Primary: To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future dosesSecondary:* To characterize the pharmacokinetic profile of each investigational drug within each treatment arm…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence and severity of AE*s and SAE*s. DLTs (incidence and nature), dose
interruptions/reductions.
Secondary outcome
Serum/plasma concentrations and PK parameters of individual investigational
drugs within combination treatments
Presence and/or concentration of anti-drug antibodies
Best overall response (BOR) and PFS per RECIST v1.1 and iRECIST
Changes from baseline of PD markers in tumor tissue (e.g.TILs, CD8, PD-L1,
LAG-3
Background summary
De eerste resultaten van een kleine groep patiënten met TNBC die behandeld werd
met spartalizumab (PDR001) in combinatie met LAG525 hebben tekenen van
effectiviteit laten zien, waarbij gezien werd dat een behandeling van
spartalizumab in combinatie met LAG525 effectiever zou kunnen zijn dan een
behandeling met alleen een PD-(L)1 remmer bij de behandeling van TNBC.
Emerging clinical data suggest that combinations of immunotherapy agents with
chemotherapy may possess greater anti-tumor activity than single agents.
Preliminary data from a small group of TNBC patients treated with spartalizumab
(PDR001) in combination with LAG525 have shown preliminary signs of efficacy
demonstrating that spartalizumab in combination with LAG525 may be more
effective than single-agent PD-(L)1 inhibitors in the treatment of TNBC.
Nonetheless, most patients did not respond as expected.
Therefore, using spartalizumab + LAG525 as a starting point, the addition of a
3rd agent (such as NIR178, capmatinib, MCS110 or canakinumab), that modulate
other mechanisms, may improve the effects of the LAG525 + spartalizumab doublet
in patients with TNBC.
Study objective
Primary: To characterize safety and tolerability of each treatment arm tested
and identify recommended doses and regimens for future doses
Secondary:
* To characterize the pharmacokinetic profile of each investigational drug
within each treatment arm
* To assess immunogenicity of monoclonal antibodies
* To evaluate preliminary anti-tumor activity of each treatment arm
* To assess the pharmacodynamics (PD) effect of each treatment arm
Study design
This is a phase Ib, multi-center, open-label study with multiple treatment
arms. The design of this study is adaptive to allow dropping of non-tolerated
or ineffective combination treatments and facilitate the introduction of new
candidate combinations. The study is comprised of a dose-escalation part and a
dose-expansion part.
During the dose-escalation part of each treatment arm, patients will be treated
with spartalizumab (fixed dose)+LAG525 (fixed dose) in combination with partner
investigational drugs NIR178, capmatinib, MCS110, or canakinumab
Each treatment arm will enroll cohorts of three to six subjects with TNBC
treated until the MTD is reached or a lower RDE is established (Figure 3-1). A
minimum of 15 subjects are expected to be enrolled in each dose-escalation
treatment arm (
There is no requirement for every dose-escalation treatment arms reaching an
MTD/RDE to proceed to dose expansion. 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. Approximately 30 subjects
(naive for anti-LAG-3, anti-PD-L1 or anti-PD-L2 therapy) may be enrolled for
each treatment arm during dose expansion.
Intervention
Spartalizumab (PDR001) 400mg intravenous administration (infusion) once every 4
weeks
LAG525 intravenous 600mg intravenous administration (infusion) once every 4
weeks
For each treatment arm the following third investigational drug will be added:
- Arm1: NIR178, oral intake BID, starting dose 80mg
- Arm 2: capmatinib, oral intake BID, starting dose 80mg 200mg
- Arm3: MCS110, 5,0 mg/kg intravenous administration (infusion) once every 4
weeks
- Arm 4: canakinumab, subcutaneous injection once every 8 weeks, starting dose
600mg
Study burden and risks
Risks:
- Adverse effects (AE's and SAE's) of Spartalizumab and LAG 525 in combination
with either
1) NIR178 or 2) capmatinib or 3) MCS110 or 4) canakinumab
- Risks associated with the assessments as blooddraw, tumor biopsy and imaging
Burden:
Burden: Cycles of 3 or 4 weeks. Cycle 1: 6 visits, cycle 2: 2 visits,
thereafter 1 visit per cycle. Duration mostly 1-4 hours.
Physical examination: once per cycle.
Blood tests (15 ml/occasion, during dose escalation part occasionally fasting):
every cycle (cycle 1: 4 times). Extra blood draws for PK (in total 50 ml) and
biomarkers (in total 50 ml).
Urine testing during screening.
Pregnancy test: every cycle.
ECG: once per cycle (cycle 1: 4 times).
CT-/MRI scan: baseline, every 8 weeks thereafter.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
ECOG Performance Status * 1
Patients with advanced/metastatic TNBC with measurable disease as determined by
RECIST version 1.1
Documented disease progression or intolerance to no more than 2 prior lines of
chemotherapy for advanced disease. Prior treatment with targeted agents or
checkpoint inhibitors will not count as a line of prior therapy unless
chemotherapy was administered concurrently.
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.
See for more details protocol section 5.1
Exclusion criteria
Dose expansion arm(s), checkpoint- inhibitor-naive group only: Prior checkpoint
inhibitor 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.
Patients with treated brain metastases should be neurologically stable for at
least 4 weeks prior to study entry and off steroids for at least 2 weeks before
administration of any study treatment.
Out of range laboratory values:
- Creatinine clearance < 40 mL/min
- Total bilirubin > 1.5 x ULN, except for patients with Gilbert*s syndrome if
total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- ALT and AST > 3 x ULN
- Absolute neutrophil count < 1.0 x 109/L
- Platelet count < 75 x 109/L
- Hemoglobin < 9 g/dL
- Potassium, magnesium, calcium or phosphate abnormality > CTCAE grade 1
despite appropriate replacement therapy
Impaired cardiac function or clinically significant cardiac disease
Cardiac Troponin T (cTnT) or Cardiac Troponin I (cTnI) elevation > Grade 1
History or current diagnosis of myocarditis.
Subjects assigned to the canakinumab arm are required to be tested using
Interferon-* release assay.
For patients assigned to the the MCS110 arm, active tuberculosis requiring
systemic antibiotic
therapy is excluded.
Other exclusion criteria may apply (see protocol section 5.2)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002244-82-NL |
| ClinicalTrials.gov | NCT03742349 |
| CCMO | NL68735.031.19 |