Colorectal Cancer, HR+/HER2- Ductal and Lobular Breast Cancer, Non-Small Cell Lung Cancer, Pancreatic Ductal Adenocarcinoma, Soft Tissue Sarcoma, Triple Negative Breast Cancer
Conditions
Keywords
PDAC, NSCLC, Breast cancer, CRC, STS, Radioligand therapy (RLT)
Brief summary
The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of \[177Lu\]Lu-DFC413 and safety and imaging properties of \[68Ga\]Ga-NNS309 in patients aged ≥ 18 years with solid tumors
Detailed description
GCJ904A12101 is first-in-human (FIH), phase I, open label study that consists of a dose escalation part followed by a dose expansion part. In both parts of the study, patients will initially be imaged with a 68Ga-NNS309 positron emission tomography (PET)/ computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan and will be evaluated for eligibility for 177Lu-DFC413 treatment. Patients eligible for treatment will receive 177Lu-DFC413. In the escalation part, different doses of 177Lu-DFC413 will be tested to assess its safety, tolerability, and dosimetry and identify the recommended radioactive administered dose(s) (RD(s)) for further evaluation. The expansion will include arms based on tumor type. 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 long-term follow-up period.
Interventions
DRUG68Ga-NNS309
Diagnostic investigational radiopharmaceutical
DRUG177Lu-DFC413
Therapeutic investigational radiopharmaceutical
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Adults ≥ 18 years with one of the following indications: * Locally advanced unresectable or metastatic PDAC, with disease progression following, or intolerance to cytotoxic therapy, 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 chemotherapy and targeted therapy, unless patient was ineligible to receive such therapy * Locally advanced unresectable or metastatic HR+/HER2- ductal and lobular breast cancer with disease progression following, or intolerance to, hormone therapy and CDK inhibitor, and at least one additional line of therapy, unless patient was ineligible to receive such therapy * Locally advanced unresectable or metastatic triple negative breast cancer (TNBC) with disease progression following, or intolerance to, at least two 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 * (Dose expansion only) Locally advanced unresectable or metastatic soft tissue sarcoma (excluding GIST and Kaposi) with disease progression following, or intolerance to, at least one line of systemic 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 * eGFR \< 60 mL/min/1.73m2, calculated using CKD-EPI 2021 or measured * Unmanageable urinary tract obstruction or urinary incontinence * Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy * Any prior radioligand therapy * Radiation therapy within 4 weeks prior to the first dose of \[177Lu\]Lu-DFC413 Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of dose limiting toxicities of 177Lu-DFC413 | Within first treatment cycle, up to maximum 6 weeks | 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. |
| Incidence and severity of adverse events and serious adverse events of 177Lu-DFC413 | From study treatment start up to approximately 42 months | The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs) and through the monitoring of relevant clinical and laboratory safety parameters. |
| Dose modifications for 177Lu-DFC413 | From study treatment start until last dose of study treatment, assessed up to approximately 24 weeks | Dose modifications (dose interruptions and reductions) for 177Lu-DFC413 will be assessed and summarized using descriptive statistics. The number of patients with dose modification and the reasons will be summarized by treatment groups. |
| Dose intensity for 177Lu-DFC413 | From study treatment start until last dose of study treatment, assessed up to approximately 24 weeks | Dose intensity for 177Lu-DFC413 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | From study treatment start up to 6 months | ORR is defined as the proportion of patients with a BOR of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines. |
| Duration of Response (DOR) | From study treatment start up to 6 months | DOR is the time between the first documented response (CR or PR) and the date of progression according to RECIST v1.1 guidelines, or death due to any cause. |
| Disease control rate (DCR) | From study treatment start up to 6 months | DCR is defined as the proportion of patients with a BOR of CR, PR or stable disease according to RECIST v1.1 guidelines. |
| Progression free survival (PFS) | From study treatment start up to 6 months | PFS is defined as the time from the date of start of treatment to the date of the first documented progression according to RECIST v1.1 guidelines or death due to any cause. |
| Area Under the Curve (AUC) of 177Lu-DFC413 | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. AUC will be determined by non-compartmental methods. |
| Total body clearance of 177Lu-DFC413 | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Total body clearance will be determined by non-compartmental methods. |
| Observed maximum blood concentration (Cmax) of 177Lu-DFC413 | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Cmax will be determined by non-compartmental methods. |
| Observed maximum radioactivity concentration (Rmax) of 177Lu-DFC413 | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Rmax will be determined by non-compartmental methods. |
| Volume of distribution (Vz) of 177Lu-DFC413 during the terminal phase | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Vz will be determined by non-compartmental methods. |
| Terminal elimination half-life (T1/2) of 177Lu-DFC413 | Up to 8 days after first dose | The 177Lu-DFC413 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. T1/2 will be determined by non-compartmental methods. |
| Urinary excretion of radioactivity expressed as a percentage of injected dose (%ID) | Up to 3 days after first dose | Urine elimination data for 177Lu-DFC413 will be assessed based on decay-corrected urine radioactivity concentration data. Urine elimination data will be expressed as percentage of injected dose (%ID). |
| Renal clearance of 177Lu-DFC413 | Up to 3 days after first dose | Urine samples will be collected over specified time intervals and analyzed for radioactivity. Renal clearance of 177Lu-DCF413 will be summarized using descriptive statistics. |
| Absorbed dose of 177Lu-DFC413 | Up to 8 days after first dose | Time activity curves (TACs) for the various organs and tumor lesions will be produced as fraction of injected activity per gram of tissue (%ID/g) as a function of time. |
| Incidence and severity of adverse events and serious adverse events of [68Ga]Ga-NNS309 | Up to 3 days after administration | The distribution of adverse events will be done via the analysis of frequencies for TEAEs and TESAEs and through the monitoring of relevant clinical and laboratory safety parameters. |
| Visual and quantitative assessment of [68Ga]Ga-NNS309 uptake in normal tissues and tumor lesions over time | Up to 3 days after administration | After \[68Ga\]Ga-NNS309 administration, \[68Ga\]Ga-NNS309 PET/CT or PET/MRI will be performed. Standardized uptake values (SUVs) of \[68Ga\]Ga-NNS309 in normal tissues and tumor lesions over time will be summarized. |
Countries
Canada, Denmark, France, Germany, Israel, Singapore
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed