Clinical trial NCT03499899: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Triple-negative Breast Cancer
Keywords: advanced triple-negative breast cancer
triple-negative breast cancer
checkpoint inhibition
LAG525
spartalizumab
PDR001
carboplatin
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-04-17
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this study was to assess the antitumor activity of three combinations: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in participants with advanced triple-negative breast cancer (TNBC) in first or second line therapy.

Detailed description: This was an open-label, Phase II, randomized, multicenter study to assess the efficacy, safety, and pharmacokinetic characteristics of the following three combinations: LAG525 + spartalizumab (PDR001) (Arm 1), LAG525 + spartalizumab (PDR001) + carboplatin (Arm 2), and LAG525 + carboplatin (Arm 3) in participants with advanced triple-negative breast cancer (TNBC) which progressed after adjuvant or one prior line of systemic therapy for metastatic disease.

Participants were assigned to one of the three treatment arms in a ratio of 1:1:1. In protocol amendment 3 (released on 28-Mar-2019), enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed due to a higher discontinuation rate due to progressive disease and all subsequent enrolled patients were randomized to Arms 2 and 3 only, in a ratio of 1:1.

Study treatment continued until disease progression, unacceptable toxicity, pregnancy, investigator/participant decision, start of a new anti-neoplastic therapy, withdrawal of consent, lost to follow-up, death, or study was terminated by the sponsor. The investigator might decide to stop carboplatin after 6 cycles, even if the above criteria were not met. Participants who continued to derive clinical benefit from the treatment based on the investigator's evaluation following their completion of this trial might receive post-trial access (PTA) i.e. rollover protocol or a post-study drug supply (PSDS).

The end of study was defined as the earliest occurrence of one of the following: (1) all participants had died or (2) discontinued from the study, or (3) another clinical study became available that could continue to provide study treatment in this participant population and all ongoing participants were eligible to be transferred to that clinical study.

Eligibility criteria: Inclusion Criteria:

* Had advanced (loco-regionally recurrent not amenable to curative therapy or metastatic) breast cancer
* Had adequate bone marrow and organ function.
* Had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Had 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 was to be considered measurable if disease progression at the treated site after completion of therapy is clearly documented)
* Progressed after adjuvant or 1 prior systemic treatment in the metastatic setting. Patients with de novo metastatic disease were eligible if they received 1 prior line of therapy
* Had received prior systemic treatment that included taxane-based chemotherapy for adjuvant or metastatic disease
* Had a site of disease amenable to biopsy, and was 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 did not need to perform a tumor biopsy at screening if patient had not received anti-cancer therapy since the biopsy was taken.
* Had histologically and/or cytologically confirmed diagnosis of advanced TNBC (based on most recently analyzed biopsy from locally recurrent or metastatic site, 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 was \<1 percent as determined by immunohistochemistry (IHC)

Exclusion Criteria:

* Had received prior immune checkpoint inhibitors as anticancer treatment such as anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (any line of therapy)
* Received prior neoadjuvant or adjuvant therapy with a platinum agent or mitomycin and experienced recurrence within 12 months after the end of the platinum-based or mitomycin containing therapy or received Platinum or mitomycin for metastatic disease
* Had major surgery within 14 days prior to starting study treatment or had not recovered to grade 1 or less from major side effects
* Presence of CTCAE grade 2 toxicity or higher due to prior cancer therapy. Exception to this criterion; patients with any grade of alopecia were allowed to enter the study.
* Had received radiotherapy ≤ 4 weeks prior to randomization (≤ 2 weeks for limited field radiation for palliation), and had not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia)
* Had a known hypersensitivity to other monoclonal antibodies, platinum-containing compounds, or to any of the excipients of LAG525, spartalizumab, or carboplatin
* Had symptomatic central nervous system (CNS) metastases or CNS metastases that required local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within the 2 weeks prior to first dose of study treatment. Patients with treated brain metastases would be neurologically stable and without CNS progression for at least 12 weeks prior to randomization and had discontinued corticosteroid treatment (with the exception of \< 10 mg/day of prednisone or equivalent for an indication other than CNS metastases) for at least 4 weeks before first dose of any study treatment
* Had clinically significant cardiac disease or impaired cardiac function

Primary outcomes:
measure: Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1
timeFrame: Up to approximately 14 months
Secondary outcomes:
measure: Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1
timeFrame: Up to approximately 14 months
measure: Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1
timeFrame: From first documented response up to disease progression or death due to underlying cancer, whichever occurs first, up to approximately 14 months
measure: Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1
timeFrame: From date of randomization to first documented response (CR or PR), up to approximately 14 months
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization to disease progression or death due to any cause, whichever occurs first, up to approximately 14 months
measure: Overall Survival (OS)
timeFrame: From date of randomization to date of death due to any cause, up to 18 months
measure: Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, Cmax of LAG525
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, AUClast of LAG525
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, Tmax of LAG525
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, AUC0-504h of PDR001
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, Cmax of PDR001
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, AUClast of PDR001
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, Tmax of PDR001
timeFrame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
measure: PK Parameter, AUC0-4h of Carboplatin (Total Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, Cmax of Carboplatin (Total Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, AUClast of Carboplatin (Total Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, Tmax of Carboplatin (Total Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum)
timeFrame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
measure: Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525
timeFrame: Baseline
measure: Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525
timeFrame: From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 3 years
measure: Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001
timeFrame: Baseline
measure: Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001
timeFrame: From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 2.8 years
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Ironwood Cancer and Research Centers
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Wooloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Luebeck
country: Germany
facility: Novartis Investigative Site
state: Schleswig-holstein
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Tübingen
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya-city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Minato ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: El Metn
country: Lebanon
facility: Novartis Investigative Site
city: Saida
country: Lebanon
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: