Safety and Efficacy of L19TNF Plus Temozolomide Chemoradiotherapy in Patients With Newly Diagnosed Glioblastoma

NCT04443010 | Recruiting Phase 1

• 1 other identifier: PH-L19TNFTMZ-01/20
• Study Type: interventional
• Target: 226
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to explore the safety profile and establish a recommended dose (RD) for phase II of the antibody-cytokine fusion protein L19TNF plus standard TMZ chemoradiotherapy in patients with newly diagnosed glioblastoma. The study will be conducted in three consecutive parts: a dose finding part to determine the RD of L19TNF in combination with chemoradiotherapy, followed by a signal seeking part that investigates first signs of activity and then an activity evaluation part that studies the efficacy of L19TNF in combination with chemoradiotherapy against chemoradiotherapy alone.

Conditions

Glioblastoma

Keywords

Glioblastoma

Outcome Measures

Primary Outcomes (2)

• For Phase 1: DLT

  Occurrence of dose limiting toxicity (DLT) assessed by frequency and grade of adverse events (AE) according to CTCAE v.5.0.

  For Cohort 1 and Cohort 2 from Day 1 to Day 28 of the maintenance cycle; for Cohort 3, 4 and 5 from Day 1 to Day 42 of the chemoradiotherapy.

• For Phase 2: Overall Survival

  Overall survival (OS) rate

  From beginning of treatment to 52 weeks

Secondary Outcomes (12)

• PFS

  From the date of enrollment to the date of progression or death for any cause, whichever came first, assessed up to 58 weeks

• ORR in CR

  At week 10, at week 22, at week 34, at week 46 and at week 58

• ORR in PR

  At week 10, at week 22, at week 34, at week 46 and at week 58

• DCR in CR

  At week 10, at week 22, at week 34, at week 46 and at week 58

• DCR in PR

  At week 10, at week 22, at week 34, at week 46 and at week 58

Study Arms (4)

Phase 1 part: Dose Finding

EXPERIMENTAL

Patients will be treated in cohorts according to a 3+3 study design with standard treatment (consisting of radiotherapy of 60 Gy/30 fractions for 6 weeks plus 75 mg/m2 TMZ (temozolomide) daily (chemoradiotherapy), followed by 4 weeks of treatment break, followed by maintenance treatment with 6 maintenance cycles of TMZ 150-200 mg/m2 on Days 1 to 5 q28) combined with L19TNF at different dose levels on Day 1, 3, 5, 22, 24 and 26 of chemoradiotherapy and on Day 1, 3 and 5 of each 28-day chemotherapy maintenance cycle.

Drug: Onfekafusp alfa

Phase 2 part: Signal Seeking

EXPERIMENTAL

32 patients will receive standard chemoradiotherapy and L19TNF at RD and with the administration scheme established in phase I part of the study.

Drug: Onfekafusp alfa

Phase 2b part: Activity Evaluation_control arm

ACTIVE COMPARATOR

Patients will be randomized 1:1 and treated with either standard chemoradiotherapy and L19TNF as established in phase I part and the phase II part of this study or only chemoradiotherapy (control). \- Arm 2: Patients will receive radiotherapy and TMZ (temozolomide).

Drug: Temozolomide

Phase IIb part: Activity Evaluation_treatment arm

EXPERIMENTAL

Patients will be randomized 1:1 and treated with either standard chemoradiotherapy and L19TNF as established in phase I part and the phase II part of this study or only chemoradiotherapy (control). \- Arm 1: Patients will receive radiotherapy, TMZ (temozolomide) and L19TNF.

Drug: Onfekafusp alfa; Drug: Temozolomide

Interventions

Onfekafusp alfa DRUG

This is an open label phase 1/2/2b study in subjects with newly diagnosed glioblastoma. The study will be conducted in three consecutive parts: First the dose finding part to determine the RD of L19TNF in combination with chemoradiotherapy, followed by a signal seeking part that investigates first signs of activity and then an activity evaluation part that studies the efficacy of L19TNF in combination with chemoradiotherapy against chemoradiotherapy alone.

Also known as: L19TNF

Phase 1 part: Dose Finding; Phase 2 part: Signal Seeking; Phase IIb part: Activity Evaluation_treatment arm

Temozolomide DRUG

Patients will receive radiotherapy and TMZ. Treatment start with chemoradiotherapy is foreseen after surgical resection or biopsy of glioblastoma

Also known as: TMZ

Phase 2b part: Activity Evaluation_control arm; Phase IIb part: Activity Evaluation_treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, age ≥18.
• Patients with histologically confirmed newly diagnosed glioblastoma.
• Karnofsky Performance Score (KPS) ≥ 70%
• 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 (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), 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.
• Female patients: negative pregnancy test for women of childbearing potential (WOCBP)\* within 14 days of starting treatment. 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.
• Personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• 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).

You may not qualify if:

• Prior treatment for glioma, except surgery.
• Inability to undergo contrast-enhanced MRI.
• Intent to be treated with tumor-treating fields prior to progression.
• Known history of allergy to TNF or TMZ, any excipient in the study medication or any other intravenously administered human proteins/peptides/antibodies.
• Absolute neutrophil count (ANC) \< 1.5 x 10\^9/L, platelets \< 100 x 10\^9/L or haemoglobin (Hb) \< 9.0 g/dl.
• Chronically impaired renal function as indicated by creatinine clearance \< 60 mL/min or serum creatinine \> 1.5 ULN.
• Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN).
• INR \> 1.5 ULN.
• 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.
• Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent.
• History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
• Clinically significant cardiac arrhythmias or requiring permanent medication.
• Abnormal LVEF 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.
• Uncontrolled hypertension.

Sponsors & Collaborators

• Philogen S.p.A.: lead

Study Sites (1)

UniversitatSpital USZ

Zurich, Switzerland

RECRUITING

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Tobias Weiss, PhD, MD

  Universitatspital Zurich - Klinik fur Neurologie & Hirntumorzentrum

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Teresa Hemmerle, PhD

CONTACT

+390577017816; regulatory@philogen.com

Serena Bettarini, Pharmacist

CONTACT

+390577017816; regulatory@philogen.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open label phase I/II study in subjects with newly diagnosed glioblastoma. The study will be conducted in three consecutive parts: (i) first the dose finding part to determine the RD of L19TNF in combination with chemoradiotherapy, (ii) followed by a signal seeking part that investigates first signs of activity and (iii) then an activity evaluation part that studies the efficacy of L19TNF in combination with chemoradiotherapy against chemoradiotherapy alone.

Study Record Dates

• First Submitted: June 17, 2020
• First Posted: June 23, 2020
• Study Start: January 20, 2021
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: October 10, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)