Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Tarlatamab · 19 trials · 31 indications
The dual primary endpoints are PFS by Blinded Independent Central Review (BICR) and OS. OS is defined as time from randomization until death due to any cause.
The percentage of patients without progression as defined by RECIST V1.1 criteria or death. PFS rate will be calculated for each treatment arm separately once 38 PFS events are reported in the first 54 patients included (27 per treatment arm). Patients alive and free of events at the date of the analysis will be censored at their last known tumor assessment. Patients who start a new treatment line without progression will be censored on the date of first dose of the subsequent anticancer treatment.
Defined as the percentage of patients alive after 12 months from the first dose of study treatment. OS will consider death from any cause as an event. Patients alive and free of events at the date of the analysis will be censored at their last known contact. OS will be calculated for each treatment arm separately. We will assess the median OS, estimated by Kaplan-Meier. Patients alive and free of events at the date of the analysis will be censored at their last known contact. Survival will be assessed by recording patient status at each visit according to protocol. Long term follow up to be performed at least every 6 months
Will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death as a result of any cause. Will be calculated as the proportion of patients who are progression-free and alive divided by the total number of evaluable patients. Exact binomial 95% confidence intervals (CIs) for the 6-month PFS true rate will be calculated.
Will be measured by RECIST v 1.1. Will be measured by the proportion of patients who have clinical and rapid clinical and radiological progression and move on to receive subsequent standard of care platinum-based chemotherapy and immune checkpoint inhibitors divided by the total number of evaluable patients. Exact binomial 95% CIs for the tarlatamab failure true rate will be calculated.
ORR based on BICR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) plus partial response (PR). CR: Disappearance of all target non-nodal lesions. Any target lymph node must have had a reduction in short axis to \<10 mm, NOT total disappearance. PR: At least a 30% decrease in the sum of the diameters of target lesions, taken as reference the baseline sum of diameters. The percentage of participants who experience a CR or PR as assessed by BICR based on RECIST 1.1 is presented.
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.
Objective response rate at 12 weeks (ORR-12W) according to immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria
The primary endpoint is safety, which will be measured by DLT using adverse events graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and ASTCT (CRS and ICANS). DLT will be defined as having 1) grade 3 - 5 non-hematologic adverse events (AEs) possibly, probably or definitely related to protocol treatment (radiation or combination of radiation and tarlatamab) by 8 weeks from start of radiation therapy; or 2) AEs possibly, probably, or definitely related to radiation or combination of radiation and tarlatamab leading to early termination of radiation or permanent discontinuation of tarlatamab. Grade 3+ AEs (or discontinuation) due to tarlatamab alone (not attributable to combination therapy) will not contribute to the primary endpoint. Frequency (%) of the patients with DLT will be reported by cohort.
Clinically significant changes in vital signs and clinical laboratory tests will be reported as adverse events.
A DLT was any of the following during the DLT window, assessed by Common Terminology Criteria for Adverse Events v4.0: * Grade 3 adverse event (AE) except for fatigue lasting \< 7 days, Grade 3 nonfebrile neutropenia that improved to ≤ Grade 1 within 3 weeks, endocrinopathies if managed with replacement therapy, Grade 3 nausea/vomiting or diarrhea for \< 72 hours, Grade 3 amylase or lipase values not associated with pancreatitis, Grade 3 hematologic laboratory abnormalities not clinically relevant, or Grade 3 electrolyte abnormality up to 72 hours. * Grade 4 AE except for Grade 4 nonfebrile neutropenia lasting ≤ 7 days, Grade 4 electrolyte abnormality lasting up to 72 hours, Grade 4 amylase or lipase values not associated with pancreatitis, or Grade 4 hematologic laboratory abnormalities no clinically relevant. * Grade 5 AE * Recurrent Grade ≥ 2 pneumonitis * Any other toxicity requiring permanent discontinuation of AMG 404.
An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. A TEAE was defined as an AE starting on or after the first dose of tarlatamab, and up to and including 47 days after the last dose of tarlatamab excluding the events reported after End of Study date. Clinically significant changes from baseline in vital signs, 12-lead electrocardiograms (ECGs) and clinical laboratory tests were also reported as TEAEs.
A TRAE was defined as a TEAE that per investigator review had a reasonable possibility of being caused by tarlatamab. Clinically significant changes from baseline in vital signs, 12-lead ECGs and clinical laboratory tests were also reported as TEAEs.
