Study of Safety and Efficacy of Novel Immunotherapy Combinations in Patients With Triple Negative Breast Cancer (TNBC).
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 1: spartalizumab + LAG525 + NIR178 phase Ib (escalation and expansion) |
Biological: spartalizumab
LIVI (Liquid in vial) Concentrate for Solution for infusion
Other Names:
Biological: LAG525
LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion
Drug: NIR178
Capsule
|
| Experimental: 2: spartalizumab +LAG525 +capmatinib phase Ib (escalation and expansion) |
Biological: spartalizumab
LIVI (Liquid in vial) Concentrate for Solution for infusion
Other Names:
Biological: LAG525
LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion
Drug: capmatinib
Tablet
Other Names:
|
| Experimental: 3: spartalizumab + LAG525 + MCS110 phase Ib (escalation and expansion) |
Biological: spartalizumab
LIVI (Liquid in vial) Concentrate for Solution for infusion
Other Names:
Biological: LAG525
LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion
Biological: MCS110
LIVI (Liquid in vial) Concentrate for Solution for infusion
|
| Experimental: 4: spartalizumab +LAG525 +canakinumab phase Ib (escalation and expansion) |
Biological: spartalizumab
LIVI (Liquid in vial) Concentrate for Solution for infusion
Other Names:
Biological: LAG525
LAG525 LIVI (Liquid in vial) Concentrate for Solution for infusion
Biological: canakinumab
LIVI (Liquid in vial) Solution for injection
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [at month 18]
Month 18 is assumed to be study end
- Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [at month 18]
Month 18 is assumed to be study end
- Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) [at Day 28]
end of first cycle
- Frequency of dose interuptions [at month 18]
Month 18 is assumed to be study end
- Frequency of dose reductions [at month 18]
Month 18 is assumed to be study end
- Dose intensities [at month 18]
Month 18 is assumed to be study end
Secondary Outcome Measures
- Best overall response (BOR) [at month 18]
Month 18 is assumed to be study end
- Progression free survival (PFS) per RECIST v1.1 and iRECIST [at month 18]
Month 18 is assumed to be study end
- Presence of anti-spartalizumab antibodies [at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT]
- Presence of anti-LAG525 antibodies [at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT]
- Presence of anti-MCS110 antibodies [at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT]
- Presence of anti-canakinumab antibodies [at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT]
- Serum concentration of spartalizumab, LAG525, MCS110, canakinumab [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]
- Plasma concentration of NIR178, NJI675, capmatinib [at Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, Day 197, Day 253, Day 309 and EOT]
- PK parameter (Tmax) of spartalizumab [at month 12]
cycle 12
- PK parameter (Cmax) of spartalizumab [at month 12]
cycle 12
- PK parameter (AUC) of spartalizumab [at month 12]
cycle 12
- PK parameter (Tmax) of LAG525 [at month 12]
cycle 12
- PK parameter (Cmax) of LAG525 [at month 12]
cycle 12
- PK parameter (AUC) of LAG525 [at month 12]
cycle 12
- PK parameter (Tmax) of NIR178 [at month 12]
cycle 12
- PK parameter (Cmax) of NIR178 [at month 12]
cycle 12
- PK parameter (AUC) of NIR178 [at month 12]
cycle 12
- PK parameter (Tmax) of capmatinib [at month 12]
cycle 12
- PK parameter (Cmax) of capmatinib [at month 12]
cycle 12
- PK parameter (AUC) of capmatinib [at month 12]
cycle 12
- PK parameter (Tmax) of MCS110 [at month 12]
cycle 12
- PK parameter (Cmax) of MCS110 [at month 12]
cycle 12
- PK parameter (AUC) of MCS110 [at month 12]
cycle 12
- PK parameter (Tmax) of canakinumab [at month 12]
cycle 12
- PK parameter (Cmax) of canakinumab [at month 12]
cycle 12
- PK parameter (AUC) of canakinumab [at month 12]
cycle 12
- Changes from baseline of PD markers in tumor tissue (TILs, CD8, PD-L1, LAG-3) [at baseline and at Day 43]
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Columbia University Medical Center- New York Presbyterian Columbia | New York | New York | United States | 10032 |
| 2 | Sarah Cannon Research Institute Sarah Cannon Research | Nashville | Tennessee | United States | 37203 |
| 3 | Novartis Investigative Site | Westmead | New South Wales | Australia | 2145 |
| 4 | Novartis Investigative Site | Shatin, New Territories | Hong Kong | ||
| 5 | Novartis Investigative Site | Tel Aviv | Israel | 6423906 | |
| 6 | Novartis Investigative Site | Milano | MI | Italy | 20133 |
| 7 | Novartis Investigative Site | Milano | MI | Italy | 20141 |
| 8 | Novartis Investigative Site | Kashiwa | Chiba | Japan | 277 8577 |
| 9 | Novartis Investigative Site | Amsterdam | Netherlands | 1066 CX | |
| 10 | Novartis Investigative Site | Singapore | Singapore | 119074 | |
| 11 | Novartis Investigative Site | Singapore | Singapore | 169610 | |
| 12 | Novartis Investigative Site | Barcelona | Catalunya | Spain | 08035 |
| 13 | Novartis Investigative Site | Valencia | Comunidad Valenciana | Spain | 46010 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CADPT01A12101C
- 2018-002244-82