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NP137 Clinical and Biological Activities Assessment in Patients With Advanced/Metastatic Solid Tumors Treated by Standard Anti PD-1/PD-L1 Immunotherapies

Recruiting
18 years of age
Both
Phase 2

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Overview

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.
  • 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.

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.

Eligibility

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.

Study details

Advanced Solid Tumors, Metastatic Solid Tumors

NCT05605496

Centre Leon Berard

19 March 2024

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