Neoadjuvant Pembrolizumab(Pbr)/Nab-Paclitaxel Followed by Pbr/Epirubicin/Cyclophosphamide in TNBC

NCT03289819 | Completed Phase 2 DMC FDA Drug

• 3 other identifiers: IFG-NIB-012016-003102-14U1111-1188-3915
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 4

Brief Summary

Despite its aggressiveness and high incidence, to date, no targeted therapies exist for the treatment of triple negative breast cancer (TNBC). Emerging evidence suggests a crucial role of tumor immunology on outcome for this entity. Checkpoint inhibitors like pembrolizumab, which target immune cells within the tumor, might therefore have an important impact on therapy response and outcome in these high risk patients. We propose a phase II study exploring pathological complete response and the safety of the combination of pembrolizumab and nab-paclitaxel as well as the combination of pembrolizumab with epirubicin and cyclophosphamide in the neoadjuvant setting for women with early TNBC. After completion of this study an extension will be determined.

Conditions

Malignant Neoplasm of Breast

Keywords

TNBC; neoadjuvant chemotherapy; triple negative breast cancer

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response (pCR) rate

  Pathological complete response (pCR) rate, defined as the complete absence of all tumor cells (ypT0/ypN0), absence of invasive tumor (ypT0/is ypN0) and regression grades after study treatment. Pathological complete response is the primary endpoint of this trial and correlates especially well with disease-free survival and overall survival in patients with TNBC. Pathological complete response also serves as a surrogate marker for prognosis in TNBC

  Pathological complete response will be assessed at final surgery for patients who received at least two cycles of Pembrolizumab. The rate will be assessed from 30 days until 120 days after last application of medication.

Secondary Outcomes (4)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  The adverse events will be assessed from first infusion until 120 days after last application of medication.

• Clinical Response

  Every 6 weeks from date of first medication administration until the date of first documented progression, surgery or date of death from any cause, whichever came first, assessed up to 120 days after last dose.

• EORTC QLQ-BR23

  Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.

• EORTC QLQ-C30

  Every two weeks from first administration of trial medication through study completion, up to 120 days after administration of last medication.

Other Outcomes (11)

• Tumor infiltrating lymphocytes (TILs)

  Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.

• Immunohistochemistry

  Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.

• Tumor Immunogenicity

  Measured from biomaterial collected at baseline, 12 weeks after treatment initiation and at surgery.

Study Arms (1)

Pembrolizumab/Nab-Paclitaxel

EXPERIMENTAL

This is a phase II, one-arm, open label neoadjuvant study of pembrolizumab in combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and cyclophosphamide in patients with triple negative breast cancer. All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w. After the 25th patient has started trial treatment, all further included patients will receive 1 additional cycle of pembrolizumab i.v. 200 mg q3w monotherapy before starting regular trial treatment. Clinical and bioptic tumor assessment will be performed after each treatment phase. Study treatment will be applied until state of the art surgery, onset of unacceptable toxicities, progression or withdrawal of consent.

Drug: Pembrolizumab; Drug: nab-paclitaxel; Drug: Epirubicin; Drug: Cyclophosphamide

Interventions

Pembrolizumab DRUG

All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w. After the 25th patient has started trial treatment, all further included patients will receive 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy followed by 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w.

Also known as: Keytruda, MK-3475

Pembrolizumab/Nab-Paclitaxel

nab-paclitaxel DRUG

All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.

Also known as: nano-particle albumin bound (NAB) paclitaxel, Abraxane

Pembrolizumab/Nab-Paclitaxel

Epirubicin DRUG

All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.

Pembrolizumab/Nab-Paclitaxel

Cyclophosphamide DRUG

All patients will receive 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA, q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg/kg q3w.