A DLT was defined as any qualifying toxicity that was at least possibly related to tarlatamab with an onset within the first 28 days following first dose with either of the following criteria: 1. Grade 3 adverse event lasting more than 3 days (with the exception of fatigue and Grade 3 non-febrile neutropenia that improved to ≤ Grade 1 within 3 weeks including the use of growth factor support per neutropenia management guidelines); 2. ≥ Grade 4 adverse event regardless of duration (with the exception of grade 4 non-febrile neutropenia lasting less than or equal to 7 days including the use of growth factor support per neutropenia management guidelines).
| Arm | Type | Description |
|---|---|---|
| Arm A: Tarlatamab in Combination with Durvalumab | EXPERIMENTAL | Tarlatamab in combination with durvalumab. 1 cycle = 28 days. |
| Arm B: Durvalumab | ACTIVE_COMPARATOR | Durvalumab only. 1 cycle = 28 days. |
| Tarlatamab + Durvalumab + Carboplatin + Etoposide | EXPERIMENTAL | Participants will receive tarlatamab in combination with durvalumab, carboplatin and etoposide for 4 cycles followed by tarlatamab and durvalumab. |
| Durvalumab + Carboplatin + Etoposide | ACTIVE_COMPARATOR | Participants will receive durvalumab, carboplatin and etoposide for 4 cycles followed by durvalumab. |
| Tarlatamab in Combination With Durvalumab | EXPERIMENTAL | Participants will receive tarlatamab once every 2 weeks (Q2W) and durvalumab once every 4 weeks (Q4W). |
| Durvalumab Alone | ACTIVE_COMPARATOR | Participants will receive durvalumab Q4W alone. |
| Tarlatamab | EXPERIMENTAL | Participants will receive tarlatamab on Cycle 1 Day 1, 8 and 15, and once every 2 weeks (Q2W) thereafter (cycle is 28 days). |
| Placebo | PLACEBO_COMPARATOR | Participants will receive placebo on Cycle 1 Day 1, 8 and 15, and Q2W thereafter (cycle is 28 days). |
| Standard of Care | ACTIVE_COMPARATOR | Participants will receive treatment per local standard of care (SOC). |
| Arm A: Tarlatamab | ACTIVE_COMPARATOR | Tarlatamab as a standalone treatment through intravenous infusion at 10 mg dose every 14 days (i.e. 2 weeks). |
| ARM B: Tarlatamab plus FOLFIRI | EXPERIMENTAL | Tarlatamab as intravenous infusion at 10mg in combination with the standard of care second-line chemotherapy (FOLFIRI) |
| Cohort 1 | EXPERIMENTAL | patients with metastatic/locally advanced SCLC with any level of DLL3 expression |
| Cohort 2 | EXPERIMENTAL | patients with metastatic/locally advanced other poorly differentiated NECs whatever the primary or high grade medullary thyroid carcinoma (MTC, capped at 4 patients) DLL3 positive by immunohistochemistry (IHC). |
| Treatment (tarlatamab) | EXPERIMENTAL | Patients receive tarlatamab IV over 60 minutes on days 1, 8, and 15 of cycle 1, then on days 1 and 15 of remaining cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Treatment Arm A: Dose 1 Tarlatamab | EXPERIMENTAL | Participants will receive dose 1 of Tarlatamab by intravenous (IV) infusion during the treatment period. |
| Treatment Arm B: Dose 2 Tarlatamab | EXPERIMENTAL | Participants will receive dose 2 of Tarlatamab by IV infusion during the treatment period. |
| Treatment Arm C: Dose 3 Tarlatamab | EXPERIMENTAL | Participants will receive dose 3 of Tarlatamab by IV infusion during the treatment period. |
| Part 1: Tarlatamab Low Dose | EXPERIMENTAL | Participants will receive the low dose of Tarlatamab. |
| Part 1: Tarlatamab High Dose | EXPERIMENTAL | Participants will receive the high dose of Tarlatamab. |
| Part 2: Dose Expansion | EXPERIMENTAL | Participants will receive the selected target dose of Tarlatamab based on findings in Part 1. |
| Part 3: Modified Monitoring Substudy | EXPERIMENTAL | Participants will receive the selected target dose of Tarlatamab based on findings in Part 1 with reduced Cycle 1 monitoring requirements. |
| 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. |
| 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. |
| 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. |
