Clinical Trials /

A Study to Evaluate Safety and Efficacy of L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression

NCT04573192

Description:

Glioblastomas are the most common and most aggressive primary brain tumors in adults. The prognosis is poor despite multimodal therapy with surgery, radiotherapy and chemotherapy. Therefore, novel treatments are urgently needed. L19TNF is a fully human fusion protein consisting of human tumor necrosis factor (TNF)-α fused to the L19 antibody in scFv format, specific to the extra-domain B of fibronectin. TNF not only induces apoptosis or necrosis in certain target cells, but also exerts inflammation and immunity. L19TNF selectively delivers TNF to the tumor site to spare normal tissues from undesired toxicity. Preclinical experiments with L19TNF have demonstrated tumor growth retardation in various mouse tumor models including models of glioma.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate Safety and Efficacy of L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression
  • Official Title: A Study to Evaluate the Safety and Efficacy of the Tumor-targeting Human Antibody-cytokine Fusion Protein L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression

Clinical Trial IDs

  • ORG STUDY ID: PH-L19TNFCCNU-02/20
  • NCT ID: NCT04573192

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
L19TNFonfekafusp alfaPhase 1 part: Dose Finding
LomustinePhase 1 part: Dose Finding

Purpose

Glioblastomas are the most common and most aggressive primary brain tumors in adults. The prognosis is poor despite multimodal therapy with surgery, radiotherapy and chemotherapy. Therefore, novel treatments are urgently needed. L19TNF is a fully human fusion protein consisting of human tumor necrosis factor (TNF)-α fused to the L19 antibody in scFv format, specific to the extra-domain B of fibronectin. TNF not only induces apoptosis or necrosis in certain target cells, but also exerts inflammation and immunity. L19TNF selectively delivers TNF to the tumor site to spare normal tissues from undesired toxicity. Preclinical experiments with L19TNF have demonstrated tumor growth retardation in various mouse tumor models including models of glioma.

Trial Arms

NameTypeDescriptionInterventions
Phase 1 part: Dose FindingExperimentalPhase I part: Dose Finding Patients will be treated in cohorts according to a traditional 3+3 design with lomustine on Day 1 and L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26, of a 42-days cycle at different dose levels. The RD will be confirmed following a traditional 3+3 design. Cohort 1: 10 µg /kg L19TNF i.v. plus 90 mg/m2 lomustine Cohort 2: 10 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine Cohort 3: 13 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine The dose of 13 ug/kg L19TNF will be declared the RD in case none of three or not more than one out of 6 patients experienced a DLT. Dose limiting toxicity will be assessed during the dose-escalation from Day 1 through Day 42 after the first administration of lomustine and study drug (Cycle 1). Not more than 2 patients might be treated simultaneously in Cycle 1.
  • L19TNF
  • Lomustine
Phase II part: Signal SeekingExperimental118 Patients will be randomized 1:1 and treated with either lomustine on day 1 and L19TNF on Days 1, 3 and 5, and on Days 22, 24, and 26 of a 42-days cycle at the RD established in the phase I part of the study or with lomustine on day 1 of a 42-days cycle. Treatment Arm 1: L19TNF plus Lomustine Treatment Arm 2: Lomustine
  • L19TNF
  • Lomustine

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female, age ≥18.

          2. Patients with histologically confirmed glioblastoma at first recurrence.

          3. MGMT promotor status known

          4. Presence of at least one lesion of measurable disease by MRI of at 10 mm in longest
             diameter on baseline MRI.

          5. Karnofsky Performance Score (KPS) ≥ 70%

          6. Documented negative test for HIV-HBV-HCV. For HBV serology, the determination of HBsAg
             and anti-HBcAg Ab is required. In patients with serology documenting previous exposure
             to HBV, negative serum HBV-DNA is required. For HCV, HCV-RNA or HCV antibody test is
             required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA
             indicating no current infection are eligible.

          7. Female patients: female patients must be either documented not Women Of Childbearing
             Potential (WOCBP)* or must have a negative pregnancy test within 14 days of starting
             treatment. Additionally WOCBP must agree to use, from the screening to 6 months
             following the last study drug administration, highly effective contraception methods,
             as defined by the "Recommendations for contraception and pregnancy testing in clinical
             trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group
             (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined
             (estrogen- and progesterone-containing) hormonal contraception associated with
             inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems,
             bilateral tubal occlusion or vasectomized partner.

             Male patients: male subjects able to father children must agree to use two acceptable
             methods of contraception throughout the study (e.g. condom with spermicidal gel).
             Double-barrier contraception is required.

          8. Personally signed and dated informed consent document indicating that the subject has
             been informed of all pertinent aspects of the study.

          9. Willingness and ability to comply with the scheduled visits, treatment plan,
             laboratory tests and other study procedures.

               -  Women of childbearing potential are defined as females who have experienced
                  menarche, are not postmenopausal (12 months with no menses without an alternative
                  medical cause) and are not permanently sterilized (e.g., tubal occlusion,
                  hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).

        Exclusion Criteria:

          1. Prior treatment for glioblastoma at recurrence, except surgery.

          2. Surgical resection or biopsy of glioma within 4 weeks of the start of study treatment.

          3. Inability to undergo contrast-enhanced MRI.

          4. Known history of allergy to TNF or lomustine, any excipient in the study medication or
             any other intravenously administered human proteins/peptides/antibodies.

          5. Absolute neutrophil count (ANC) < 1.5 x 10^9/L; platelets < 100 x 10^9/L or
             haemoglobin (Hb) < 9.0 g/dl.

          6. Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min
             or serum creatinine > 1.5 ULN.

          7. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN).

          8. INR > 1.5 ULN.

          9. Any severe concomitant condition which makes it undesirable for the patient to
             participate in the study or which could jeopardize compliance with the protocol, in
             the opinion of the investigator.

         10. Active or history of autoimmune disease that might deteriorate when receiving an
             immuno-stimulatory agent, in the judgement of the investigator.

         11. History within the last year of cerebrovascular disease and/or acute or subacute
             coronary syndromes including myocardial infarction, unstable or severe stable angina
             pectoris.

         12. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).

         13. Clinically significant cardiac arrhythmias or requiring permanent medication.

         14. LVEF <55% or any other abnormalities observed during baseline ECG and echocardiogram
             investigations that are considered as clinically significant by the investigator.
             Subjects with current or a history of QT/QTc prolongation are excluded.

         15. Uncontrolled hypertension.

         16. Known arterial aneurism at high risk of rupture.

         17. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine
             classification).

         18. Medically documented history of or active major depressive episode, bipolar disorder
             (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt
             or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or
             patients with active severe personality disorders.

         19. Anxiety ≥ CTCAE Grade 3.

         20. Severe diabetic retinopathy such as severe non-proliferative retinopathy and
             proliferative retinopathy.

         21. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)
             within 4 weeks of administration of study treatment.

         22. Known history of tuberculosis.

         23. Pregnancy or breast feeding.

         24. Requirement of chronic administration of high dose corticosteroids or other
             immunosuppressant drugs. Subjects must have been either off corticosteroids, or on a
             stable or decreasing dose ≤ 4 mg daily dexamethasone (or equivalent) for 7 days prior
             to start of treatment. Limited or occasional use of corticosteroids to treat or
             prevent acute adverse reactions is not considered an exclusion criterion.

         25. Presence of active and uncontrolled infections or other severe concurrent disease,
             which, in the opinion of the investigator, would place the patient at undue risk or
             interfere with the study.

         26. Concurrent malignancies unless the patient has been disease-free without intervention
             for at least 2 years.

         27. Growth factors or immunomodulatory agents within 7 days prior to the administration of
             study treatment.

         28. Serious, non-healing wound, ulcer, or bone fracture.

         29. Requirement of concurrent therapy with anticoagulants at therapeutic doses.

         30. Requirement of concurrent use of other anti-cancer treatments or agents other than
             study medication.

         31. Any recent live vaccination within 4 weeks prior to treatment or plan to receive
             vaccination during the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:For Phase 1: DLT
Time Frame:For Cohort 1 to Cohort 3 from Day 1 to Day 42 after the first administration of lomustine and study drug (Cycle 1)
Safety Issue:
Description:Occurrence of dose limiting toxicity (DLT) assessed by frequency and grade of adverse events (AE) according to CTCAE v.5.0.

Secondary Outcome Measures

Measure:PFS
Time Frame:From the date of enrollment to the date of progression or death for any cause, whichever came first, assessed up to 52 weeks
Safety Issue:
Description:Progression-free survival (PFS) based on iRANO criteria and a standardized MRI protocol will be assessed for all enrolled subjects.
Measure:PFS-rate at 6 months
Time Frame:From the date of enrollment to the date of progression or death for any cause, whichever came first, assessed up to 6 months
Safety Issue:
Description:Progression-free survival (PFS) based on iRANO criteria and a standardized MRI protocol will be assessed for all enrolled subjects
Measure:OS-rate at 12 months
Time Frame:From beginning of treatment to 12 months
Safety Issue:
Description:
Measure:Adverse Events (AE)
Time Frame:Throughout study completion for each patient, a maximum of 52 weeks for each patient
Safety Issue:
Description:Safety of administration of L19TNF, through an assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Measure:Serious Adverse Events (AE)
Time Frame:Throughout study completion for each patient, a maximum of 52 weeks for each patient
Safety Issue:
Description:Safety of administration of L19TNF, assessed by Common Toxicity Criteria (version 5.0, CTCAE)
Measure:Safety (DILI)
Time Frame:Throughout study completion for each patient, a maximum of 52 weeks for each patient
Safety Issue:
Description:Evaluation of possible Drug Induce Liver Injury, caused by L19TNF, assessed by Common Toxicity Criteria (version 5.0, CTCAE)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Philogen S.p.A.

Last Updated

October 1, 2020