Trial Title:
NP137 Clinical and Biological Activities Assessment in Patients with Advanced/Metastatic Solid Tumors Treated by Standard Anti PD-1/PD-L1 Immunotherapies
NCT ID:
NCT05605496
Condition:
Advanced Solid Tumors
Metastatic Solid Tumors
Conditions: Official terms:
Neoplasms
Conditions: Keywords:
Solid Tumors
NP137
anti-PD1/PDL1
Stable disease
Primary refractory
Secondary Refractory
Netrin-1
monoclonal antibody
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The 3 cohorts of patients will be conducted and analyzed independently. The sample size
calculation will use an adaptive Simon 2-stage design based on the strategy developed by
Lin and Shih (Biometrics 2004). This method allows checking the result at the first
stage, adjusting the power and success rate if necessary, and adapting the decision rule
accordingly.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
NP137
Description:
IV infusion, 14mg/kg, Q3W
Arm group label:
Primary refractory
Arm group label:
Secondary refractory
Arm group label:
Stable Disease
Intervention type:
Drug
Intervention name:
anti-PD-1/PD-L1
Description:
IV infusion, Q3W or Q6W anti-PD1/PDL1 are standard treatments and are prepared and
administred as per respective SmPC and institutional practice.
Arm group label:
Primary refractory
Arm group label:
Secondary refractory
Arm group label:
Stable Disease
Summary:
This study is a multicenter, open-label, proof-of-concept study aiming to assess the
clinical and biological impact of NP137 when added to standard PD-1/PD-L1 blockade
therapy in 3 independent cohorts of advanced or metastatic solid tumors with various
sensitivity to anti-PD-1/PD-L1:
- Cohort 1 [Stable Disease]: Patients with a radiological documentation of SD
according to RECIST V1.1 criteria following at least 12 weeks under standard anti
PD-1/PD-L1 therapy. Note: This treatment arm closed on 27/09/2024 due to
non-feasibility.
- Cohort 2 [primary refractory]: Patients with documented radiological PD according to
RECIST V1.1 but with clinical benefit under anti PD-1/PD-L1 standard therapy.
- Cohort 3 [secondary refractory]: Patients with documented radiological PD following
an initial Objective Response according to RECIST V1.1, with clinical benefit under
standard anti-PD-1/PD-L1.
Detailed description:
To be eligible to cohort 1 [stable disease], the initial evidence of SD is to be
confirmed by a second assessment, no less than 4 weeks from the date of the first
documented SD. To be eligible to cohorts 2 and 3 [primary and secondary refractory
patients], patients must meet all the following criteria:
- Evidence of clinical benefit according to investigator assessment. The assessment of
clinical benefit should be balanced by clinical judgment as to whether the patient
is clinically deteriorating and unlikely to receive any benefit from continued
anti-PD-1/PD-L1 treatment.
- Absence of symptoms and signs (including laboratory values, such as new or worsening
hypercalcemia) indicating unequivocal progression of disease,
- Absence of decline in ECOG PS that can be attributed to disease progression,
- Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal
disease) that cannot be managed by protocol-allowed medical interventions.
- No ongoing clinically significant AE related to anti-PD-1/PD-L1.
During this study:
- All patients will receive NP137 (14 mg/kg, IV, Q3W) as add-on treatment to their
standard anti-PD1 or anti-PDL1 treatment administered.
- To facilitate the study treatments administration and to not over burden patients,
the study drug NP137 which is administered every 3 weeks (Q3W) will be associated to
standard PD-1/PD-L1 therapies for which dosing are administered every 3 weeks or
every 6 weeks (Q3W or Q6W). A treatment delay of up to 3 days is allowed before the
start of a new cycle.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
I1. Male or female patients aged ≥ 18 years at time of inform consent signature.
I2. Patient with histologically confirmed locally advanced / metastatic solid tumors of
any histological types
I3. Patients treated with standard anti-PD-1/PD-L1 (e.g. pembrolizumab, atezolizumab, or
any other ICI to be approved and reimbursed in France during the course of this trial,
with a Q3W or Q6W schedule, either as monotherapy or in combination with chemotherapies
according to their approved label). A positive list of eligible solid tumour types
together with the associated anti-PD-1/PD-L1 standard therapy approved for each
indication is provided in appendix 7. For any pathology not listed in this appendix but
for which an anti-PD-1/PD-L1 has newly obtained a MA and is now reiumbursed in France,
please refer to the section 1.6.2 of this protocol) and meet the following criteria :
- I3a. Cohort 1: Patient with RECIST 1.1.-defined SD under at least 12 weeks
anti-PD-1/PD-L1. The initial evidence of SD is to be confirmed by a second
assessment, no less than 4 weeks from the date of the first documented SD.
- I3b. Cohort 2: Patient with RECIST 1.1-defined PD under anti-PD-1/PD-L1.
- I3c. Cohort 3: Patients with RECIST 1.1-defined PD under anti-PD1/PD-L1 after
initial objective response (CR or PR according to RECIST V1.1)
Note 1 : For patients treated with an anti-PD-1/ PD-L1 previously combined to another
anti-cancer agents of any type (including but not limited to chemotherapy/ other
immunotherapy/ biological -or targeted agents) theseagents must be stopped 2 weeks or 5*
t ½ whichever is shorter before C1D1 while anti-PD1 or anti PDL1 is continued according
to Market Authorisation.
Note 2: Patients may have received a line of chemotherapy or any other standard
anti-cancer agent after PD under anti-PD-1/PD-L1 but recurrence/progression under
aPD-1/aPD-L1 y must have been documented ≤ 12 months before inclusion. Intercurrent
chemotherapy or other standard agents must be stopped 2 weeks or 5* t ½ whichever is
shorter before C1D1. Those patients will be then recruited in one of the refractory
cohorts and could re-start an anti-PD1/PD-PL1 immediately in combination with NP137 at
inclusion.
I4. Refractory cohorts: To be eligible in these cohorts, patients must meet all the
following criteria:
- Evidence of clinical benefit according to investigator assessment. The assessment of
clinical benefit should be balanced by clinical judgment as to whether the patient
is clinically deteriorating and unlikely to receive any benefit from continued ICI
treatment.
- Absence of symptoms and signs (including laboratory values, such as new or worsening
hypercalcemia) indicating unequivocal progression of disease,
- Absence of decline in ECOG PS that can be attributed to disease progression,
- Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal
disease) that cannot be managed by protocol-allowed medical interventions.
- No ongoing clinically significant AE related to ICI.
I5. Patient with of at least one lesion measurable and evaluable as per RECIST V1.1
according to central imaging review before C1D1. Tumour lesions located in a previously
irradiated area, or in an area subjected to other locoregional therapy, cannot be
considered as measurable/evlaluable unless there has been a documentation of progression
in the lesion.
I6. Availability of a representative archival tumor sample in formalin-fixed paraffin
embedded (FFPE) block (primary tumor or metastasis) or newly obtained core or excisional
biopsy of a tumor lesion together with an associated pathology report.
I7. Presence of at least one tumor lesion with a diameter ≥10 mm (≥20mm in case of a
single biospsiable and RECIST 1.1 target lesion) visible by medical imaging and
accessible to repeatable percutaneous sampling that permits core needle biopsy without
unacceptable risk of a significant procedural complications, and suitable for retrieval
of 4 cores using a 16-gauge diameter needle or larger.
Note: lesions to be biopsied should not be selected as RECIST target lesions unless there
are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy,
the lesion must be ≥ 2 cm in longest diameter. Bone lesions are not adequate lesions for
biopsies. Osteolytic lesions with soft tissue involvement cannot be biopsied.
