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

Phase 2

Completed

• Conditions: Triple-negative Breast Cancer
• Interventions: Drug: LAG525; Drug: PDR001; Drug: Carboplatin

• Registration Number: NCT03499899
• Lead Sponsor: Novartis Pharmaceuticals

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.

Study Timeline

• Study First Submitted: 2018-03-26
• Study First Submitted QC: 2018-04-09
• Study First Posted: 2018-04-17
• Study Start: 2018-07-02
• Primary Completion: 2020-02-27
• Disposition First Submitted: 2020-04-22
• Disposition First Submitted QC: 2020-04-22
• Disposition First Posted: 2020-04-27
• Study Completion: 2021-11-24
• Results First Submitted: 2022-04-20
• Results First Submitted QC: 2022-04-20
• Results First Posted: 2022-05-13
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-27
• Last Update Posted: 2023-01-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 88

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LAG525 + PDR001	PDR001	Participants received LAG525 and PDR001 administered as infusion once every 3 weeks
LAG525 + PDR001 + carboplatin	PDR001	Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.
LAG525 + PDR001	LAG525	Participants received LAG525 and PDR001 administered as infusion once every 3 weeks
LAG525 + carboplatin	LAG525	Participants received LAG525 and carboplatin administered as infusion once every 3 weeks
LAG525 + PDR001 + carboplatin	Carboplatin	Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.
LAG525 + PDR001 + carboplatin	LAG525	Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.
LAG525 + carboplatin	Carboplatin	Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1	Up to approximately 14 months	Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. The 95% CIs were computed using two-sided exact binomial method.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From date of randomization to date of death due to any cause, up to 18 months	OS is defined as the time from date of randomization to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date). The OS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley
Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h.
Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1	Up to approximately 14 months	CBR is defined as the percentage of participants with a best overall response (BOR) of confirmed CR or PR, or stable disease (SD) lasting 24 weeks or longer, according to RECIST 1.1 criteria. The 95% CI were computed using two-sided exact binomial method.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.; SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
PK Parameter, Cmax of LAG525	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed plasma LAG525 concentration
Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1	From date of randomization to first documented response (CR or PR), up to approximately 14 months	TTR is the time from date of randomization to first documented response of CR or PR based on investigators' assessment and according to RECIST 1.1. Median TTR was summarized using descriptive statistics.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1	From first documented response up to disease progression or death due to underlying cancer, whichever occurs first, up to approximately 14 months	DOR is the time between the first documented response (CR or PR) and the first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator's assessment. The DOR distribution was estimated using the Kaplan-Meier method and the 95% confidence intervals using the method of Brookmeyer and Crowley. If progression or death did not occur, the participant was censored at the date of last adequate tumor assessment.; CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm.; PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.; Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm.
Progression Free Survival (PFS)	From date of randomization to disease progression or death due to any cause, whichever occurs first, up to approximately 14 months	PFS is defined as time from date of randomization to the date of first documented progression or death due to any cause. PFS was assessed via investigator's assessment according to RECIST 1.1. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed prior to the analysis cut-off date or before the start of the new anticancer therapy date, whichever is earlier. The PFS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.
PK Parameter, Cmax of Carboplatin (Total Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as total platinum)
PK Parameter, Cmax of PDR001	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed PDR001 serum concentration
PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as ultrafilterable platinum)
PK Parameter, AUC0-504h of PDR001	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h.
PK Parameter, Tmax of PDR001	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum PDR001 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
PK Parameter, AUC0-4h of Carboplatin (Total Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as total platinum).
PK Parameter, Tmax of Carboplatin (Total Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as total platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as ultrafilterable platinum).
Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525	From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 3 years	Number of participants who were treatment-induced ADA positive for LAG525 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for LAG525 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)
PK Parameter, AUClast of LAG525	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of LAG525
PK Parameter, Tmax of LAG525	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum LAG525 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
PK Parameter, AUClast of PDR001	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of PDR001
PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as ultrafilterable platinum)
Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525	Baseline	Number of participants who had an ADA positive result at baseline for LAG525
Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001	Baseline	Number of participants who had an ADA positive result at baseline for PDR001.
Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001	From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 2.8 years	Number of participants who were treatment-induced ADA positive for PDR001 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for PDR001 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)
PK Parameter, AUClast of Carboplatin (Total Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as total platinum)
PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum)	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	Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as ultrafilterable platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

Trial Locations

Locations (3)

Ironwood Cancer and Research Centers; 🇺🇸 Chandler, Arizona, United States

Novartis Investigative Site; 🇹🇭 Songkla, Thailand

Highlands Oncology Group; 🇺🇸 Fayetteville, Arkansas, United States