Addition of PD-L1 Antibody MEDI4736 to a Taxane-anthracycline Chemotherapy in Triple Negative Breast Cancer

NCT02685059 | Completed Phase 2 DMC

• 1 other identifier: GBG89
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 1

Brief Summary

To date no targeted agents are available to treat TNBC. Therefore chemotherapy is the only treatment option. TNBC often has a high amount of tumour infiltrating lymphocytes. Stimulating the immune cells of TNBC might therefore be an option for these patients to increase the pathological complete response. pCR is highly correlated with outcome in TNBC. Therefore the addition of a checkpoint inhibitor in addition to chemotherapy might be an additional option for these patients.

Conditions

Breast Cancer

Keywords

breast cancer; Medi4736; Anti PD-L1; Nab-Paclitaxel; Placebo; triple negative

Outcome Measures

Primary Outcomes (1)

• pathological complete response (pCR= ypT0 ypN0)

  To compare the pathological complete response (pCR= ypT0 ypN0) rates of neoadjuvant treatment of sequential, nab-Paclitaxel followed by EC +/- the PD-L1 antibody MEDI4736 in patients with early triple negative breast cancer.

  22 weeks

Secondary Outcomes (10)

• pCR rates per arm

  22 weeks

• Rates of ypT0/is ypN0

  22 weeks

• Rates of ypT0/is ypN0/+

  22 weeks

• Rates of ypT(any) ypN0

  22 weeks

• Rates of ypT0 ypN0/+

  22 weeks

Study Arms (5)

MEDI4736

EXPERIMENTAL

part 1: MEDI4736 (with half dose as monotherapy for the first two weeks) part 2: MEDI4736 1.5 g total for 20 weeks

Drug: MEDI4736 (Anti PD-L1)

Placebo

PLACEBO COMPARATOR

part 1: Placebo (for the first two weeks) part 2: Placebo for 20 weeks

Drug: Placebo

Taxane

ACTIVE COMPARATOR

Nab-Paclitaxel 125 mg/m² weekly for 12 weeks

Drug: nab-Paclitaxel

Epirubicin

ACTIVE COMPARATOR

Epirubicin 90 mg/m² 2-weekly for 8 weeks

Drug: Epirubicin

Cyclophosphamide

ACTIVE COMPARATOR

Cyclophosphamide 600 mg/m² 2-weekly for 8 weeks

Drug: Cyclophosphamide

Interventions

MEDI4736 (Anti PD-L1) DRUG

MEDI4736 1.5g total i.v. every 4 weeks As monotherapy for the first two weeks (0.75g absolute) (part 1) followed by: MEDI4736 in combination with nab-paclitaxel 125 mg/m² every week for 12 weeks (part 2) followed by MEDI4736 in combination with epirubicin 90mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles (part 3).

Also known as: Antibody against cell death ligand 1 (PD-L1)

MEDI4736

Placebo DRUG

Placebo i.v. every 4 weeks As monotherapy for the first two weeks (0.75g absolute) (part 1) followed by: Placebo in combination with nab-paclitaxel 125 mg/m² every week for 12 weeks (part 2) followed by MEDI4736/Placebo in combination with epirubicin 90mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles (part 3).

Placebo

nab-Paclitaxel DRUG

nab-Paclitaxel 125 mg/m² weekly for 12 weeks

Also known as: non-solvent based taxane

Taxane

Epirubicin DRUG

Epirubicin 90 mg/m² 2-weekly for 8 weeks

Also known as: Farmorubicin

Epirubicin

Cyclophosphamide DRUG

Cyclophosphamide 600 mg/m² 2-weekly for 8 weeks

Also known as: Endoxan

Cyclophosphamide

Eligibility Criteria

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

You may qualify if:

• Written informed consent for all study 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.
• Tumor lesion in the breast or the nodes must 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: cT1b - cT4a-d irrespective of nodal involvement.
• In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
• Triple negative disease with centrally confirmed ER negative/PR negative/HER-2 negative, and centrally confirmed Ki-67 value. ER negative is defined as \<1% stained cells, PR negative is defined as \<10% stained and HER2-negative is defined as either IHC 0/1+ or IHC 2+ and in-situ hybridisation (ISH) of either ratio \<2.0 or less than 6 copies of HER2 per tumor cell. Stromal TILs will be evaluated in three groups: low immune infiltrate (0-10% stromal TILs) intermediate immune infiltrate (11-59% stromal TILs), LPBC 60-100% stromal TILs. PD-L1 status and other predefined markers will be prospectively assessed during the study. 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.
• ECOG Performance status 0-1.
• 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.
• Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: \>=60 years old and no menses for \>=1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
• Complete staging work-up within 3 months prior to randomization. All patients must have had breast imaging by breast ultrasound plus either bilateral mammography or breast MRI (one of those \<= 21 days). All patients must have had chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan (according to guidelines). In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
• Patients must be available and compliant for central diagnostics, treatment and follow-up.
• Laboratory requirements: Hematology, Hepatic function, Renal Function, Thyroid function

You may not qualify if:

• 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 at maximum two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
• Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett's Correction
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• History of primary immunodeficiency
• History of allogeneic organ transplant
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
• Known history of previous clinical diagnosis of tuberculosis
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736
• Autoimmune disease and conditions (i.e. inflammatory bowel disease)
• History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• AstraZeneca: collaborator
• Celgene: collaborator

Study Sites (1)

Centrum für Hämatologie und Onkologie am Bethanien-Krankenhaus

Frankfurt am Main, Hesse, 60389, Germany

Location

Related Publications (3)

• Massa C, Karn T, Denkert C, Schneeweiss A, Hanusch C, Blohmer JU, Zahm DM, Jackisch C, van Mackelenbergh M, Thomalla J, Marme F, Huober J, Muller V, Schem C, Mueller A, Stickeler E, Biehl K, Fasching PA, Untch M, Loibl S, Weber K, Seliger B. Differential effect on different immune subsets of neoadjuvant chemotherapy in patients with TNBC. J Immunother Cancer. 2020 Nov;8(2):e001261. doi: 10.1136/jitc-2020-001261.

  PMID: 33199511 DERIVED

• Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.

  PMID: 32450725 DERIVED

• Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, Grischke EM, Furlanetto J, Tesch H, Hanusch C, Engels K, Rezai M, Jackisch C, Schmitt WD, von Minckwitz G, Thomalla J, Kummel S, Rautenberg B, Fasching PA, Weber K, Rhiem K, Denkert C, Schneeweiss A. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019 Aug 1;30(8):1279-1288. doi: 10.1093/annonc/mdz158.

  PMID: 31095287 DERIVED

Related Links

• Sponsor study homepage

MeSH Terms

Conditions

Breast Neoplasms

Interventions

durvalumab; 130-nm albumin-bound paclitaxel; Epirubicin; Cyclophosphamide

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

Study Officials

• Sibylle Loibl, Prof. Dr.

  GBG Forschungs GmbH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2016
• First Posted: February 18, 2016
• Study Start: June 1, 2016
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2018
• Last Updated: February 15, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)