Combination of Tarlatamab and Temozolomide in Patients With Central Nervous System Tumors

NCT07243470 | Recruiting Phase 1 DMC

• 2 other identifiers: ET23-0402023-510568-11-00
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 11

Brief Summary

This clinical trial is a 2-phase trial designed to evaluate the safety of tarlatamab in combination with a fixed dose of metronomic temozolomide in adolescents and adults with CNS tumors (stratified into two age-based cohorts), and to assess the clinical activity of this therapeutic strategy in three parallel, histology-defined cohorts (IDH-mutant glioma, other gliomas, and other CNS tumors). A pre-screening to detect DLL3 expression by IHC on archival tumor sample must be performed before the therapeutic part. Only patients with DLL3 positive tumor on IHC can be enrolled in the therapeutic part. This pre-screening must be optimally performed during the ongoing treatment line i.e. before documented progression to not delay treatment starts at time of progression. Tumor samples (surgery or biopsy specimen) will be sent to a central lab for IHC testing.

Conditions

Glioma; CNS Tumor, Adult; CNS Tumor, Childhood

Keywords

temozolomide; tarlatamab; phase 1/2; RP2D; glioma

Outcome Measures

Primary Outcomes (2)

• Phase I : Dose limiting toxicities (DLT) assessed as related at least to tarlatamab, occurring during the first 2 cycles of treatment

  Dose limiting toxicities (DLT) defined as the following adverse event (AE) graded according to NCI CTCAE V5.0 or specific grading system for ICANS and CRS, assessed as related at least to tarlatamab, occurring during the first 2 cycles of treatment (i.e. DLT period is 8 weeks for DL1 or 12 weeks if DL-1 is investigated) : - Any Grade 4 non-laboratory toxicity (including CRS). * Any Grade 3 non-laboratory toxicity (including CRS) lasting \>7 days despite optimal supportive care and with the following exceptions: Grade 3 fatigue, Grade ≥ 3 Diarrhea/Vomiting/Nausea adequately managed with supportive care measures within 14 days. * Grade ≥ 3 ICANS. * Any Grade 3 or Grade 4 laboratory value if medical intervention is required or the abnormality persists for \>1 week. * Febrile neutropenia Grade ≥ 3 * Grade 4 anemia * Any Grade 5 toxicity (i.e., toxic death) * Any other significant toxicity deemed by the investigator and/or member of the steering meeting to be dose limiting.

  From Cycle 1 Day 1 to week 8

• Phase II : To assess the clinical activity of the proposed therapeutic strategy in 3 parallel and independent cohorts of CNS tumors (IDH-mutant glioma, other glioma and other CNS tumors).

  Objective response rate at 12 weeks (ORR-12W) according to immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria

  12 weeks from the date of first study drug administration (Cycle 1 Day 1)

Secondary Outcomes (6)

• Evaluation of the Duration of Response (DoR)

  From the time of first documented response (Complete Response or Partial Response as per iRANO) until the first documented disease progression or death due to underlying cancer, or censored at the date of the last available tumor assessment

• Evaluation of the time to objective response (ToR)

  From Cycle 1 Day 1 to first documented objective response

• Evaluation of Disease Control Rate (DCR)

  From enrollment to the end of treatment at 12 months

• Evaluation of Progression-Free Survival (PFS)

  From Cycle 1 Day 1 to the date of the first disease progression or death

• Evaluation of Overall Survival (OS)

  From Cycle 1 Day 1 to the date of death from any cause

Other Outcomes (1)

• To identify biomarkers predictive of tumor response including DLL3 expression during treatment using descriptive statistics and appropriate multivariate models

  From enrollment to the end of treatment at 12 months

Study Arms (3)

Patients with IDH-mutant glioma

EXPERIMENTAL

Patients must have histologically confirmed diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma or other high-grade CNS tumors.

Drug: Tarlatamab; Drug: Temozolomide (TMZ)

Patients with other glioma

EXPERIMENTAL

Patients must have histologically confirmed diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma or other high-grade CNS tumors.

Drug: Tarlatamab; Drug: Temozolomide (TMZ)

Patients with other CNS tumors

EXPERIMENTAL

Patients must have histologically confirmed diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma or other high-grade CNS tumors.

Drug: Tarlatamab; Drug: Temozolomide (TMZ)

Interventions

Tarlatamab DRUG

At the starting dose (DL1): All patients will receive a step dose (1 mg) on C1D1 administered as a 60-minute intravenous (IV) infusion then 10mg at C1D8 and C1D15 of tarlatamab single agent (no temozolomide administered during cycle 1) then tarlatamab at 10mg every D1 \& D15 of each 4-week cycle thereafter in combination with temozolomide from C2D1. At DL-1: a cycle period will be 6 weeks with tarlatamab administration every 3 weeks after Cycle 1.

Patients with IDH-mutant glioma; Patients with other CNS tumors; Patients with other glioma

Temozolomide (TMZ) DRUG

At DL1 : Metronomic temozolomide will not be administered during the first cycle. It will be administered from the first day of the second cycle, at a dose of 50 mg/m²/day, continuously. At DL-1 : Metronomic temozolomide will not be administered during the first cycle. It will be administered from the first day of the second cycle, at a dose of 50 mg/m²/day, continuously.

