Phase I Study of [177Lu]Lu-NNS309 in Patients With Pancreatic, Lung, Breast and Colorectal Cancers

Official title

Phase I Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry, and Preliminary Activity of [177Lu]Lu-NNS309 in Patients With Pancreatic, Lung, Breast and Colorectal Cancers

Overview

The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of \[177Lu\]Lu-NNS309 and the safety, dosimetry and imaging properties of \[68Ga\]Ga-NNS309 in patients aged ≥ 18 years with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), HR+/HER2- ductal and lobular breast cancer (BC), triple negative breast cancer (TNBC) and colorectal cancer (CRC).

Detailed description

The study will be done in two parts. The first part is called "escalation" and the second part is called "expansion". In both parts of the study, patients will initially be imaged with a \[68Ga\]Ga-NNS309 positron emission tomography (PET)/ computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan and will be evaluated for eligibility for \[177Lu\]Lu-NNS309 treatment. In the escalation part, different doses of \[177Lu\]Lu-NNS309 will then be tested to identify recommended dose(s) (RD(s)) for further evaluation. The expansion part of the study will examine the safety and preliminary efficacy of \[177Lu\]Lu-NNS309 at the RD(s) determined during the escalation part. The end of study will occur when all patients per disease group in the expansion part have completed the follow-up for disease progression or discontinued from the study for any reason, and all patients have completed treatment and the 36-month long-term follow-up period.

Interventions

• Drug [68Ga]Ga-NNS309
  Radioligand imaging agent
• Drug [177Lu]Lu-NNS309
  Radioligand therapy

Primary outcome measures

• Number of patients with dose limiting toxicities of [177Lu]Lu-NNS309 [Time frame: From start of study treatment until 6 weeks or 4 weeks after, depending on dosing schedule]
• Incidence and severity of adverse events and serious adverse events of [177Lu]Lu-NNS309 [Time frame: From start of study treatment until completion of the 36 month follow up, assessed up to approximately 42 months]
• Dose modifications for [177Lu]Lu-NNS309 [Time frame: From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks]
• Dose intensity for [177Lu]Lu-NNS309 [Time frame: From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks]

Secondary outcome measures (12)

• Overall response rate (ORR) [Time frame: Up to approximately 42 months]
• Duration of Response (DOR) [Time frame: Up to approximately 42 months]
• Disease control rate (DCR) [Time frame: Up to approximately 42 months]
• Progression free survival (PFS) [Time frame: Up to approximately 42 months]
• Area Under the Curve (AUC) of [177Lu]Lu-NNS309 [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Total body clearance of [177Lu]Lu-NNS309 [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Observed maximum blood concentration (Cmax) of [177Lu]Lu-NNS309 [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Observed maximum radioactivity concentration (Rmax) of [177Lu]Lu-NNS309 [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Volume of distribution (Vz) of [177Lu]Lu-NNS309 during the terminal phase [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Terminal elimination half-life (T1/2) of [177Lu]Lu-NNS309 [Time frame: Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.]
• Urinary excretion of radioactivity expressed as a percentage of injected dose (%ID) [Time frame: Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition to 6 hr post end of infusion (EOI), 6-24hr post EOI, 24-48hr post EOI, 48-72hr post EOI. The duration of a cycle is 4 weeks or 6 weeks.]
• Renal clearance of [177Lu]Lu-NNS309 [Time frame: Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition to 6 hr post end of infusion (EOI), 6-24hr post EOI, 24-48hr post EOI, 48-72hr post EOI. The duration of a cycle is 4 weeks or 6 weeks.]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years old
• Patients with one of the following indications:
• Locally advanced unresectable or metastatic PDAC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy
• Locally advanced unresectable or metastatic NSCLC without any actionable genomic alterations with disease progression following, or intolerance to chemotherapy and immunotherapy, unless patient was ineligible to receive such therapy, or locally advanced unresectable or metastatic NSCLC with an actionable genomic alteration with disease progression following, or intolerance to targeted therapy, unless patient was ineligible to receive such therapy
• Locally advanced unresectable or metastatic HR+/HER2- ductal or lobular BC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy
• Locally advanced unresectable or metastatic TNBC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy
• Locally advanced or metastatic unresectable CRC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy. Patients with known microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status must also have had disease progression following, or intolerance to immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
• Patients must have lesions showing 68Ga-NNS309 uptake

Exclusion criteria

• Absolute neutrophil count (ANC) < 1.5 x 10\^9/L, hemoglobin < 9 g/dL, or platelet count < 100 x 10\^9/L
• QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
• Calculated estimated glomerular filtration rate < 60 mL/min/1.73m2
• Unmanageable urinary tract obstruction or urinary incontinence
• Radiation therapy within 4 weeks prior to the first dose of \[177Lu\]Lu-NNS309

Other protocol-defined inclusion/exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 9 centers

• Uni of Alabama at Birmingham — Birmingham
• University of California LA — Los Angeles
• Stanford University Medical Center — Palo Alto
• Mayo Clinic Jacksonville — Jacksonville
• Massachusetts General Hospital — Boston
• BAMF Health — Grand Rapids
• Mayo Clinic Rochester — Rochester
• Uni Of TX MD Anderson Cancer Cntr — Houston
• … and 1 more center

Germany · 4 centers

• Novartis Investigative Site — Cologne
• Novartis Investigative Site — Essen
• Novartis Investigative Site — München
• Novartis Investigative Site — Rostock

Canada · 3 centers

• Novartis Investigative Site — Toronto
• Novartis Investigative Site — Montreal
• Novartis Investigative Site — Montreal

Spain · 3 centers

• Novartis Investigative Site — Barcelona
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid

France · 2 centers

• Novartis Investigative Site — Bron
• Novartis Investigative Site — Villejuif

Italy · 2 centers

• Novartis Investigative Site — Milan
• Novartis Investigative Site — Reggio Emilia

Netherlands · 2 centers

• Novartis Investigative Site — Nijmegen
• Novartis Investigative Site — Utrecht

Switzerland · 2 centers

• Novartis Investigative Site — Geneva
• Novartis Investigative Site — Lausanne

Belgium · 1 center

• Novartis Investigative Site — Brussels

Israel · 1 center

• Novartis Investigative Site — Tel Aviv

Identifiers

NCT: NCT06562192 · CFXX489A12101 · 2023-510356-23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