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A Study of Efficacy and Safety of LAG525 in Combination With Spartalizumab, or With Spartalizumab and Carboplatin, or With Carboplatin, in Patients With Advanced Triple-negative Breast Cancer

NCT03499899

Description:

The purpose of this study is to assess the efficacy, safety, and PK characteristics of the following three combinations: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in subjects with advanced TNBC and up to one prior line of systemic treatment for metastatic disease. A thorough biomarker strategy to address key aspects of tumor immunogenicity will be implemented in the study. LAG525 and spartalizumab are two immuno-agents targeting different immune checkpoints, and have been tested as single agents and in combination. To further enhance the efficacy of checkpoint inhibition, carboplatin will be given with LAG525 or with LAG525 and spartalizumab, based on the observation that the addition of chemotherapy can change the tumor microenvironment to be more favorable to immune response.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Efficacy and Safety of LAG525 in Combination With Spartalizumab, or With Spartalizumab and Carboplatin, or With Carboplatin, in Patients With Advanced Triple-negative Breast Cancer
  • Official Title: A Phase II Open-label, Randomized, Three-arm, Multicenter Study of LAG525 Given in Combination With Spartalizumab (PDR001), or With Spartalizumab and Carboplatin, or With Carboplatin, as First or Second Line Therapy in Patients With Advanced Triple-negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: CLAG525B2101
  • NCT ID: NCT03499899

Conditions

  • Triple-negative Breast Cancer

Interventions

DrugSynonymsArms
LAG525LAG525 + spartalizumab
spartalizumabPDR001LAG525 + spartalizumab
carboplatinLAG525+spartalizumab+carboplatin

Purpose

The purpose of this study is to assess the efficacy, safety, and PK characteristics of the following three combinations: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in subjects with metastatic TNBC and up to one prior line of systemic treatment for metastatic disease. A thorough biomarker strategy to address key aspects of tumor immunogenicity will be implemented in the study. LAG525 and spartalizumab are two immuno-agents targeting different immune checkpoints, and have been tested as single agents and in combination. To further enhance the efficacy of checkpoint inhibition, carboplatin will be given with LAG525 or with LAG525 and spartalizumab, based on the observation that the addition of chemotherapy can change the tumor microenvironment to be more favorable to immune response.

Trial Arms

NameTypeDescriptionInterventions
LAG525 + spartalizumabExperimentalapproximately 32 patients will be randomized in this arm
  • LAG525
  • spartalizumab
LAG525+spartalizumab+carboplatinExperimentalapproximately 32 patients will be randomized in this arm
  • LAG525
  • spartalizumab
  • carboplatin
LAG525 + carboplatinExperimentalapproximately 32 patients will be randomized in this arm
  • LAG525
  • carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Patient has advanced (loco-regionally recurrent not amenable to curative therapy or
             metastatic) breast cancer.

          -  Patient must have measurable disease, i.e., at least one measurable lesion as per
             RECIST 1.1 criteria (Tumor lesions previously irradiated or subjected to other
             loco-regional therapy will only be considered measurable if disease progression at the
             treated site after completion of therapy is clearly documented)

          -  Patient progressed after adjuvant or 1 prior systemic treatment in the metastatic
             setting. Patients with de novo metastatic disease are eligible if they received 1
             prior line of therapy

          -  Patient must have received prior systemic treatment that included taxane-based
             chemotherapy for adjuvant or metastatic disease

          -  Patient must have a site of disease amenable to biopsy, and must be willing to undergo
             a new tumor biopsy at screening and during therapy on this study, the latter if
             medically feasible. Patients with an available archival tumor tissue do not need to
             perform a tumor biopsy at screening if patient has not received anti-cancer therapy
             since the biopsy was taken.

          -  Patient has histologically and/or cytologically confirmed diagnosis of TNBC (based on
             most recently analyzed biopsy, local lab) meeting the following criteria: HER2
             negative in situ hybridization test or an IHC status of 0 or 1+, and ER and PR
             expression is <1 percent as determined by immunohistochemistry (IHC)

        Exclusion Criteria:

          -  Patient has received prior treatment with anti-LAG-3, anti-PD-1, anti-PD-L1, or
             anti-PD-L2 antibody (any line of therapy).