| Concurrent Main Cohort | EXPERIMENTAL | Patients enrolled to this cohort will receive tarlatamab with concurrent radiation therapy (RT) to extracranial sites (n=20-24 extracranial RT with a minimum of 10 thoracic patients). Patients will receive tarlatamab at a step-up dose of 1 mg on Cycle 1 Day 1 and then 10 mg on cycle 1 Day 8 and Cycle 1 Day 15 and every 2 weeks thereafter (on days 1 and 15 of each cycle) until radiographic progression or disease progression or 24 months, whichever is earlier. Patients will receive concurrent RT to extracranial sites as per standard of care starting as early as Cycle 1 Day 16 and as late as Cycle 2 Day 28, assuming there is no ongoing cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicity Syndrome (ICANS). |
| Concurrent Cranial Cohort | EXPERIMENTAL | If the safety endpoint in the Concurrent Main Cohort is met, enrollment will expand to the Concurrent Cranial Cohort. 6-10 patients will receive tarlatamab with concurrent radiation therapy to cranial sites as described in the Concurrent Main Cohort. |
| Sequential radiation therapy cohort | EXPERIMENTAL | If the concurrent main cohort safety endpoint is not met, then the study will proceed to de-escalation, where 20 patients will be enrolled on the sequential radiation therapy cohort. In this cohort patients will receive sequential tarlatamab and RT to cranial and extracranial RT sites. Standard of care RT can occur prior to Cycle 1 Day 1(if radiation treatment is completed \<7 days prior to the start of tarlatamab) or be interdigitated with tarlatamab with a 7-day washout between RT and infusion, with RT to begin as early as Cycle 1 Day 22 and as late as cycle 2 Day 28, assuming no ongoing CRS/ICANS. |
| Tarlatamab Monotherapy Cohort | EXPERIMENTAL | If the sequential safety endpoint is not met, then the study will proceed to another de-escalation phase, where 10 patients will receive tarlatamab alone. |
| Dose Exploration | EXPERIMENTAL | Multiple dose levels of AB248 will be explored in combination with tarlatamab administered via intravenous (IV) infusion. |
| Dose Expansion | EXPERIMENTAL | The dose expansion part will test tarlatamab in combination with the MTCD/recommended dose for expansion of AB248 identified in the dose exploration part. An optional cohort may be opened based on emerging data to study tarlatamab in combination with AB248 at a lower dose than the MTCD/recommended dose for expansion or with an alternative dose regimen at a AB248 dose lower than or equal to MTCD/recommended dose for expansion. |
| Part 1 Dose Exploration | EXPERIMENTAL | Tarlatamab will be administered as a SC injection in Part 1. |
| Part 2 Dose Expansion | EXPERIMENTAL | Following the selection of a SC dosing regimen in Part 1, tarlatamab will be administered in Part 2 at the dose deemed safe and tolerable in Part 1. |
| Part 3 Alternative Dosing | EXPERIMENTAL | Following the selection of a SC dosing regimen from Part 1 that will be used in Part 2 dose expansion, Part 3 may open to test alternative dosing of SC tarlatamab. |
| Part 1: Dose Exploration Combination Regimen 1 | EXPERIMENTAL | Tarlatamab+Atezolizumab+Carboplatin+Etoposide |
| Part 2: Dose Exploration Combination Regimen 2 | EXPERIMENTAL | Tarlatamab+Atezolizumab+Carboplatin+Etoposide |
| Part 3: Dose Exploration Combination Regimen 3 | EXPERIMENTAL | Tarlatamab+Atezolizumab+Carboplatin+Etoposide |
| Part 4: Dose Expansion | EXPERIMENTAL | Expansion of Part 1, Part 2, or Part 3 with Atezolizumab |
| Part 5: Dose Exploration Maintenance | EXPERIMENTAL | Tarlatamab+Atezolizumab |
| Part 6: Dose Expansion Maintenance | EXPERIMENTAL | Expansion of Part 5 with Atezolizumab |
| Part 7: Dose Expansion | EXPERIMENTAL | Expansion of Part 1, 2, or 3 with Durvalumab |
| Part 8: Dose Expansion Maintenance | EXPERIMENTAL | Expansion of Part 5 with Durvalumab |
| Part 9: Dose Expansion Maintenance | EXPERIMENTAL | Expansion with Tarlatamab+Durvalumab |
| Phase 1: Dose Exploration | EXPERIMENTAL | The recommended phase 2 target dose (RP2D) of tarlatamab in combination with AMG 404 will be estimated using a modified toxicity probability interval (mTPI-2) design. A combination RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an maximum tolerated dose (MTD). |
