reaching hemoglobin (Hb) levels ≥ 11g/dl 6 weeks after treatment start of a first episode of anemia grade ≥2

  Only for those patients randomized for the supportive anemia treatment: To compare the frequency of patients reaching hemoglobin (Hb) levels ≥ 11g/dl 6 weeks after treatment start of a first episode of anemia grade ≥2 (Hb \< 10g/dl) between patients receiving supportive treatment for iron deficiency with parental ferric carboxymaltose versus physician's choice (no supportive treatment, oral iron substitution, erythropoiesis-stimulating agent (ESA), or both).

  18 weeks (time window + 3 weeks)

Secondary Outcomes (20)

• pcR rates per arm

  18 weeks (time frame + 3 weeks)

• Clinical and imaging response

  18 weeks (time window + 3 weeks)

• Rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and the residual cancer burden (RCB) score.

  18 weeks (time frame + 3 weeks)

• Toxicity and Compliance including incidence of febrile neutropenia

  18 weeks (time frame + 3 weeks)

• Breast conservation rate

  18 weeks (time frame: + 3 weeks)

Study Arms (2)

PM(Cb)

EXPERIMENTAL

PM(Cb): paclitaxel 80mg/m² 18 times weekly simultaneously with NPLD (Myocet®)20mg/m² 18 times weekly simultaneously with carboplatin AUC 1.5 18 times weekly (only in patients with TNBC) Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all cycles.

Drug: non-pegylated liposomal doxorubicin; Drug: Carboplatin; Drug: Paclitaxel; Drug: Pertuzumab; Drug: Trastuzumab; Drug: Ferric carboxymaltose

ETC

ACTIVE COMPARATOR

ETC: epirubicin 150mg/m² every 2 weeks for 3 cycles followed by paclitaxel 225 mg/m² every 2 weeks for 3 cycles followed cyclophosphamide 2000 mg/m² every 2 weeks for 3 cycles. Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all T and C cycles.

Drug: Paclitaxel; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Pertuzumab; Drug: Trastuzumab; Drug: Ferric carboxymaltose

Interventions

non-pegylated liposomal doxorubicin DRUG

20 mg/m2, i.V. 18 times weekly

Also known as: Myocet

PM(Cb)

Carboplatin DRUG

Carboplatin AUC 1.5 18 times weekly (only in patients with triple-negative breast cancer).

Also known as: Carbomedac

PM(Cb)

Paclitaxel DRUG

paclitaxel 80mg/m² 18 times weekly

Also known as: var.

ETC; PM(Cb)

Epirubicin DRUG

150mg/m² every 2 weeks for 3 cycles.

Also known as: Farmorubicin

ETC

Cyclophosphamide DRUG

2000 mg/m² every 2 weeks for 3 cycles.

Also known as: Endoxan

ETC

Pertuzumab DRUG

420 (840) mg every 3 weeks simultaneously to all T and C cycles in the ETC arm and to all cycles in the PM(Cb) arm.

Also known as: Perjeta

ETC; PM(Cb)

Trastuzumab DRUG

Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all T and C cycles in the ETC arm and to all cycles in the PM(Cb) arm.

Also known as: Herceptin

ETC; PM(Cb)

Ferric carboxymaltose DRUG

after first anemia grade ≥2 and in case of randomisation: Ferric carboxymaltose i.V. 1000 mg followed 1 week later by an injection of ferric carboxymaltose i.V. 500 mg (if body weight is \<70 kg) or 1000 mg (if body weight is ≥70 kg). In case body weight is \<50 kg, both dosages will be reduced to 500 mg each.

Also known as: Ferinject

ETC; PM(Cb)

Eligibility Criteria

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

You may qualify if:

• Patients will be eligible for study participation only if they comply with the following criteria:
• Written informed consent according to local regulatory requirements prior to beginning specific protocol procedures.
• Complete baseline documentation must be submitted via MedCODES to GBG Forschungs GmbH.
• Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration from the breast lesion alone is not sufficient. Incisional biopsy or axillary clearance is not allowed.
• In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
• Tumor lesion in the breast with a palpable size of 2 cm or a sonographical size of 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
• Patients must have stage cT1c - cT4a-d disease. Patients with HER2- positive or TNBC are eligible irrespective of nodal status (cN0-cN3). Patients with luminal B-like tumors (defined here as ER and/or PgR \>1% stained cells, HER2 negative, Ki-67 \>20%) only with histologically (sentinel-node biopsy, core- or fine-needle biopsy) involved lymph nodes (pN1-3).
• In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
• Centrally confirmed ER, PR and HER2 status. Central pathology includes also assessment of Ki-67 and LPBC status on core biopsy. ER/PR negative is defined as \<=1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridization (ISH) and according to ASCO-CAP guidelines as of 2013). Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization.
• Age \>=18 years.
• Karnofsky Performance status index 90%.
• Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 4 weeks prior to randomization. LVEF must be above 55%.
• Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
• Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (21 days), breast MRI (optional). Chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan in case of high risk for primary metastasis. In case of a positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
• Patients must agree with central pathology testing of core biopsy specimen and final pathology specimen and be available and compliant for treatment and follow-up.

