Clinical trial NCT03742349: Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC).
Official title: A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Immunotherapy Combinations in Adult Patients With Triple-negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Triple Negative Breast Cancer (TNBC)
Keywords: Phase Ib, TNBC, advanced, metastatic, immunotherapy, PDR001,
LAG525, NIR178, INC280, MCS110, ACZ885
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-11-15
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase Ib, open label, dose escalation study of spartalizumab + LAG525 in combination with NIR178, capmatinib, MCS110, or canakinumab, followed by a dose expansion in adult patients with advanced or metastatic TNBC.

During the dose-escalation part of each treatment arm, patients will be treated with fixed doses of spartalizumab + LAG525 in combination with partner investigational drugs to be escalated until the MTD is reached or a lower RDE is established: NIR178, capmatinib, MCS110, or canakinumab. It is anticipated that other partner study drugs may be added in the future by protocol amendment.

After the determination of the MTD/RDE for a particular treatment arm, dose expansion may begin in that arm in order to further assess safety, tolerability, PK/PD, and anti-tumor activity of each combination at the MTD/RDE. Dose expansion arms may initiate only after consideration by the Investigators and Novartis of all available toxicity information, the assessment of risk to future patients from the BLRM, and the available PK, preliminary efficacy, and PD information. There is no requirement for dose-escalation treatment arms reaching an MTD/RDE to proceed to dose expansion.


Eligibility criteria: Main Inclusion Criteria:

* Patients with advanced/metastatic TNBC (defined as HER-2 negative with \<1% of tumor cell nuclei immunoreactive for estrogen receptor (ER) and progesterone receptor (PR)), with measurable disease as determined by RECIST version 1.1 (refer to Appendix 16.1). Tumor lesions previously irradiated or subjected to other loco-regional therapy will only be considered measurable if there is documented disease progression at the treated site prior to study entry.
* Patients should have received standard chemotherapy for advanced or metastatic disease but should not have received more than 2 prior lines of chemotherapy. Neoadjuvant or adjuvant chemotherapy will count as one prior line.
* Patients must have received prior systemic treatment that included taxane-based chemotherapy for neoadjuvant or metastatic disease.
* Patients must have a site of disease amenable to core needle biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at screening, and during therapy on the study. Exceptions may be considered after documented discussion with Novartis. Patients with available archival tumor tissue obtained ≤6 months prior to study treatment initiation do not need to undergo a new tumor biopsy at screening, if the patient has not received any anti-cancer therapy since the biopsy was taken, and if adequate tissue is available.

Main exclusion criteria applicable to all treatment arms:

* Patient has received prior treatment with anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (any line of therapy).
* Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within 2 weeks prior to initiating study treatment.
* History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
* Impaired cardiac function or clinically significant cardiac disease.
* HIV infection.
* Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, including those with inactive disease for patients receiving either capmatinib, MCS110 or canakinumab.
* Active, known or suspected autoimmune disease.
* History of or current interstitial lung disease or pneumonitis grade ≥ 2.
* Subjects with tuberculosis (TB), for patients receiving either MCS110 or canakinumab.

Other eligibility criteria apply.

Primary outcomes:
measure: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
timeFrame: at month 18
measure: Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
timeFrame: at month 18
measure: Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
timeFrame: at Day 28
measure: Frequency of dose interuptions
timeFrame: at month 18
measure: Frequency of dose reductions
timeFrame: at month 18
measure: Dose intensities
timeFrame: at month 18
Secondary outcomes:
measure: Best overall response (BOR)
timeFrame: at month 18
measure: Progression free survival (PFS) per RECIST v1.1 and iRECIST
timeFrame: at month 18
measure: Presence of anti-spartalizumab antibodies
timeFrame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: Presence of anti-LAG525 antibodies
timeFrame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: Presence of anti-MCS110 antibodies
timeFrame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: Presence of anti-canakinumab antibodies
timeFrame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: Serum concentration of spartalizumab, LAG525, MCS110, canakinumab
timeFrame: at Day 1, Day 8, Day 15, Day 29, Day 57, Day 65, Day 70, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: Plasma concentration of NIR178, NJI675, capmatinib
timeFrame: at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT
measure: PK parameter (Tmax) of spartalizumab
timeFrame: at month 12
measure: PK parameter (Cmax) of spartalizumab
timeFrame: at month 12
measure: PK parameter (AUC) of spartalizumab
timeFrame: at month 12
measure: PK parameter (Tmax) of LAG525
timeFrame: at month 12
measure: PK parameter (Cmax) of LAG525
timeFrame: at month 12
measure: PK parameter (AUC) of LAG525
timeFrame: at month 12
measure: PK parameter (Tmax) of NIR178
timeFrame: at month 12
measure: PK parameter (Cmax) of NIR178
timeFrame: at month 12
measure: PK parameter (AUC) of NIR178
timeFrame: at month 12
measure: PK parameter (Tmax) of capmatinib
timeFrame: at month 12
measure: PK parameter (Cmax) of capmatinib
timeFrame: at month 12
measure: PK parameter (AUC) of capmatinib
timeFrame: at month 12
measure: PK parameter (Tmax) of MCS110
timeFrame: at month 12
measure: PK parameter (Cmax) of MCS110
timeFrame: at month 12
measure: PK parameter (AUC) of MCS110
timeFrame: at month 12
measure: PK parameter (Tmax) of canakinumab
timeFrame: at month 12
measure: PK parameter (Cmax) of canakinumab
timeFrame: at month 12
measure: PK parameter (AUC) of canakinumab
timeFrame: at month 12
measure: Changes from baseline of PD markers in tumor tissue (TILs, CD8, PD-L1, LAG-3)
timeFrame: at baseline and at Day 43
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Columbia
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Sarah Cannon Research
state: Tennessee
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
Study officials:
References: