Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC

NCT03025880 | Completed Phase 2 Results

• 2 other identifiers: GEICAM/2015-042016-001779-54
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 9

Brief Summary

Study Design and Treatment: This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically contraindicated). In hormone receptor positive patients, previous treatment with 2 or more lines of hormone therapy will also be required. Patients must have at least one measurable lesion that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on the results of the run-in-phase) will be included in this trial.

Conditions

Advanced Breast Cancer

Keywords

Advanced Breast Cancer; Pembrolizumab; HER2-negative

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle

  DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting \> 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.

  Up to cycle 1

• Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab

  The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.

  Up to cycle 1

• Objective Response Rate (ORR)

  Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions.

  Through study treatment, and average of 3 months

Secondary Outcomes (11)

• Progression-Free Survival (PFS)

  Through study treatment, and average of 3 months

• Clinical Benefit Rate (CBR)

  Through study treatment, and average of 3 months

• Clinical Benefit Rate (CBR) at Least 24 Weeks

  24 weeks

• Response Duration (RD)

  Through study treatment, and average of 3 months

• Overall Survival (OS)

  Up to 2 years

Study Arms (1)

Single arm

EXPERIMENTAL

Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.

Drug: Pembrolizumab; Drug: Gemcitabine

Interventions

Pembrolizumab DRUG

Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.

Also known as: Keytruda

Single arm

Gemcitabine DRUG

Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Also known as: Gemzar

Single arm

Eligibility Criteria

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

You may qualify if:

• The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
• Female ≥ 18 years of age on day of signing informed consent.
• Histological/cytological confirmation of breast cancer with evidence of advanced disease, not amenable to resection or radiation therapy with curative intent.
• Documented luminal A, luminal B (HER2-negative) or triple negative disease by immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on local testing on the most recent tumour biopsy defined as follows:
• Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio \< 2 or for single probe assessment a HER2 copy number \< 4) and high progesterone receptor (PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (\< 14%).
• Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio \< 2 or for single probe assessment a HER2 copy number \< 4) and either low or negative PgR (\< 20% of tumour cells with PgR expression) and/or high Ki67 (≥ 14%).
• Triple negative: tumour with negative hormone receptor status (\<1% of tumour cells with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio \< 2 or for single probe assessment a HER2 copy number \< 4).
• Have at least one unidimensionally measurable lesion by RECIST 1.1.
• Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Demonstrate adequate organ function as follows (all screening labs should be performed within 7 days of study treatment initiation):
• Bone marrow:
• Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3 (100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Hepatic:
• Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl
• Renal:

You may not qualify if:

• HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).
• Patient is currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug/medication.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or anti-PD-L2 agent.
• Has received a live vaccine within 30 days of planned start of study therapy.
• o Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
• Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and all neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug/medication.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a current or prior malignancy within the previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (9)

Institut Català d'Oncologia. Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Canary Islands, 38320, Spain

Location

Hospital Universitario Virgen de la Arrixaca

El Palmar, Murcia, 30120, Spain

Location

Clínica Universitaria de Navarra

Pamplona, Navarre, 31008, Spain

Location

Centro Oncológico de Galicia

A Coruña, 15009, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico Universitario San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario Virgen de la Macarena

Seville, 41009, Spain

Location

Hospital Clínico Universitario de Zaragoza "Lozano Blesa"

Zaragoza, 50009, Spain

Location

Related Publications (2)

• de la Cruz-Merino L, Gion M, Cruz J, Alonso-Romero JL, Quiroga V, Moreno F, Andres R, Santisteban M, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Cortes A, Henao F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Soto A, Puertes A, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study. BMC Cancer. 2022 Dec 3;22(1):1258. doi: 10.1186/s12885-022-10363-3.

  PMID: 36463104 RESULT

• de la Cruz-Merino L, Gion M, Cruz-Jurado J, Quiroga V, Andres R, Moreno F, Alonso-Romero JL, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Henao-Carrasco F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study. Cancers (Basel). 2021 Oct 29;13(21):5432. doi: 10.3390/cancers13215432.

  PMID: 34771596 RESULT

Related Links

• GEICAM is a Spanish Breast Cancer Research Group

MeSH Terms

Interventions

pembrolizumab; Gemcitabine

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Scientific Director / Medical Lead / Project Manager
• Organization: Spanish Breast Cancer Research Group

geicam@geicam.org

+34916592870

Study Officials

• Study Director

  Hospital Universitario Virgen Macarena

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

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: January 11, 2017
• First Posted: January 20, 2017
• Study Start: June 28, 2017
• Primary Completion: June 3, 2019
• Study Completion: July 22, 2021
• Last Updated: April 3, 2023
• Results First Posted: January 10, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (9)