Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer (PANACEA)
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|ClinicalTrials.gov Identifier: NCT02129556|
Recruitment Status : Active, not recruiting
First Posted : May 2, 2014
Last Update Posted : December 13, 2017
A significant amount of preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immune¬therapeutic approaches. The presence of HER2-overexpression in breast cancers is associated with higher levels of proliferation, high histologic grade and higher levels of tumor infiltrating lymphocytes (TILs) compared with HER2-negative tumors. The investigators therefore hypothesize that for HER2-positive tumors, avoidance of destruction by the host immune system must be an important mechanism contributing to tumor growth and progression.
The term "immune evasion" refers to the ability of the tumor to suppress and change host anti-tumor immune reactions. The programmed cell death 1 (PD-1) pathway represents a major immune control switch which may be engaged by tumor cells to overcome active T-cell immune surveillance. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in various tumors. High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various other solid tumor types. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in patients with malignant melanoma. These observations suggest that the PD-1/PD-L1 pathway plays a critical role in the tumor immune evasion and could be considered an attractive target for therapeutic intervention in several solid organ types.
MK-3475 (previously known as SCH 900475) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primatesMK-3475 also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines.
The investigators therefore propose to evaluate if the addition of an immunotherapy can reverse trastuzumab resistance and improve clinical outcomes in HER2-positive disease. In this study the investigators will determine if a monoclonal antibody targeted against PD-1, a T cell negative regulator, can reverse trastuzumab resistance in patients previously progressing on trastuzumab.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Breast Cancer||Drug: MK-3475||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||58 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib/II Trial Evaluating the Efficacy of MK-3475 and Trastuzumab in Patients With Trastuzumab-resistant, HER2-positive Metastatic Breast Cancers|
|Study Start Date :||December 2014|
|Estimated Primary Completion Date :||March 2018|
|Estimated Study Completion Date :||December 2023|
Experimental: MK-3475 with trastuzumab
Phase Ib: MK-3475 at dose of 1 mg/kg, 2 mg/kg or 10 mg/kg (i.v.) 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.
The phase Ib trial will determine the recommended dose from three MK-3475 dose levels: 1mg/kg, 2 mg/kg or 10 mg/kg.
Other Name: Pembrolizumab
- Recommended dose of MK-3475 in combination with trastuzumab [ Time Frame: Within the first 21 days ]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).
- Efficacy and safety profile of MK-3475 combined with trastuzumab [ Time Frame: Clinical and radiological tumor assessment will be performed by CT scan or MRI at progression or 24 weeks after stop of treatment, whichever occurs first. ]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.
- Safety and Tolerability [ Time Frame: Adverse events are reported from the date of first dose of trial treatment until 90 days following treatment completion which occur after a maximum of 24 months. ]The incidence of events that are new or worsening will be summarized according to system organ class and/or preferred term, severity (based on CTCAE V4.0 grade), type of adverse event, and relation to study treatment.
- Disease control (DC) [ Time Frame: From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer ]Disease control (DC) defined as best overall response of confirmed CR, PR, or SD lasting for 24 weeks or longer.
- Duration of Response (DoR) [ Time Frame: From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months) ]Duration of response (DoR) is defined among patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
- Time to Progression (TTP) [ Time Frame: From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months) ]Time to progression (TTP) defined as the interval between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment
- Progression-free survival (PFS) [ Time Frame: From the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months ]For patients without progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within 12 weeks following the date last known progressionfree, in which case the death will be counted as a PFS event. Patients who discontinue or initiate non-protocol treatment prior to documented disease progression will be followed for disease progression
- Overall survival (OS) [ Time Frame: Time from start of trial treatment to death from any cause, assessed up to 30 months ]For patients who are lost to follow-up or who have no documentation of death at the time of final analysis, follow-up will be censored at the date of last assessment of vital status.
- Efficacy and safety of the drug combination in PD-L1 negative pts [ Time Frame: Clinical and radiological tumor assessment will be performed by CT scan or MRI at progression or 24 weeks after stop of treatment, whichever occurs first. ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02129556
|Peter MacCallum Cancer Centre|
|East Melbourne, Australia|
|Medical University of Vienna|
|Vienna, Austria, 1090|
|Jules Bordet Institute|
|Brussels, Belgium, 1000|
|CHU Sart Tilman|
|Liège, Belgium, 4000|
|Institut de Cacérologie de l`OUEST|
|Centre Leon Berard|
|Lyon, France, 69008|
|Institut Gustave Roussy|
|Villejuif, France, 94805|
|Istituto Europeo di Oncologia|
|Milan, Italy, 435|
|Azienda USL4 Prato|
|Prato, Italy, 59100|
|Study Chair:||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|