I8. Life expectancy ≥ 3 months. I9. Eastern Cooperative Oncology Group performance status
0 or 1
I10. Demonstrate adequate cardiovascular function:
- QTcF < 470ms
- Resting BP systolic < 160mmHg and diastolic < 100mmHg
- LVEF > 50% as determined by transthoracic echocardiogram.
I11. Demonstrate adequate organ function as defined in table below, all screening
laboratory tests should be performed within 7 days prior C1D1:
- Hematological : Absolute neutrophil count (ANC) ≥ 1.5 G/L (1500/µL)
Platelets ≥ 100 G/L (100000/µL) (transfusion within 21 days before C1D1 is allowed).
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L-1 Packed red blood cell(pRBC) transfusion is allowed
within past 2 weeks. Patient can be on stable dose of erythropoietin (≥3 months)
- Renal : Serum creatinine OR Creatinine clearance according to CKD-EPI (Appendix 3) ≤
1.5 X upper limit of normal (ULN) OR ≥ 30 mL/min/1.73m2 for patient with creatinine
levels > 1.5 ULN
- Hepatic : Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients
with total bilirubin levels > 1.5 ULN
AST and ALT ≤ 2.5 X ULN (up to 5 ULN in case of liver metastases)
- Coagulation : International Normalized Ratio (INR) and Activated Partial
Thromboplastin Time (aPTT) ≤ 1.5 X ULN Note: This is applicable only for patients
not receiving an anticoagulant treatment: patients receiving therapeutic
anticoagulation must be on stable dose.
I12. Women of child-bearing potential must have a negative urine pregnancy test at
screening (within 72 hours prior C1D1) and must agree to use 2 effective forms of
contraception from the time of the treatment period and of the negative pregnancy test up
6 months after the end of their treatment. Effective forms of contraception are listing
in Appendix 4.
I13. Fertile males must use a highly effective contraception during dosing period and
through 3 months after final dose of study treatments.
I14. Patient should be able and willing to comply with study visits and procedures as per
protocol.
I15. Patient should understand, sign, and date the written voluntary informed consent
form at the screening visit prior to any protocol-specific procedures performed.
I16. Patients must be covered by a medical insurance.
Exclusion Criteria:
E1. Patients eligible to curative treatment E2. For refractory cohorts: patients eligible
to standard treatment with documented proof of activity in the tumor type or to other
therapeutic options (approved or investigational) with documented evidence of clinical
activity.
E3. For patients under chemotherapy /Immunotherapy/ biological- or targeted- or any other
type of therapy + ICI before inclusion: Persistence of CTCAE ≥ Grade 2 toxicity due to
prior combined agent (except alopecia (any grades), blood tests values according to
inclusion criteria).
E4. Patient with any history of CTCAE Grade 4 irAEs under anti-PD-1/PD-L1 treatment or
any history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day prednisone or
equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis regardless of steroid
treatment.
E5. History of severe (≥ Grade 3) allergic anaphylactic reactions to one of the
components of NP137, standard ICI, premedication and/or any of their excipients.
E6. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to first
dose of study treatment.
E7. Has a known additional malignancy that is progressing or has required active
treatment within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded.
E8. Prior therapy or needs to be treated with a forbidden concomitant/concurrent
therapies/procedures including:
- Any investigational agent or have used an investigational device. Note: Participants
who have entered the follow-up phase of an investigational study may participate as
long as it has been 2 weeks or 5* ½ whichever is shorter after the last dose of the
previous investigational agent.
- Radiotherapy within 4 weeks of start of study treatment. Participants must have
recovered from all radiation-related toxicities, not require corticosteroids, and
not have had radiation pneumonitis.Palliative radiation (≤ 2 weeks of radiotherapy)
to non-CNS disease and on non-target lesion is allowed.
- Major surgery within 4 weeks of start of study treatment. Participants must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting study treatment, C1D1.
- Anti-cancer treatment other than those specified in the protocol i.e. standard
anti-PD1/PDL1
- Live or live-attenuated vaccine within 30 days prior to the first dose of study
treatments. Note: killed are allowed.
