Primary Objective:To evaluate the safety and tolerability of FL-101 as monotherapy.Timepoint of evaluation of primary objective: From first dose to 3 months after surgerySecondary Efficacy Objectives1. Cohort 1: To evaluate the activity of FL-101…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Incidence and severity of AEs and SAEs graded according to NCI CTCAE v5.0
2. Incidence of immune-related toxicities
3. Incidence of events that inhibit or delay surgery beyond the preplanned
surgical date
4. Changes from baseline in clinical safety laboratory values, ECGs, and vital
signs
Secondary outcome
Secondary Efficacy parameters
1. Pathological response (% residual tumor) as assessed by independent
pathology review.
2. Major pathologic response (MPR), defined as <=10% viable tumor at time of
surgery.
3. Complete pathologic response (CPR), defined as the absence of residual
invasive cancer in resected lung specimens and lymph nodes following completion
of neoadjuvant therapy at time of surgery
4. ORR defined by RECIST v1.1 in computed tomography scans.
5. MRD measurement by ctDNA
Secondary Pharmacologic (PK/PD) parameters
1. Estimates of the following FL-101 PK parameters: Cmax, Cmin, AUC0-t,
AUC0-inf, CL, Vz, t*
2. Change from baseline in serum hsCRP, IL-6, and neutrophil / lymphocyte ratio.
3. Change from baseline in plasma IL-1β levels
Secondary Safety Parameters
1. Prevalence and incidence of anti-FL-101 antibodies.
Background summary
Advances in both targeted and immunotherapies for NSCLC have led to meaningful
reductions in incidence-based mortality (Howlader 2020). Nevertheless, an
estimated 230,000 new cases of NSCLC are still diagnosed in the US, with some
135,000 deaths annually (Siegel 2020).
In response to local inflammation, IL-1β orchestrates a cascade of myeloid
responses and signals bone marrow derived myeloid cells to accumulate at the
site of local inflammation supporting both tumor genesis and then local and
systemic immunosuppression. Evidence from preclinical and clinical studies
shows that this local and systemic inflammatory response can be identified in
NSCLC patients and that inhibiting it protects from tumor development,
progression, and metastasis.
There is a significant unmet medical need in patients undergoing resection with
curative intent, with 5-year survival of 77% for Stage IA3, dropping to 60% for
patients with Stage IIA and 53% for patients with Stage IIIA. The perioperative
addition of conventional cytotoxic chemotherapy, either in the preoperative or
postoperative period, yields an approximate 5% increase in 5-year overall
survival (OS) rates (Bunn 2019).
FL-101 has not yet been administered for patients diagnosed with NSCLC.
However, based on the results of the CANTOS study with another IL-1β blocking
antibody, canakinumab, patients with NSCLC who receive FL-101 monotherapy are
hypothesized to benefit from FL-101 treatment. Nonclinical, clinical, and
pharmacodynamic evidence supports a potential clinical benefit for inhibition
of IL-1β driven inflammation and suppression of anti-tumor immune responses in
NSCLC and other tumor types.
Study objective
Primary Objective:
To evaluate the safety and tolerability of FL-101 as monotherapy.
Timepoint of evaluation of primary objective: From first dose to 3 months after
surgery
Secondary Efficacy Objectives
1. Cohort 1: To evaluate the activity of FL-101 neoadjuvant monotherapy in
patients with Stage IA3 or IB NSCLC
(2. Cohort 2: To evaluate the effect of FL-101 in combination with nivolumab
compared to nivolumab plus placebo in neoadjuvant therapy in patients with
Stage II-IIIA NSCLC - Not applicable for the Netherlands)
3. To determine major pathologic response (MPR) rate
4. To estimate complete pathologic response (CPR) rate
5. To estimate the objective response rate (ORR) by RECIST 1.1 following
neoadjuvant FL-101
6. To describe the time course of minimal residual disease (MRD) response by
ctDNA and recurrence in correlation with clinical
response
Pharmacologic (PK/PD) Objectives
1. To evaluate the PK of FL-101 in patients with NSCLC
2. To evaluate the effect of FL-101 onD biomarkers
Safety Objectives
1. To evaluate possible immunogenicity, anti-drug antibodies
Time of evaluation of secondary objectives: At time of surgery
Study design
This is a 2-Cohort, Phase 2, multicenter, parallel-design trial in patients
with surgically resectable non-small cell lung cancer. The Netherlands will
only participate in Cohort 1
Patients in Cohort 1 will be enrolled to receive FL-101 (200 mg) monotherapy
administered IV on Day 1 of a 2-week cycle for 3 cycles preoperative.
Screening can occur up to 4 weeks before visit Day 1 of Cycle 1. There will be
a total of 3 treatment visits, which will occur at Day 1 of each treatment
cycle. One additional cycle of the assigned therapy can be administered if
surgery is delayed for reasons other than toxicity of the therapy, such as
Covid-19-related logistic delays.
Surgery should be conducted no earlier than 6 weeks after the first dose of
study drug but no longer than 8 weeks after the first dose of study drug.
4 weeks after surgery an End of Treatment visit will take place and a follow up
visit will be performed 12 weeks after surgery.
Intervention
Patients will receive FL-101 (200 mg) monotherapy administered IV on Day 1 of a
2-week cycle for 3 cycles preoperative.
Study burden and risks
FL-101 is an investigational medicinal product and has not yet been approved
for any indication, therefore, it is not guaranteed that subjects will
experience a clinical benefit from participation in this clinical study.
However, based on the results of the CANTOS study with another IL-1β blocking
antibody, canakinumab, patients with NSCLC who receive FL-101 monotherapy are
hypothesized to benefit from FL-101 treatment. Nonclinical, clinical and
pharmacodynamic evidence supports a potential clinical benefit for inhibition
of IL-1β driven inflammation and suppression of anti-tumor immune responses in
NSCLC and other tumor types.
In addition, the data from this study may have an indirect benefit in that it
will be used to further understand and characterize the safety and potential
clinical benefit of FL-101 and may therefore help patients with certain types
of cancer by contributing to medical research. The results of this study are
expected to provide further insight into the safety, tolerability and efficacy
of FL-101 as monotherapy in patients with NSCLC.
Prior to this study FL-101 (formerly LY2189102) has been tested in 4 clinical
studies of 220 healthy volunteers and patients with Rheumatroid Arthritis or
Type 2 diabetes at doses ranging from a single IV dose of LY2189102(0.05-5.0
mg/kg) to multiple (5 weekly) IV doses of LY2189102 (2.5 mg/kg).
LY2189102 was generally well tolerated at all doses and regimens tested. The
most common side effects were headache, nausea, gastroenteritis, rhinitis
(runny nose), urinary tract infection, influenza, back pain, cough, upper
respiratory infection, rash, skin infection, hypertension, insomnia and
injection site or infusion site reactions. Most treatment-emergent adverse
events (TEAEs) were considered not related or unlikely related to study drug.
The potential burden and risk of participation in this study are not expected
to be different than other comparable clinical research studies.
There are a total of 9 planned visits plus screening.
The number and amount of each blood draw, while more frequent than would be
associated with normal clinical care has been planned to keep the total volume
of blood drawn as low as possible. The patient will have a few extra visits
scheduled for PK and ADA blood testing during the first cycle of treatment
(cycle 1). The patient is offered the opportunity to have PK study visit Day 2,
Day 4 and Day 8 performed at home or at another convenient alternate location
by a home care service to reduce the burden.
Tumor tissue will be collected for the study during the planned surgery. The
surgery and tissue resection is performed during normal clinical care to remove
the tumor disease.
An ECG will be performed 5 times during the study. Risk associated with this
test is minimal, where localized skin irritation from the gel pads is rarely
seen.
Subject will require to have a CT-scan 4 times during the study. Possible side
effects of CT scans involve the risks of the radiation that is used to obtain
the images. If contrast material is used, there is a slight risk of developing
an allergic reaction, which may cause symptoms ranging from mild itching or a
rash to severe difficulty breathing, shock, or rarely, death. The contrast
material may also cause kidney problems, especially if the subject is
dehydrated or has poor kidney function. The investigator will ask the subject
about any allergies or related conditions before the procedure. If the subject
has any of these problems, they may not be allowed to have a CT scan. CT-scan
is performed during normal clinical care to assess disease progression in
subjects with NSCLC.
A brain-MRI scan will be performed at screening. Some subjects find it
uncomfortable to be confined in a small partially enclosed space and may feel
claustrophobic or experience nervousness, sweating or other minor discomfort.
As the machine attracts metals, subjects with metal in their bodies will be
excluded from the study. There are no other known site effects resulting from
exposure to MRI scan.
Union Square Drive 280
New Hope 18938
US
Union Square Drive 280
New Hope 18938
US
Listed location countries
Age
Inclusion criteria
Main Inclusion criteria Cohort 1
Patients are eligible to be included in the study only if ALL the following
criteria apply:
1. Male and female patients >=18 years of age.
2. Previously untreated and pathologically confirmed, surgically resectable
Stage IA3, IB, II, or IIIA NSCLC of squamous or non-squamous histology. Staging
is based on the eighth edition of the AJCC/UICC staging system.
3. >=1 radiologically measurable tumor >2 cm in diameter, as defined by
RECIST v1.1 (Eisenhauer 2009).