Pembrolizumab/Nab-Paclitaxel

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 prior to beginning of trial specific procedures.
• Subject must be female and aged ≥ 18 years on day of signing informed consent.
• ECOG(Eastern Cooperative Oncology Group) 0-1
• Histologically confirmed, early TNBC determined by core biopsy of breast tumor lesion. ER and PR negativity are defined as ≤ 1% of cells expressing hormonal receptors via IHC (immuno-histochemistry) analysis. HER2(human epidermal growth factor receptor 2) negativity is defined as either of the following by local laboratory assessment: In situ hybridization (ISH) non-amplified (ratio ≤ 2.2), or IHC 0 or IHC 1+.
• Measurable tumor lesion with a size of ≥ 1 cm assessed by sonography or magnetic resonance imaging (MRI) within ≤ 21 days prior to entry. In case of inflammatory disease the extent of inflammation will be measured.
• Indication for chemotherapy.
• Complete staging work up within 8 weeks prior to entry with no evidence of distant disease, including bilateral mammography, breast ultrasound, chest-X-ray (or chest CT-scan), liver ultrasound (or liver CT-scan or liver MRI) and bone scan.
• Subjects must provide a core biopsy from tumor lesion at 3 time points (before, after first phase of treatment and at surgery) for central confirmation of TNBC status and biomarker analyses.
• Adequate organ function, defined as:
• Absolute neutrophil count (ANC)≥ 1.5 x10³/μl, Hemoglobin ≥ 10.0 g/dl OR ≥ 6.2 mmol/l, Platelets ≥ 100 x10³/μl, Creatinine ≤ 1.5 x ULN OR GFR ≥ 30 ml/min, Total bilirubin ≤ 1.5 x ULN, AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN, Alkaline phosphatase ≤ 2.5 x ULN, International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN, Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN,
• Female subjects of childbearing potential must have a negative urine pregnancy test within 72 hours prior to study entry and be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

You may not qualify if:

• Concurrent participation in a study with an investigational agent/device or within 14 days of study entry.
• Prior chemotherapy, radiation therapy or small molecule therapy for any reason.
• Previous malignant disease being disease-free for less than 3 years (except in situ carcinoma of the cervix and basal cell carcinoma of the skin).
• Pregnancy or lactation.
• Prior therapy with an anti-PD1, anti-PD L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
• Active infection requiring systemic therapy.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Active autoimmune disease or other diseases that requires systemic treatment with corticosteroids or immunosuppressive drugs (physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency is allowed).
• History of primary or acquired immunodeficiency (including allogenic organ transplant).
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• Known history of following infections:
• Human immunodeficiency virus (HIV)
• History of acute or chronic Hepatitis B or Hepatitis C
• Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted
• Known congestive heart failure \>NYHA I (New York Heart Association) and/or coronary heart disease, angina pectoris, previous history of myocardial infarction, uncontrolled or poorly controlled arterial hypertension (e.g. blood pressure \>160/90 mmHg under treatment with two or more antihypertensive drugs), rhythm disorders with clinically significant valvular heart disease.

Sponsors & Collaborators

• Institut fuer Frauengesundheit: lead
• Merck Sharp & Dohme LLC: collaborator
• Celgene Corporation: collaborator

Study Sites (4)

Department of Gynecology, Tübingen University Hospital

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Department of Gynecology and Obstetrics, Erlangen University Hospital

Erlangen, Bavaria, 91054, Germany

Location

Department for Gynecology and Obstetrics, Marienhospital Bottrop gGmbH

Bottrop, North Rhine-Westphalia, 46236, Germany

Location

Department of Gynecology and Obstetrics, HELIOS Hospital Berlin Buch GmbH

Berlin, 13125, Germany

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

pembrolizumab; 130-nm albumin-bound paclitaxel; Paclitaxel; Albumin-Bound Paclitaxel; Epirubicin; Cyclophosphamide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Peter A Fasching, MD, Prof.

  Department of Gynecology and Obstetrics, Erlangen University Hospital

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: October 11, 2016
• First Posted: September 21, 2017
• Study Start: March 23, 2018
• Primary Completion: August 27, 2020
• Study Completion: January 22, 2021
• Last Updated: April 8, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (4)