Extrapulmonary Neuroendocrine Carcinoma (EP-NEC), Gastroenteropancreatic NEC (GEP NEC), Large Cell Neuroendocrine Carcinoma, Large Cell Pulmonary Neuroendocrine Carcinoma of the Lung (LCNEC), NEC of the Bladder, Other DLL3 Expressing epNEC, Small Cell Lung Cancer (SCLC)
Conditions
Keywords
DARPin, Alpha Emitter, Pb203, Pb212, DLL3, Radioligand therapy (RLT), SCLC, Neuroendocrine cancer, [203Pb]Pb-DOTAM-MAM279, [212Pb]Pb-DOTAM-MAM279, EP-NEC, Lead 212, Lead 203, 203Pb, 212Pb
Brief summary
The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of \[212Pb\]Pb-MP0712, in patients aged ≥18 years with Small Cell Lung Cancer and other locally advanced or metastatic DLL3 positive tumors.
Detailed description
This is a phase I/IIa, open-label, multi-center study to evaluate the safety, tolerability, dosimetry, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of \[212Pb\]Pb-MP0712 in patients with SCLC and other advanced DLL3-expressing solid tumors. The study consists of a dose escalation part, followed by a dose expansion part. Once the recommended radioactive dose(s) \[212Pb\]Pb-MP0712 for further clinical evaluation are determined, the dose expansion part will further characterize the safety, tolerability, and preliminary anti-tumor activity of \[212Pb\]Pb-MP0712. The study will enable evaluation of the safety, dosimetry, PK, and imaging properties of \[203Pb\]Pb-MP0712.
Interventions
DRUG[212Pb]Pb-MP0712
Radioligand Therapy
OTHER[203Pb]Pb-MP0712
Radioligand Imaging Agent
Sponsors
Molecular Partners AG
Orano Med LLC
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a phase 1/2a, multicenter, open-label study evaluating the safety, tolerability, and preliminary efficacy of \[212Pb\]Pb-DOTAM-MAM279 in patients with: * SCLC or LC NECs of the lung * epNECs The study is divided into two parts: * Part 1 (Phase 1): Dose escalation * Part 2 (Phase 2a): Dose expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age ≥ 18 years old * Histologically or cytologically confirmed: I. advanced extensive or limited SCLC or LC NECs of the lung * SCLC (extensive stage, or limited stage) patients with progression or recurrence following at least two prior line of systemic platinum based therapy and immunotherapy or are not suitable or tolerating the standard of care treatment as second line of systemic therapy, or * LC NEC of the lung patients with progression or recurrence following at least one prior line of systemic therapy, or II. epNECs with progression or recurrence following at least one prior line of systemic therapy: * Gastroenteropancreatic NECs (GEPNEC), or * Cervical NECs, or * Bladder NECs, or * other epNECs with previously confirmed DLL3 expression by IHC. * Patients with prior DLL3-targeted therapy are allowed. * For epNECs in Part 1 and Part 2 and SCLC or LC NECs of the lung in Part 2: DLL3-positivity by \[203Pb\]Pb-DOTAM-MAM279 SPECT/CT * Radiographically documented disease progression or recurrence during or after the last line of systemic treatment therapy * At least one measurable disease per RECIST v1.1. * Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at Screening * Adequate blood counts: Hemoglobin ≥9 g/dL; Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L; Platelets ≥100 × 10\^9/L; White blood cells (WBC) ≥2.5 x 10\^9/L; * Adequate hepatic function * Adequate renal function: Calculated glomerular filtration rate (GFR) \>60mL/min (using Cockroft-Gault formula). * Patients with known central nervous system (CNS) metastasis will be eligible if they are clinically stable. Key
Exclusion criteria
* Uncontrolled intercurrent illness * Patients who have not had resolution of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 (except for grade ≤2 alopecia, or stable grade 2 sensory neuropathy, according to the last CTCAE version). * Active clinically significant cardiac disease * Evidence of interstitial lung disease or active, non-infectious pneumonitis. * History of other malignancy within the past 2 years with exceptions. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess incidence and severity of safety events following administration of [212Pb]Pb-DOTAM-MAM279 | until 5 years after last dose | Type, frequency and severity of adverse events (AEs), and serious adverse events (SAEs), Adverse events of special interest (AESI) and Dose Limiting Toxicities (DLT) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) |