4. Lung function capacity capable of tolerating the proposed lung surgery.
5. Smoking history >=10 pack years.
6. High-sensitivity C-reactive protein (hsCRP) level >=2 mg/L
7. Adequate organ function as defined by ALL of the following:
- Absolute neutrophil count (ANC) >=1500/µL
- Platelets >=100,000 /µL
- Hemoglobin >=9 g/dL
- AST/ALT <=2.5× upper limit of normal (ULN)
- Total serum bilirubin <=1.5×ULN; patients with Gilbert*s disease: <=3×ULN
- Alkaline phosphatase <=2.5×ULN
- INR and aPTT <=1.5×ULN unless the patient is on therapeutic anticoagulation
- Serum creatinine <=1.5×ULN
OR
Creatinine clearance >=30 mL/min/1.73 m2 by Cockcroft-Gault estimation. The
patient*s estimated CrCl will be calculated by the local laboratory (for
eligibility purposes) using screening/baseline height (m), actual weight (kg),
and serum creatinine:
Males: CrCl = ((140 - age in years) × weight (kg))/72× serum creatinine (mg/dL)
Females: CrCl = ((140 - age in years) × weight (kg) ×0.85)/72× serum creatinine
(mg/dL)
8. Available tissue block for analysis from a core needle biopsy (or similar
sample).
-Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in
paraffin blocks (blocks are preferred) or at least 10 unstained slides, with an
associated pathology report, for central testing.
-Acceptable samples include core-needle biopsies for deep tumor tissue (minimum
of 3 cores) or excisional, incisional, punch, or forceps biopsies for
cutaneous, subcutaneous, or mucosal lesions.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
(Appendix 2).
10. Men must agree to use contraception or practice abstinence as well as
refrain from donating sperm during the treatment period and for >=180 days after
the last dose of study treatment. (Section 5.3).
11. Women may participate if not pregnant, not breastfeeding, and at least 1 of
the following conditions apply:
- Not a woman of childbearing potential (WOCBP)
- WOCBP who agrees to follow contraceptive guidance (Section 5.3) during the
treatment period and for at least 180 days after the last dose of study
treatment.
Female patients will be considered of non-reproductive potential (not a WOCBP)
if they are either:
(1) postmenopausal (defined as at least 12 months with no menses without an
alternative medical cause. In women < 45 years of age, a high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to
confirm a post-menopausal state in women not using hormonal contraception or
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a
single FSH measurement is insufficient.
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to
screening
OR
(3) have a congenital or acquired condition that prevents childbearing.
12. Able and willing to comply with protocol-specified requirements and to
provide written informed consent.
Exclusion criteria
Main exclusion criteria Cohort 1:
1. Any prior exposure to chemotherapy, radiotherapy, or systemic anti-cancer
therapy for lung cancer
2. Malignancies other than NSCLC within 2 years prior to Cycle 1, Day 1, with
the exception of those with a negligible risk of metastasis or death and with
expected curative outcome (such as adequately treated carcinoma in situ of the
cervix, basal or squamous cell skin cancer, localized prostate cancer treated
surgically with curative intent, or ductal carcinoma in situ treated surgically
with curative intent) or undergoing active surveillance per standard-of-care
management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer
with Gleason score <=6, and prostate specific antigen [PSA] <=10 mg/mL, etc.)
3. Currently participating in, or has participated in, a trial of an
investigational agent within 4 weeks prior to the first dose of trial treatment
or 5 half-lives, whichever is longer, or without recovery of clinically
significant toxicities from that therapy.
4. Any of the following tumor locations/types: a. NSCLC involving the superior
sulcus. b. Large cell neuro-endocrine cancer. c. Sarcomatoid tumor.
5. Tumors known to express driver mutations of EGFR or ALK pathways. Patients
whose driver mutation status is unknown may enroll in the study; tissue will be
checked after enrollment. SAP will describe how patients found to have one of
the 2 driver mutations will be handled.
6. History of non-infectious pneumonitis /interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease that
requires steroids.
7. Had allogenic tissue/sold organ transplant.
8. Known severe hypersensitivity (Grade >=3) to FL-101, its active substance, or
any of its excipients.
9. Known history of human immunodeficiency virus (HIV) or active Hepatitis B or
Hepatitis C infection.
10. Received radiotherapy within 2 weeks of start of study treatment.
11. Symptomatic herpes zoster within the past 30 days, a serious bacterial
infection within the past 6 months or have had other recent or ongoing signs of
infections
12. Received a live or attenuated vaccine within 30 days prior to the first
dose of study treatment.
13. Clinically unstable disease in any organ system despite current therapy,
including, but not limited to ongoing or active infection including
tuberculosis, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations.
14. Use of illicit drugs or excess intake of alcohol, based on the judgement of
the investigator.
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 |
|---|---|
| Other | 2020-005602-26 |
| EudraCT | EUCTR2020-005602-26-NL |
| CCMO | NL79189.100.21 |