Also known as: Temodal

Patients with IDH-mutant glioma; Patients with other CNS tumors; Patients with other glioma

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• I1. Patients aged ≥ 12 years old at time of inform consent signature.
• I2. Histologically proven diagnosis of central nervous system (CNS) malignant tumor: IDH-mutant high-grade glioma, other high-grade glioma, or other high-grade CNS tumors.
• I3. Tumors expressing DLL3 based on IHC staining performed on archival tumor sample i.e. at least 1+ on IHC \[patient with no tumor expression of DLL3 are not eligible\].
• Note- This pre-screening by IHC should be optimally initiated during an ongoing line of treatment i.e. before documented progression. The ICF1 must be signed before to initiate this pre-screening.
• I4. Confirmed progressive or refractory disease after at least one line of standard therapy containing radiotherapy and for which no further effective standard therapy exists.
• I5. Evaluable or measurable disease as per iRANO criteria.
• I6. Performance status (See Appendix 01):
• Karnofsky PS for pediatric patients ≥16 years of age ≥ 70%;
• Lansky PS for patients between 12 and 15y: ≥ 70%;
• PS ECOG for adult patients: 0 or 1.
• I7. Life expectancy ≥ 3 months.
• I8. Adequate end organ function according to laboratory values defined below :
• Hematologic criteria :
• Peripheral absolute neutrophil count (ANC) ≥1.5 G/L (without growth factor support within 7 days)
• Platelet count ≥ 100 G/L (unsupported for \> 7 days)

You may not qualify if:

• E1. Diagnosis of non-CNS tumor.
• E2. Diagnosis of diffuse intrinsic pontine glioma.
• E3. Current treatment with bevacizumab.
• E5. Neurologically unstable or require increasing doses of corticosteroids during the 7 days before C1D1 or local CNS-directed therapy to control their CNS disease. Note: Patients on low doses of corticosteroids (\< 0.25mg/kg/d of prednisolone or equivalent) during the 7 days prior to receiving study drugs are eligible.
• E6. Evidence of Grade \> 1 recent CNS hemorrhage on the baseline MRI scan.
• E7. Bulky tumor on imaging defined as:
• i. Tumor with any evidence of uncial herniation or severe midline shift ii. Tumor with diameter of \> 6 cm in one dimension on contrast-enhanced MRI iii. Tumor that in the opinion of the investigator shows significant mass effect.
• E8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
• E9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to C1D1.
• E10. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 6 months of C1D1).
• E11. Other malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints (basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, localized prostate cancer), or with no evidence of disease for ≥ 2 years.
• E12.History of hypophysitis or pituitary dysfunction.
• E13.History of severe allergic or other hypersensitivity reactions to
• chimeric or humanized antibodies or fusion proteins,
• biopharmaceuticals produced in Chinese hamster ovary cells,

Sponsors & Collaborators

• Centre Leon Berard: lead
• Amgen: collaborator
• National Cancer Institute, France: collaborator

Study Sites (11)

Institut de Cancérologie de l'Ouest

Angers, 49055, France

RECRUITING

Hôpital Universitaire d'Angers

Angers, 49933, France

NOT YET RECRUITING

CHU de Bordeaux

Bordeaux, 33000, France

NOT YET RECRUITING

Hôpital Saint-André

Bordeaux, 33075, France

NOT YET RECRUITING

Hôpital Neurologique Pierre Wertheimer

Bron, 69677, France

RECRUITING

Centre Oscar Lambret

Lille, 59000, France

NOT YET RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Hôpital de la Timone

Marseille, 13005, France

NOT YET RECRUITING

Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix

Paris, 75013, France

NOT YET RECRUITING

IUCT - Claudius Regaud

Toulouse, 31100, France

NOT YET RECRUITING

Institut Gustave Roussy

Villejuif, 94085, France

NOT YET RECRUITING

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MeSH Terms

Conditions

Glioma; Central Nervous System Neoplasms

Interventions

Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases

Intervention Hierarchy (Ancestors)

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

Central Study Contacts

Pierre LEBLOND, MD, PhD

CONTACT

+33469166550; pierre.leblond@ihope.fr

Aurélien MAUREILLE, MD

CONTACT

+33469166645; aurelien.maureille@lyon.unicancer.fr

Study Design

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

Model Details: The study consists of 2 parts: A Phase I (safety run-in) part to confirm the safety of tarlatamab single agent followed by combination with a fixed dose of metronomic temozolomide (TMZ). Patients start at DL1 with a test dose of tarlatamab 1 mg (C1D1), followed by 10 mg on D8 and D15 of cycle 1 without TMZ. From cycle 2 onward, they receive 10 mg of tarlatamab on D1 and D15 of each 4-week cycle in combination with TMZ. Adult safety run in cohort will be opened first, then adolescent safety run in cohort will be evaluated only once the adult safety run in is cleared. A one-week delay period between each pediatric enrolment will be required during pediatric safety run in. A Phase II part to assess the clinical activity of the proposed strategy in 3 independent and parallel cohorts: IDH-mutant high-grade glioma, other high-grade glioma, and other high-grade CNS tumors. Enrolment in phase II will be possible only after validation of safety run in in adults then in paediatric patients.

Study Record Dates

• First Submitted: September 30, 2025
• First Posted: November 24, 2025
• Study Start: November 4, 2025
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2030
• Last Updated: April 22, 2026

Record last verified: 2026-04

Locations

FR (11)