Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer

NCT02129556 | Completed Phase 1 Results DMC

• 2 other identifiers: IBCSG 45-13 / BIG 4-132013-004770-10
• Study Type: interventional
• Target: 58
• Locations: 4 countries
• Sites: 10

Brief Summary

Panacea is a phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients with trastuzumab-resistant, HER2- positive metastatic breast cancers

Conditions

Metastatic Breast Cancer

Keywords

Metastatic; Breast; trastuzumab-resistant; PD-L1 expressing; HER2-positive

Outcome Measures

Primary Outcomes (2)

• Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab

  Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0). 1. Any grade-3 or greater non-hematological adverse event lasting at least one week; 2. Any grade-4 hematological toxicity; or, 3. Any adverse event resulting in a delay starting cycle 2 of more than 14 days.

  Within the first 21 days

• Objective Response Rate (ORR)

  Confirmed CR or PR as best overall response. At the time of each restaging, patients will be classified as achieving complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.

  Clinical and radiological tumor assessment will be performed by CT scan or MRI at baseline, at weeks 12, 18 and 24, then every 12 weeks until progression, or 24 weeks after stop of treatment if before progression.

Secondary Outcomes (5)

• Duration of Response (DoR)

  From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months)

• Time to Progression (TTP)

  From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months)

• Disease Control Rate (DCR)

  From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer

• Progression-Free Survival (PFS)

  From the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months

• Overall Survival (OS) at 12 Months

  Time from start of trial treatment to death from any cause, assessed up to 30 months

Study Arms (1)

MK-3475 with trastuzumab (single arm)

EXPERIMENTAL

Phase Ib: MK-3475 at dose of 2 mg/kg or 10 mg/kg (i.v.), or a fall-back dose of 1 mg/kg, together with trastuzumab 6mg/kg by (i.v.) once every 3 weeks. Phase II: MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment. A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.

Drug: MK-3475

Interventions

MK-3475 DRUG

The phase Ib trial will determine the recommended dose from three MK-3475 dose levels: 1mg/kg, 2 mg/kg or 10 mg/kg.

Also known as: Pembrolizumab

MK-3475 with trastuzumab (single arm)

Eligibility Criteria

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

You may qualify if:

• Female gender
• Age ≥ 18 years
• Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, or metastatic.
• Locally confirmed HER2-positivity (immunohistochemistry score 3+) or ERBB2-amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6) of primary tumor or of biopsy from metastatic or unresectable loco-regional lesion.
• Trastuzumab resistant disease, defined by:
• progression of disease while on-treatment with trastuzumab
• recurrence while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab
• Any number of prior lines of anti-HER2 therapy acceptable. Patients for whom the treatment with the current first-line combination of trastuzumab, pertuzumab and taxanes is not an option can be considered for enrollment
• If a patient has received a subsequent anti-HER2 therapy, she must also have progressed on the subsequent therapy.
• Presence of at least one measurable lesion (RECIST 1.1)
• LVEF ≥50%
• Patient agrees to submit an FFPE tumor biopsy for central confirmation of HER2 positivity and central assessment of PD-L1 status.
• Written Informed Consent (IC) for screening procedures and trial participation must be signed and dated by the patient and the Investigator prior to screening.
• Written consent to biological material submission, indicating the patient has been informed of and agrees to tissue and blood material use, transfer and handling, must be signed and dated by the patient and the investigator prior to any procedures specific for this trial, including consent to translational research on FFPE and fresh frozen tumor biopsies in case the patient is enrolled into the trial.
• The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.

You may not qualify if:

• Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy.
• No FFPE material to centrally assess HER2-positivity and PD-L1 expression.
• Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA \[qualitative\]).
• Interstitial lung disease
• History of or active pneumonitis requiring treatment with steroids
• Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of CNS metastases or spinal cord compression are eligible if they are clinically and radiologically stable for at least 4 weeks before first dose of investigational product and have not required high-dose steroid treatment in the last 4 weeks).
• Leptomeningeal disease
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification ≥3), angina, myocardial infarction or ventricular arrhythmia.
• Previous severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Active infection requiring systemic therapy.
• Chronic systemic therapy with immunosuppressive agents including cortico¬steroids.
• Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety.
• Known history of uncontrolled hypertension (≥ 180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen.
• Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent.
• Treatment with an investigational agent in the 4 weeks before enrollment.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• Breast International Group: collaborator

Study Sites (11)

Peter MacCallum Cancer Centre

East Melbourne, Australia

Location

Westmead Hospital

Westmead, Australia

Location

Medical University of Vienna

Vienna, 1090, Austria

Location

Jules Bordet Institute

Brussels, 1000, Belgium

Location

CHU Sart Tilman

Liège, 4000, Belgium

Location

Institut de Cacérologie de l'OUEST

Angers, France

Location

Institut Bergonie

Bordeaux, France

Location

Centre Leon Berard

Lyon, 69008, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Istituto Europeo di Oncologia

Milan, 435, Italy

Location

Azienda USL4 Prato

Prato, 59100, Italy

Location

Related Publications (5)

• Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. doi: 10.1056/NEJM200103153441101.

  PMID: 11248153 BACKGROUND

• Hurvitz SA, Betting DJ, Stern HM, Quinaux E, Stinson J, Seshagiri S, Zhao Y, Buyse M, Mackey J, Driga A, Damaraju S, Sliwkowski MX, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Marathe O, Slamon DJ, Timmerman JM. Analysis of Fcgamma receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res. 2012 Jun 15;18(12):3478-86. doi: 10.1158/1078-0432.CCR-11-2294. Epub 2012 Apr 13.

  PMID: 22504044 BACKGROUND

• Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1;28(1):105-13. doi: 10.1200/JCO.2009.23.7370. Epub 2009 Nov 16.

  PMID: 19917869 BACKGROUND

• Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860-7. doi: 10.1200/JCO.2011.41.0902. Epub 2013 Jan 22.

  PMID: 23341518 BACKGROUND

• Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F; International Breast Cancer Study Group and the Breast International Group. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. Epub 2019 Feb 11.

  PMID: 30765258 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Heidi Roschitzki-Voser
• Organization: International Breast Cancer Study Group (IBCSG)

heidi.roschitzki@ibcsg.org

+41 31 511 94 18

Study Officials

• Sherene Loi, MD

  Department of Medical Oncology,Peter MacCallum Cancer Centre,East Melbourne, Victoria, Australia

  STUDY CHAIR

• Fabrice André, Prof.

  Department of Medical Oncology Institut Gustave Roussy,Villejuif,France

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2014
• First Posted: May 2, 2014
• Study Start: December 1, 2014
• Primary Completion: August 4, 2017
• Study Completion: August 4, 2017
• Last Updated: February 15, 2019
• Results First Posted: February 15, 2019

Record last verified: 2018-09

Locations

AU (2); BE (2); IT (2); FR (4)