| Phase 2: Dose Expansion | EXPERIMENTAL | Participants will receive the RP2D of tarlatamab in combination with AMG 404 identified in Phase 1 (dose exploration) of the study. |
| Part 1: Dose Exploration | EXPERIMENTAL | The maximum tolerated dose (MTD) will be estimated using isotonic regression (Ji et al, 2010). The recommended phase 2 dose (RP2D) may be identified based on emerging safety data prior to reaching an MTD. |
| Part A | EXPERIMENTAL | Tarlatamab monotherapy |
| Part C | EXPERIMENTAL | Tarlatamab with Pembrolizumab |
| Part D | EXPERIMENTAL | Tarlatamab with additional CRS mitigation strategies |
| Part E | EXPERIMENTAL | Tarlatamab administration with 24-hour monitoring |
| Part F | EXPERIMENTAL | Tarlatamab administered in outpatient infusion centers with 8-hour monitoring Optional wearable digital device substudy (US sites only) |
| Part G | EXPERIMENTAL | Tarlatamab additional dosing schedule Optional wearable digital device substudy (US sites only) |
| Name | Type | Description |
|---|---|---|
| Tarlatamab | DRUG | Tarlatamab Intravenous (IV): Cycle 1 Step Dose: Day 1- 1 mg; Day 8- 10 mg; Day 15- 10 mg of a 28-day cycle, then Cycle 2 and Subsequent Cycles: Day 1- 10 mg and Day 15- 10 mg every 28-day cycle up to 12 months from cycle 1 day 1 unless other treatment discontinuation or rechallenge criteria are met. |
| Durvalumab | DRUG | Durvalumab 1500 mg IV: Every 4 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months from cycle 1 day 1, unless other treatment discontinuation criteria are met. |
| Carboplatin | DRUG | Carboplatin will be administered as an IV infusion. |
| Etoposide | DRUG | Etoposide will be administered as an IV infusion. |
| Placebo | DRUG | IV infusion |
| Lurbinectedin | DRUG | Lurbinectedin will be administered per local SOC. |
| Topotecan | DRUG | Topotecan will be administered per local SOC. |
| Amrubicin | DRUG | Amrubicin will be administered per local SOC. |
| standard of care second-line chemotherapy (FOLFIRI) | DRUG | FOLFIRI:: irinotecan intravenously 180 mg/m2 on day 1, followed by 400 mg/m2 folinic acid or 200 mg/m² levofolinate in a 2-h infusion, a 10-min bolus of 400 mg/m2 5-FU, and 2400 mg/m2 5-FU over 46 hours; every 14 days). |
| Biopsy Procedure | PROCEDURE | Undergo biopsies |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Computed Tomography | PROCEDURE | Undergo computed tomography |
| Echocardiography Test | PROCEDURE | Undergo ECHO |
| Electronic Health Record Review | OTHER | Ancillary studies |
| Magnetic Resonance Imaging | PROCEDURE | Undergo MRI |
| Multigated Acquisition Scan | PROCEDURE | Undergo MUGA |
| Questionnaire Administration | OTHER | Ancillary studies |
| 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. |
| Concurrent Radiation Therapy | RADIATION | Standard of care RT can begin as early as Cycle 1 Day 16 and as late as Cycle 2 Day 28, assuming there is no ongoing CRS (extracranial)/ICANS (cranial). |
| Sequential Radiation therapy | RADIATION | Standard of care radiation therapy can occur prior to Cycle 1 Day 1 (if radiation treatment is completed \<7 days prior to the start of tarlatamab) or be interdigitated with tarlatamab with a 7-day washout between RT and infusion, with RT to begin as early as Cycle 1 Day 22 and as late as cycle 2 Day 28, assuming no ongoing CRS (extracranial)/ICANS (cranial). |
| AB248 | DRUG | Administered either as an IV infusion followed by a flush or using a syringe pump without a flush. |
| Atezolizumab | DRUG | Atezolizumab will be administered as an intravenous (IV) infusion. |
| AMG 404 | DRUG | AMG 404 will be administered as an intravenous (IV) infusion. |
| Pembrolizumab | DRUG | Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2 |
| CRS Mitigation Strategies | DRUG | Participants will be treated with one of the CRS mitigation strategies. |
* Patient must have histologically or cytologically confirmed Small Cell Lung Cancer (SCLC). * SCLC must be diagnosed as Limited-Stage-SCLC (LS-SCLC) (Stage I-III, disease can be encompassed within a radical radiation portal per investigator assessment) and treated with 3 to 4 cycles of chemotherapy...