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

ConditionsGlioma CNS Tumor, Adult CNS Tumor, Childhood

Trial statusRecruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

Age12+

SponsorCentre Leon Berard

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Peripheral absolute neutrophil count (ANC) ≥1.5 G/L (without growth factor support within 7 days)

Disqualifiers

chimeric or humanized antibodies or fusion proteins,

biopharmaceuticals produced in Chinese hamster ovary cells,

or any component of the tarlatamab formulation.

Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA, or

Trial design

Design model

Sequential

Treatments tested in this trial

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.
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.

Treatment groups

70 Participants

are divided into 3 treatment groups

Group A: Patients with IDH-mutant gliomaExperimental treatment 2 interventions

Group B: Patients with other gliomaExperimental treatment 2 interventions

Group C: Patients with other CNS tumorsExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

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.

Time frame

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

Time frame

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

Secondary outcomes

Evaluation of the Duration of Response (DoR)

Time frame

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)

Time to objective Response is defined as time to first documented objective response (Complete Response or Partial Response as per iRANO) following Cycle 1 Day 1

Time frame

From Cycle 1 Day 1 to first documented objective response

Evaluation of Disease Control Rate (DCR)

Disease Control Rate (DCR) will be calculated as the percentage of patients who achieve complete response, partial response, or at least six months of stable disease.

Time frame

From enrollment to the end of treatment at 12 months

Evaluation of Progression-Free Survival (PFS)

Progression-Free Survival will be measured from C1D1 to the date of the first disease progression or death and will be estimated using the Kaplan-Meier method.

Time frame

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

Other outcomes

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

Exploratory analyses in tumor will be performed in an effort to understand the association of DLL3 expression with treatment response. Exploratory data will be summarized using descriptive statistics (e.g. N, medians, inter-quartile range, and mean, standard deviation, minimum and maximum for continuous variables and frequency counts and percentages for categorical variables). The relationship between biomarker and efficacy variables will be assessed using appropriate multivariate models.

Time frame

From enrollment to the end of treatment at 12 months

Locations12

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