Assessing the Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel / Carboplatin Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With HER2-negative Early Breast Cancer and Homologous Recombination Deficiency

NCT02789332 | Completed Phase 2 DMC

• 1 other identifier: GBG90
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 12

Brief Summary

This is a multicenter, prospective, randomized, open-label phase II study evaluating the efficacy and safety of PO→EC as neoadjuvant treatment of operable and locally advanced breast cancer in patients with HR deficiency. Patients will be randomized to receive

• paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks (65 patients) or
• paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) both followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery. The control arm was chosen to allow direct comparison with one of the currently considered standard of care regimen.

Conditions

Breast Cancer; Triple Negative Breast Neoplasms; HRpos Breast Neoplasms; BRCA 1 /2 and / or HRD

Keywords

carboplatin; olaparib; pCR; neoadjuvant; triple-negative; hormonreceptor-positive; BRCA1/2; HRD, homologous recominant deficient; breast cancer; genetic testing (somatic and germline mutations)

Outcome Measures

Primary Outcomes (1)

• response by pCR =ypT0/is ypN0

  Assess the efficacy of olaparib in HER2-negative early Breast Cancer and HRD (BRCA 1/2 mutations and/or HRD positive). Pathological complete response of breast and lymph nodes (ypT0/is ypN0) defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.

  24 weeks

Secondary Outcomes (8)

• response by pCR =ypT0/is ypN0

  12 weeks

• response by pCR =ypT0/is ypN0 in stratified subgroups

  24 weeks

• response by pCR according to other definitions

  24 weeks

• response by pCR in HRD high versus tBRCA

  24 weeks

• Response rate by sono and/or mammo

  12 weeks

Other Outcomes (1)

• Potential biomarkers predicting safety and compliance, like SNPs, TILs, PARP, 53BP1, REV7 and other biomarkers considered for breast cancer

  24 weeks

Study Arms (2)

Paclitaxel with Carboplatin (PwCb)

ACTIVE COMPARATOR

paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.

Drug: PwCb; Drug: EC; Procedure: Surgery after neoadjuvant Therapy; Other: Stratification

Paclitaxel with Olaparib (PwO)

EXPERIMENTAL

paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (65 patients) followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.

Drug: PwO; Drug: EC; Procedure: Surgery after neoadjuvant Therapy; Other: Stratification

Interventions

PwO DRUG

paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (PwO) (65 patients)

Also known as: Paclitaxel Olaparib over 12 weeks

Paclitaxel with Olaparib (PwO)

PwCb DRUG

paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (PwCb) (37 patients)

Also known as: Paclitaxel Carboplatin over 12 weeks, Control arm currently considered standard of care regimen

Paclitaxel with Carboplatin (PwCb)

EC DRUG

both Arms followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.

Also known as: Epirubicin 90 mg/m² and Cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks

Paclitaxel with Carboplatin (PwCb); Paclitaxel with Olaparib (PwO)

Surgery after neoadjuvant Therapy PROCEDURE

In both study arms, treatment will be given until surgery, disease progression, unacceptable toxicity, or withdrawal of consent of the patients.

Paclitaxel with Carboplatin (PwCb); Paclitaxel with Olaparib (PwO)

Stratification OTHER

Hormone-receptor status (HR+ vs HR-) Age \< 40 years vs \>= 40 years

Also known as: Randomization will be performed using Pocock minimization method, stratified for the following criteria:

Paclitaxel with Carboplatin (PwCb); Paclitaxel with Olaparib (PwO)

Eligibility Criteria

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

You may qualify if:

• Written informed consent for all study specific procedures according to local regulatory requirements prior to beginning specific protocol procedures.
• Complete baseline documentation must be sent to GBG Forschungs GmbH.
• Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
• Centrally confirmed negative HER2-status. Centrally confirmed estrogen and progesterone receptor, and Ki-67 status detected on core biopsy. ER/PR positive is defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridisation (ISH) ratio ≥2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
• Centrally confirmed tumor Homologous Recombinant Deficiency score (tBRCA positive/mutated and/or HRD high). Patients with known gBRCA and/or tBRCA status can be enrolled prior to the central test results available.
• Tumor lesion in the breast with a palpable size of \> 2 cm or a sonographical size of \>1 cm in maximum diameter. If the tumor is not detectable with sonography mammography assessment can be considered. 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 be in the following stages of disease:
• cT2 - cT4a-d or
• cT1c and cN+ or cT1c and pNSLN+ or
• cT1c and ER-neg and PR-neg or
• cT1c and Ki67\>20% In patients with multifocal or multicentric breast cancer, the largest lesion should be measured and at least one lesion has to meet the above criteria
• Age \> 18 years.
• Karnofsky Performance status index ≥ 80%.
• Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution.
• Laboratory requirements:

You may not qualify if:

• Prior chemotherapy for any malignancy within 5 years.
• Prior radiation therapy for breast cancer within 5 years.
• 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 anthracycline-taxane-targeted agents-based chemotherapy).
• Previous malignant disease without 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.
• Patients currently in an institution by order of jurisdictional or governmental grounds.
• Currently active infection.
• Definite contraindications for the use of corticosteroids.
• Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
• Concurrent treatment with:
• chronic corticosteroids unless initiated \> 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).
• sex hormones. Prior treatment must be stopped before study entry.
• other experimental drugs or any other anti-cancer therapy.

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• AstraZeneca: collaborator

Study Sites (12)

Kliniken Esslingen, Gynäkologie Onkologie

Esslingen am Neckar, Baden-Wurttemberg, 73730, Germany

Location

Universitätsklinikum Erlangen

Erlangen, Bavaria, 91054, Germany

Location

Onkologisches Zentrum am Rotkreuzklinikum München

München, Bavaria, 80638, Germany

Location

Elisabeth Krankenhaus

Kassel, Hesse, 34117, Germany

Location

Sana Klinikum Hameln-Pyrmont

Hamelin, Lower Saxony, 31785, Germany

Location

Gemeinschaftspraxis

Hildesheim, Lower Saxony, 31134, Germany

Location

Klinikum Südstadt

Rostock, Mecklenburg-Vorpommern, 18059, Germany

Location

Marienhospital Witten

Witten, North Rhine-Westphalia, 58452, Germany

Location

Martin-Luther-Universität Halle Wittenberg

Halle, Saxony-Anhalt, 06120, Germany

Location

Johanniter-Krankenhaus Genthin-Stendal

Stendal, Saxony-Anhalt, 39576, Germany

Location

SRH Wald-Klinikum Gera GmbH

Gera, Thuringia, 07548, Germany

Location

Praxisklinik

Berlin, 10367, Germany

Location

Related Publications (6)

• Von Minckwitz G, Timms K, Untch M, Elkin E P, Fasching P A, Schneeweiss A et al. Prediction of pathological complete response (pCR) by Homologous Recombination Deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC: Results from GeparSixto. J Clin Oncol 33, 2015 (suppl; abstr 1004)

  BACKGROUND

• Tutt A, Ellis P, Kilburn L et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. SABCS 2014.

  BACKGROUND

• Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. doi: 10.1200/JCO.2014.57.0572. Epub 2014 Aug 4.

  PMID: 25092775 BACKGROUND

• von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, Zahm DM, Kummel S, Eidtmann H, Klare P, Huober J, Costa S, Tesch H, Hanusch C, Hilfrich J, Khandan F, Fasching PA, Sinn BV, Engels K, Mehta K, Nekljudova V, Untch M. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014 Jun;15(7):747-56. doi: 10.1016/S1470-2045(14)70160-3. Epub 2014 Apr 30.

  PMID: 24794243 BACKGROUND

• DOI: 10.1200/JCO.2019.37.15_suppl.506 Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 506-506. Fasching PA, Jackisch J, Rhiem K et al. GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD). J Clin Oncol 2019; 37.15_suppl.506; oral presentation

  RESULT

• Fasching PA, Link T, Hauke J, Seither F, Jackisch C, Klare P, Schmatloch S, Hanusch C, Huober J, Stefek A, Seiler S, Schmitt WD, Uleer C, Doering G, Rhiem K, Schneeweiss A, Engels K, Denkert C, Schmutzler RK, Hahnen E, Untch M, Burchardi N, Blohmer JU, Loibl S; German Breast Group and Arbeitsgemeinschaft Gynakologische Onkologie Breast. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol. 2021 Jan;32(1):49-57. doi: 10.1016/j.annonc.2020.10.471. Epub 2020 Oct 21.

  PMID: 33098995 DERIVED

Related Links

• GeparOla website

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms; Kenny-Caffey syndrome, Type 1

Interventions

Epirubicin; Cyclophosphamide; Vernalization

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Plant Development; Growth and Development; Physiological Phenomena; Plant Physiological Phenomena

Study Officials

• Sibylle 0 Loibl, Prof., MD

  Sibylle Loibl, Prof., MD ASCO, ESGO, ESMO, DKG, DGGG, AGO, DGS, BIG, BCIRG, St. Gallen Faculty Member, SABCS Faculty member

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2016
• First Posted: June 3, 2016
• Study Start: September 1, 2016
• Primary Completion: February 1, 2019
• Study Completion: February 1, 2020
• Last Updated: March 17, 2020

Record last verified: 2020-03

Locations

DE (12)