CNS Tumor, Adult, CNS Tumor, Childhood, Glioma
Conditions
Keywords
temozolomide, tarlatamab, phase 1/2, RP2D, glioma
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.
Interventions
DRUGTarlatamab
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.
DRUGTemozolomide (TMZ)
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.
Sponsors
Centre Leon Berard
Amgen
National Cancer Institute, France
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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): 1. Karnofsky PS for pediatric patients ≥16 years of age ≥ 70%; 2. Lansky PS for patients between 12 and 15y: ≥ 70%; 3. 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) * Hemoglobin ≥ 9.0 g/dL (unsupported for \> 7 days) Renal and hepatic function : * Creatinine * Adult patient: Creatinine clearance as per CKD-EPI \> 30 mL/min/1.73 m² * Pediatric patients: Creatinine \<1.5 ULN for age or an estimated glomerular filtration rate (GFR) \> 60 mL/min/1.73m2 GFR based on the Schwartz equation (Mian and Schwartz 2017) or as per institutional guidelines * Total bilirubin ≤1.5 x ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome) * Alanine aminotransferase (ALAT) ≤ 3 x ULN; aspartate aminotransferase (ASAT) ≤ 3 x ULN Coagulation function : Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5 x ULN. Patients on chronic anticoagulation therapy who do not meet the criteria above may be eligible to enrol after discussion with the Sponsor. I9. Adequate cardiac function defined by Left ventricular ejection fraction (LVEF) ≥50% at baseline. I10. Adequate pulmonary function as per investigator judgment and no clinically significant pleural effusion. Pleural effusion managed with indwelling pleural catheter (e.g, PleurX) are allowed. I11. Availability of a representative formalin-fixed paraffin-embedded (FFPE) sample of tumor tissue (resection or biopsy, archival) with an associated pathology report must be available. This tumor sample must meet the following quality/quantity control criteria: ≥30 % of tumor cells. I12. Patients must have discontinued all previous anti-cancer treatments (approved or investigational) for CNS treatment with respect of wash-out period at time of C1D1 as shown below: * Cytotoxic and myelosuppressive chemotherapy : ≥21 days (or ≥42 days if prior nitrosourea) * Metronomic chemotherapy regimen : ≥21 days or ≥5 half-lives of the treatment with the longest half-life (whichever is shorter) * Targeted agent : ≥21 days or ≥5 half-lives (whichever is shorter) * Cellular therapy : ≥42 days for any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells) agent * Antibody therapy : ≥21 days after the last infusion except for bevacizumab for which a wash out period of 3 months is requested * Radiotherapy : * ≥14 days since small port radiation therapy (i.e. local palliative) * ≥84 days since large-field radiation therapy (i.e. TBI, craniospinal, whole abdominal, total lung, ≥50% or greater pelvic radiation, ≥50% marrow space) * ≥42 days for other substantial bone marrow radiation * Surgery : Major surgery ≥ 21 days. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48-hour interval must be maintained before C1D1 I13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior C1D1 and must agree to use highly effective contraceptive measures starting with the Screening Visit through 6 months after the last dose of study drugs and to not breastfeed during this period. Highly effective contraception is defined in Appendix 02. I14. Sexually active male must agree to use adequate and appropriate contraception while on study drugs and for 6 months after stopping the study drugs. I15. Ability to understand and sign informed consent and willingness to comply with the study procedures before study entry and written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines. I16. Covered by a medical insurance.
Exclusion criteria
E1. Diagnosis of non-CNS tumor. E2. Diagnosis of diffuse intrinsic pontine glioma. E3. Current treatment with bevacizumab. E4. Prior treatment with a DLL3-directed therapy. Note: Prior treatment with TMZ is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I : Dose limiting toxicities (DLT) assessed as related at least to tarlatamab, occurring during the first 2 cycles of treatment | From Cycle 1 Day 1 to week 8 | 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. |
| 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). | 12 weeks from the date of first study drug administration (Cycle 1 Day 1) | Objective response rate at 12 weeks (ORR-12W) according to immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 |
| Evaluation of Disease Control Rate (DCR) | From enrollment to the end of treatment at 12 months | 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. |
| Evaluation of Progression-Free Survival (PFS) | From Cycle 1 Day 1 to the date of the first disease progression or death | 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. |
| Evaluation of Overall Survival (OS) | From Cycle 1 Day 1 to the date of death from any cause | Overall survival will be estimated using the Kaplan-Meier method. |
| To collect nature, incidence and severity of Adverse Events graded using Common Terminology Criteria for Adverse Events (CTCAE) V5.0 or specific grading system for ICANS and CRS [safety and tolerability] | From enrollment to the end of treatment at 12 months | To characterize the safety and tolerability profile of the proposed therapeutic strategy |
Countries
France
Contacts
CONTACTPierre LEBLOND, MD, PhD
CONTACTAurélien MAUREILLE, MD
Outcome results
None listed