- Immunosuppressive medication within 2 weeks with the exceptions of intranasal,
topical and inhaled corticosteroids or systemic corticosteroids at doses which are
not to exceed 10 mg/day of prednisone, or equivalent doses of another
corticosteroid.
E9. Have a history of autoimmune disease that has required systemic treatment in past 2
years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of
systemic treatment and is allowed.
History of autoimmune disease which include but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple
sclerosis, vasculitis, or glomerulonephritis with the following exceptions:
- patients with a history of autoimmune-related hypothyroidism who are on stable
thyroid replacement hormone therapy,
- patients with controlled Type 1 diabetes mellitus,
- patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
excluded) are eligible provided that they meet the following conditions:
- Rash must cover less than 10% of body surface area (BSA).
- Disease is well controlled at baseline and only requiring low potency topical
steroids.
- No acute exacerbations of underlying condition within the previous 12 months
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoid,
biologic agents, oral calcineurin inhibitors, high potency or oral steroids.
E10. Patients with HIV, active B or C hepatitis infection. Notes: Active hepatitis B i.e.
chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test
at screening before C1D1. Patients with past hepatitis B virus (HBV) infection or
resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc]
and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients
prior to C1D1. Patients with a positive HBcAb test must have a negative HBV DNA test at
screening. Active hepatitis C i.e. Patients positive for hepatitis C virus (HCV) antibody
are eligible only if PCR is negative for HCV RNA at screening.
E11. Patients with active tuberculosis. E12. Prior allogeneic bone marrow transplantation
or solid organ transplant for another malignancy in the past.
E13. History of idiopathic pulmonary fibrosis, non-infectious pneumonitis/ interstitial
lung disease that required steroids or has current pneumonitis / interstitial lung
disease, drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans,
cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest
CT scan.
E14. Have an active infection requiring systemic therapy. E15. Pregnant or breastfeeding
women. A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to
treatment. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required.
E16. Patients placed under a legal protection regimen: Judicial Safeguards, curatorship
or guardianship.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Centre Léon Bérard
Address:
City:
Lyon
Zip:
69008
Country:
France
Status:
Recruiting
Contact:
Last name:
Jérôme FAYETTE, MD
Phone:
+33 4.78.78.51.03
Email:
jerome.fayette@lyon.unicancer.fr
Contact backup:
Last name:
Jérôme FAYETTE, MD
Facility:
Name:
Centre Antoine Lacassagne
Address:
City:
Nice
Zip:
06189
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Esma SAADA-BOUZID, MD
Phone:
04 92 03 15 14
Email:
esma.saada-bouzid@nice.unicancer.fr
Contact backup:
Last name:
Esma SAADA-BOUZID, MD
Facility:
Name:
Institut Curie
Address:
City:
Paris
Zip:
75005
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Christophe LE TOURNEAU, MD
Phone:
01 53 10 40 06
Email:
christophe.letourneau@curie.fr
Contact backup:
Last name:
Christophe LE TOURNEAU, MD
Facility:
Name:
Institut de Cancérologie Strasbourg Europe (ICANS)
Address:
City:
Strasbourg
Zip:
67033
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Mickaël BURGY, MD
Phone:
03 68 76 73 60
Email:
m.burgy@icans.eu
Contact backup:
Last name:
Mickaël BURGY, MD
Facility:
Name:
Institut Claudius Regaud (IUCT Oncopole)
Address:
City:
Toulouse
Zip:
31059
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Jean-Pierre DELORD, MD
Phone:
05 31 15 55 01
Email:
delord.jean-pierre@iuct-oncopole.fr
Contact backup:
Last name:
Jean-Pierre DELORD, MD
Start date:
January 6, 2023
Completion date:
November 24, 2026
Lead sponsor:
Agency:
Centre Leon Berard
Agency class:
Other
Collaborator:
Agency:
NETRIS Pharma
Agency class:
Industry
Source:
Centre Leon Berard
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05605496