          -  Patient received prior therapy with a platinum agent or mitomycin and experienced
             recurrence within 12 months after the end of the platinum-based or mitomycin
             containing therapy

          -  Patient has had major surgery within 14 days prior to starting study treatment or has
             not recovered to grade 1 or less from major side effects.

          -  Patient with presence of CTCAE ≥ grade 2 toxicity (except alopecia, peripheral
             neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer
             therapy.

          -  Patient has received radiotherapy ≤ 4 weeks prior to randomization (≤ 2 weeks for
             limited field radiation for palliation), and has not recovered to grade 1 or better
             from related side effects of such therapy (with the exception of alopecia).

          -  Patient has a known hypersensitivity to other monoclonal antibodies,
             platinum-containing compounds, or to any of the excipients of LAG525, spartalizumab,
             or carboplatin.

          -  Patient with history or presence of central nervous system (CNS) metastases, treated
             or untreated.

        Other protocol-defined inclusion/exclusion criteria may apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) per RECIST v1.1 per investigators' assessment
Time Frame:24 months
Safety Issue:
Description:To assess the antitumor activity of the three treatment arms LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + carboplatin, in subjects with advanced TNBC in first or second line therapy, as measured by the objective response rate (ORR) per investigator's assessment according to RECIST v1.1.

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:Up to disease progression or death due to any cause, whichever occurs first (3 years)
Safety Issue:
Description:To assess the efficacy of the three treatment arms with respect to DOR per investigator's assessment according to RECIST v1.1
Measure:Overall Survival (OS)
Time Frame:Up to death due to any cause (3 years)
Safety Issue:
Description:To assess Overall Survival for each treatment arm
Measure:Pharmacokinetics (PK) parameter, Ctrough, of LAG525, spartalizumab and carboplatin
Time Frame:Up to cycle 7 (each cycle is 21 days) and at end of treatment (up to 3 years)
Safety Issue:
Description:To characterize the PK parameter, Ctrough, of LAG525, spartalizumab, and carboplatin in the three investigated combinations
Measure:Time to response (TTR)
Time Frame:Up to death due to any cause (3 years)
Safety Issue:
Description:To assess the efficacy of the three treatment arms with respect to TTR per investigator's assessment according to RECIST v1.1
Measure:Progression free survival (PFS)
Time Frame:Up to disease progression or death due to any cause, whichever occurs first (3 years)
Safety Issue:
Description:To assess the efficacy of the three treatment arms with respect to PFS per investigator's assessment according to RECIST v1.1
Measure:Clinical Benefit Rate (CBR)
Time Frame:24 months
Safety Issue:
Description:To assess the efficacy of the three treatment arms with respect to CBR per investigator's assessment according to RECIST v1.1
Measure:PK parameter, Cmax of LAG525, spartalizumab and carboplatin
Time Frame:Up to cycle 7 (each cycle is 21 days)
Safety Issue:
Description:To characterize the PK parameter, Cmax, of LAG525, spartalizumab, and carboplatin in the three investigated combinations
Measure:PK parameter, AUC, of LAG525, spartalizumab and carboplatin
Time Frame:Up to cycle 7 (each cycle is 21 days) and at end of treatment (up to 3 years)
Safety Issue:
Description:To characterize the PK parameter, AUC, of LAG525, spartalizumab, and carboplatin in the three investigated combinations
Measure:Anti-drug antibodies (ADA) prevalence at baseline for LAG525 and spartalizumab
Time Frame:At baseline
Safety Issue:
Description:To assess immunogenicity of LAG525 and spartalizumab in the three investigated combinations
Measure:Anti-drug antibodies (ADA) incidence on treatment for LAG525 and spartalizumab
Time Frame:Throughout study until 150 days after last drug administration
Safety Issue:
Description:To assess immunogenicity of LAG525 and spartalizumab in the three investigated combinations

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • triple-negative breast cancer
  • checkpoint inhibition
  • LAG525
  • spartalizumab
  • PDR001
  • carboplatin

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