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
- Phase
- Phase 1
- Intervention
- [177Lu]Lu-NNS309
- Conditions
- Pancreatic Ductal Adenocarcinoma
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 162
- Locations
- 35
- Primary Endpoint
- Dose modifications for [177Lu]Lu-NNS309
- Status
- Recruiting
- Last Updated
- 8 days ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of [177Lu]Lu-NNS309 and the safety 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.
Investigators
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
- •(Dose escalation part only) 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 109/L, hemoglobin \< 9 g/dL, or platelet count \< 100 x 109/L
- •QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
- •Creatinine clearance \< 60 mL/min
- •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.
Arms & Interventions
Arm 1
Patients will receive \[68Ga\]Ga-NNS309, and if eligible, \[177Lu\]Lu-NNS309
Intervention: [177Lu]Lu-NNS309
Arm 1
Patients will receive \[68Ga\]Ga-NNS309, and if eligible, \[177Lu\]Lu-NNS309
Intervention: [68Ga]Ga-NNS309
Outcomes
Primary Outcomes
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 modifications (dose interruptions and reductions) for \[177Lu\]Lu-NNS309 will be assessed and summarized using descriptive statistics. The number of patients with dose modification will be summarized by treatment groups.
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
A dose limiting toxicity (DLT) is defined as any adverse event or abnormal laboratory value of CTCAE (version 5.0) Grade 3 or higher that occurs within the DLT evaluation period and that is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications with a few exceptions defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not Grade 3 or higher.
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
Dose intensity for \[177Lu\]Lu-NNS309 will be assessed and summarized using descriptive statistics. Dose intensity is computed as the ratio of actual cumulative dose received and actual duration of exposure.
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
The distribution of adverse events will be done via the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) and through the monitoring of relevant clinical and laboratory safety parameters.
Secondary Outcomes
- Overall response rate (ORR)(Up to approximately 42 months)
- Duration of Response (DOR)(Up to approximately 42 months)
- Area Under the Curve (AUC) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Total body clearance of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Disease control rate (DCR)(Up to approximately 42 months)
- Progression free survival (PFS)(Up to approximately 42 months)
- Observed maximum blood concentration (Cmax) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Observed maximum radioactivity concentration (Rmax) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Volume of distribution (Vz) of [177Lu]Lu-NNS309 during the terminal phase(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Terminal elimination half-life (T1/2) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Urinary excretion of radioactivity expressed as a percentage of injected dose (%ID)(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(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.)
- Absorbed dose of [177Lu]Lu-NNS309(Cycle 1 Day 1, Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Incidence and severity of adverse events and serious adverse events of [68Ga]Ga-NNS309(From Imaging visit until 3 days after 68Ga-NNS309 administration, assessed up to approximately 3 days.)
- Visual and quantitative assessment of [68Ga]Ga-NNS309 uptake in normal tissues and tumor lesions over time(From 0 up to approximately 3 hrs after [68Ga]Ga-NNS309 dosing)
- Area Under the Curve (AUC) of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 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(Samples collected pre infusion to 360 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(Samples collected pre infusion to 360 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(Samples collected pre infusion to 360 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(Samples collected pre infusion to 360 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(Samples collected pre infusion to 360 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.)
- Absorbed dose of [177Lu]Lu-NNS309(Samples collected 5 hours to 360 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.)