You may not qualify if:

• Patients with ER- and/or PR-positive, HER2-negative breast cancer and Ki- 67 \<= 20% (any luminal A-like subtype) or luminal B-like (Ki67\>20%) subtype without nodal involvement.
• Patients with stages cT1a, cT1b, or any M1.
• Patients with pure lobular invasive breast cancer.
• Prior chemotherapy for any malignancy.
• Prior radiation therapy for breast cancer.
• Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
• Inadequate general condition (not fit for dose-dense, dose-intensified anthracycline-taxane-targeted agents-based chemotherapy).
• Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
• Known or suspected congestive heart failure (\>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \>140/90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
• History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
• Pre-existing motor or sensory neuropathy of a severity grade 2 by NCI-CTC criteria v 4.0.
• Currently active infection.
• Incomplete wound healing.
• Definite contraindications for the use of corticosteroids.
• Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• Amgen: collaborator
• Roche Pharma AG: collaborator
• Teva Pharmaceuticals USA: collaborator
• Vifor Pharma: collaborator

Study Sites (1)

NTC

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Related Publications (5)

• Schneeweiss A, Michel LL, Mobus V, Tesch H, Klare P, Hahnen E, Denkert C, Kast K, Pohl-Rescigno E, Hanusch C, Link T, Untch M, Jackisch C, Blohmer JU, Fasching PA, Solbach C, Schmutzler RK, Huober J, Rhiem K, Nekljudova V, Lubbe K, Loibl S; GBG and AGO-B. Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer. Eur J Cancer. 2022 Jan;160:100-111. doi: 10.1016/j.ejca.2021.10.011. Epub 2021 Nov 17.

  PMID: 34801353 DERIVED

• Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, Wimberger P, Forberger A, Tesch H, Jackisch C, Schmatloch S, Reinisch M, Solomayer EF, Schmitt WD, Hanusch C, Fasching PA, Lubbe K, Solbach C, Huober J, Rhiem K, Marme F, Reimer T, Schmidt M, Sinn BV, Janni W, Stickeler E, Michel L, Stotzer O, Hahnen E, Furlanetto J, Seiler S, Nekljudova V, Untch M, Loibl S. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021 Aug;22(8):1151-1161. doi: 10.1016/S1470-2045(21)00301-6. Epub 2021 Jul 9.

  PMID: 34252375 DERIVED

• Ruger AM, Schneeweiss A, Seiler S, Tesch H, van Mackelenbergh M, Marme F, Lubbe K, Sinn B, Karn T, Stickeler E, Muller V, Schem C, Denkert C, Fasching PA, Nekljudova V, Garfias-Macedo T, Hasenfuss G, Haverkamp W, Loibl S, von Haehling S. Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial. J Am Heart Assoc. 2020 Dec;9(23):e018143. doi: 10.1161/JAHA.120.018143. Epub 2020 Nov 16.

  PMID: 33191846 DERIVED

• Pohl-Rescigno E, Hauke J, Loibl S, Mobus V, Denkert C, Fasching PA, Kayali M, Ernst C, Weber-Lassalle N, Hanusch C, Tesch H, Muller V, Altmuller J, Thiele H, Untch M, Lubbe K, Nurnberg P, Rhiem K, Furlanetto J, Lederer B, Jackisch C, Nekljudova V, Schmutzler RK, Schneeweiss A, Hahnen E. Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):744-748. doi: 10.1001/jamaoncol.2020.0007.

  PMID: 32163106 DERIVED

• Schneeweiss A, Mobus V, Tesch H, Hanusch C, Denkert C, Lubbe K, Huober J, Klare P, Kummel S, Untch M, Kast K, Jackisch C, Thomalla J, Ingold-Heppner B, Blohmer JU, Rezai M, Frank M, Engels K, Rhiem K, Fasching PA, Nekljudova V, von Minckwitz G, Loibl S. Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial. Eur J Cancer. 2019 Jan;106:181-192. doi: 10.1016/j.ejca.2018.10.015. Epub 2018 Dec 5.

  PMID: 30528802 DERIVED

MeSH Terms

Conditions

Carcinoma, Ductal, Breast; Inflammatory Breast Neoplasms

Interventions

Doxorubicin; Carboplatin; Paclitaxel; Epirubicin; Cyclophosphamide; pertuzumab; Trastuzumab; ferric carboxymaltose

Condition Hierarchy (Ancestors)

Carcinoma, Ductal; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Coordination Complexes; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Andreas Schneeweiss, MD, Prof.

  NTC Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2014
• First Posted: April 29, 2014
• Study Start: December 1, 2014
• Primary Completion: November 1, 2016
• Study Completion: January 30, 2017
• Last Updated: July 13, 2017

Record last verified: 2017-07

Locations

DE (1)