| To assess dose modifications of [212Pb]Pb-DOTAM-MAM279 | until 5 years after last dose | Frequency and duration of dose changes |
| To estimate the maximum tolerated dose (MTD) and/or to define the recommended phase 2 dose (RP2D) for SCLC/LCNEC of the lung and epNECs | Phase 1, from start of treatment to end of first cycle (day 1 - 28) | Incidence of dose limiting toxicities |
| To evaluate the preliminary anti-tumor activity of [212Pb]Pb-DOTAM-MAM279 in the dose expansion part | Phase 2a only; 12 months | Objective Response Rate (ORR) in the expansion phase ORR is defined as the percentage of patients with partial response (PR) or complete response (CR) as per RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess maximum concentration (Cmax) of [203Pb]Pb-DOTAM-MAM279 / [212Pb]Pb-DOTAM-MAM279 | up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration; up to 14 days following [212Pb]Pb-DOTAM-MAM279 administration] | Blood and serum samples will be drawn to determine maximum concentration (Cmax) of \[203Pb\]Pb-DOTAM-MAM279 / \[212Pb\]Pb-DOTAM-MAM279 |
| To assess the area under the curve (AUC) from time 0 to the time of the last quantifiable concentration of [203Pb]Pb-DOTAM-MAM279 | up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration; up to 14 days following [212Pb]Pb-DOTAM-MAM279 administration] | Blood and serum samples will be drawn to determine AUC of \[203Pb\]Pb-DOTAM-MAM279 / \[212Pb\]Pb-DOTAM-MAM279 |
| To assess half-live(s) (t½) of [203Pb]Pb-DOTAM-MAM279 / [212Pb]Pb-DOTAM-MAM279 | up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration; up to 14 days following [212Pb]Pb-DOTAM-MAM279 administration] | Blood and serum samples will be drawn to determine half-live(s) (t½) of \[203Pb\]Pb-DOTAM-MAM279 / \[212Pb\]Pb-DOTAM-MAM279 |
| To assess the clearance (CL) of [203Pb]Pb-DOTAM-MAM279 / [212Pb]Pb-DOTAM-MAM279 | up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration; up to 14 days following [212Pb]Pb-DOTAM-MAM279 administration] | Blood and serum samples will be drawn to determine clearance (CL) of \[203Pb\]Pb-DOTAM-MAM279 / \[212Pb\]Pb-DOTAM-MAM279 |
| To assess the volume of distribution (Vd) of [203Pb]Pb-DOTAM-MAM279 / [212Pb]Pb-DOTAM-MAM279 | up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration; up to 14 days following [212Pb]Pb-DOTAM-MAM279 administration] | Blood and serum samples will be drawn to determine the volume of distribution (Vd) of \[203Pb\]Pb-DOTAM-MAM279 / \[212Pb\]Pb-DOTAM-MAM279 |
| To quantitatively predict radiation absorbed doses for therapeutic [212Pb]Pb-DOTAM-MAM279 from [203Pb]Pb-DOTAM-MAM279 | Phase 1; up to 7 days following [203Pb]Pb-DOTAM-MAM279 administration | Estimation of \[212Pb\]Pb-DOTAM-MAM279 absorbed dose for healthy organs and tumor lesions based on dosimetry analysis of \[203Pb\]Pb-DOTAM-MAM279 |
| To assess incidence and severity of safety events following administration of [203Pb]Pb-DOTAM-MAM279 | up to 10 days following [203Pb]Pb-DOTAM-MAM279 administration | Type, frequency and severity of adverse events (AEs) and serious adverse events (SAEs) using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 |
| To evaluate PFS | Phase 2a only; 12 months | Progression-Free Survival (PFS) determined as the time from C1D1 to the date of progression, defined as the first documented progression as per RECIST v1.1 or death for any cause |
| To evaluate DoR | Phase 2a only; 12 months | Duration of response (DoR) in patients with a CR or PR from date of first date of response to the date of RECIST 1.1 progression or death |
| To evaluate DCR | Phase 2a only; 12 months | Disease control rate (DCR) defined as the percentage of patients who have achieved CR, PR, or stable disease (SD) |
| To evaluate OS | Phase 2a only; approx. 5 years | Overall survival (OS) defined as the time from C1D1 to death from any cause |
Countries
United States
Contacts
CONTACTMedical Director MPAG
Outcome results
None listed