Evaluation of [177Lu]Lu-FAP-2286 Safety and Efficacy in Advanced Solid Tumors with mFOLFIRINOX or Nab-Paclitaxel Combinations in NSCLC, BC, and PDAC
- Trial ID
- 2023-508995-12-01
- Protocol
- CAAA614A12101
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **objective response rate (ORR)** during the Phase 2 dose expansion. Additionally, the study aims to assess the safety and tolerability of **[177Lu]Lu-FAP-2286** and determine the recommended Phase 2 dose (RP2D) when combined with mFOLFIRINOX in pancreatic ductal adenocarcinoma (PDAC) and with nab-paclitaxel in non-small cell lung cancer (NSCLC) during the Phase 2 dose escalation for combination therapy. These objectives are clinically relevant as they aim to establish the efficacy and safety profile of the investigational drug in treating advanced solid tumors, which could potentially lead to improved therapeutic strategies for these malignancies.
Secondary objectives include: - Evaluating the duration of response (DOR) during Phase 2 dose expansion. - Assessing the disease control rate (DCR) during Phase 2 dose expansion. - Evaluating progression-free survival (PFS) during Phase 2 dose expansion. - Further evaluating the safety of **[177Lu]Lu-FAP-2286** at the RP2D for monotherapy, in combination with mFOLFIRINOX in PDAC, and with nab-paclitaxel in NSCLC during Phase 2 dose expansion. - Evaluating the safety and tolerability of **[68Ga]Ga-FAP-2286**.
Participants
The clinical trial involves a total of **120 participants** diagnosed with **recurrent or metastatic non-small cell lung cancer (NSCLC)**, **metastatic breast carcinoma (BC)**, or **locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC)**. The study population includes both male and female subjects aged **18 years and older**, with a focus on individuals who have progressed after specific prior treatments. Participants were selected based on their confirmed diagnosis and progression of disease, ensuring they meet the necessary health criteria, such as adequate organ function and a life expectancy of at least six months. The trial does not exclude based on lifestyle factors such as diet or physical activity, but participants must have an **Eastern Oncology Group (ECOG) performance status** of 0 or 1. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. The selection process ensures that participants have measurable disease per RECIST v1.1 criteria, and they must have signed an Institutional Review Board (IRB) approved informed consent form prior to any study-specific evaluations.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of [177Lu]Lu-FAP-2286 in combination with mFOLFIRINOX for pancreatic ductal adenocarcinoma (PDAC) and nab-paclitaxel for non-small cell lung cancer (NSCLC). This is a Phase 1/2, open-label, non-randomized study involving participants with advanced solid tumors, specifically targeting recurrent or metastatic NSCLC, metastatic breast carcinoma, and locally advanced unresectable or metastatic PDAC. The trial employs a dose-escalation approach to determine the recommended Phase 2 dose (RP2D) for combination therapies. The study is expected to run until October 2032, with recruitment starting in July 2025.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, disease status, and organ function. The trial will include multiple follow-up visits to monitor the **objective response rate** (ORR) and assess any dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs). The end-of-study visit will evaluate the overall treatment response and safety profile. The expected duration of participant involvement varies, with a maximum treatment period of 60 days for most investigational products, except for AAA514, which has a maximum treatment period of 1 day.
Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's primary endpoints include investigator-assessed ORR per RECIST v1.1 and the incidence of DLTs, AEs, SAEs, and clinical laboratory abnormalities. Secondary endpoints focus on the duration of response (DOR), disease progression, and safety at the RP2D for both monotherapy and combination therapies. The trial aims to provide valuable insights into the therapeutic potential of [177Lu]Lu-FAP-2286 in combination with established chemotherapy regimens for advanced solid tumors.
Treatment
The clinical trial involves the administration of several experimental and non-experimental medications. **PACLITAXEL** is utilized in two forms: a dispersion for infusion and a powder for solution for injection. It is administered intravenously with a maximum daily dose of 100 mg/m² and a total dose of 24 g/m² over a treatment period of up to 60 days. The product is relabeled for clinical trial use by Fisher Clinical Services.
**AAA614**, containing the active substance **177LU-FAP-2286**, is provided as a solution for injection/infusion. This investigational product is administered via intravenous infusion. The dosing is measured in gigabecquerels (GBq), with a treatment period of up to 24 days. The product is developed by Novartis Pharma AG.
**OXALIPLATIN** is administered as a concentrate for solution for infusion. The intravenous administration involves a maximum daily dose of 85 mg/m² and a total dose of 10.2 g/m² over a 60-day period. The product is relabeled for clinical trial purposes.
**IRINOTECAN** is also provided as a concentrate for solution for infusion, administered intravenously. The dosing schedule allows for a maximum daily dose of 150 mg/m² and a total dose of 18 g/m² over a 60-day treatment period. This product is similarly relabeled for the trial.
**CALCIUM FOLINATE** is administered as a solution for injection/infusion. The intravenous injection involves a maximum daily dose of 400 mg/m² and a total dose of 48 g/m² over a 60-day period. The product is relabeled for clinical trial use.
**FLUOROURACIL** is provided as a solution for injection/infusion, administered intravenously. The dosing schedule includes a maximum daily dose of 2400 mg/m² and a total dose of 288 g/m² over a 60-day treatment period. The product is relabeled for the trial.
**AAA514**, containing the active substance **FAP-2286**, is provided as a kit for radiopharmaceutical preparation. It is administered via intravenous injection, with dosing measured in megabecquerels (MBq). The treatment period is limited to 1 day. This product is also developed by Novartis Pharma AG.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **objective response rate (ORR)** as assessed by investigators according to RECIST v1.1 criteria, and the evaluation of dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs), and clinical laboratory abnormalities. These assessments will help determine the safety and tolerability of the investigational product, [177Lu]Lu FAP 2286, in combination with mFOLFIRINOX in pancreatic ductal adenocarcinoma (PDAC) and with nab-paclitaxel in non-small cell lung cancer (NSCLC).
Secondary endpoints will include the duration of response (DOR) per RECIST v1.1, confirmed partial response (PR) or complete response (CR), or stable disease (SD) of at least 12 weeks, and disease progression according to RECIST v1.1 or death due to any cause. Additionally, the trial will monitor AEs, SAEs, and clinical laboratory abnormalities at the recommended Phase 2 dose (RP2D) of [177Lu]Lu-FAP-2286 for monotherapy, as well as in combination therapies. The trial will also assess AEs and SAEs during and after the administration of [68Ga]Ga-FAP-2286.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved Informed Consent Form (ICF) prior to any study-specific evaluation.
- Be ≥ 18 years of age at the time the ICF is signed.
- Have consented to submission of fresh or archival tumor tissue, if available.
- Have adequate organ function confirmed by the following laboratory values obtained within the Screening Period prior to administration of [68Ga]Ga-FAP-2286 and prior to first cycle of chemotherapy in the combination groups: a. Bone Marrow Function (independent of transfusion or growth factor support within 21 days prior to planned first administration of [177Lu]Lu-FAP-2286): i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; ii. Platelets > 100 × 109/L; and iii. Hemoglobin ≥ 9 g/dL. b. Hepatic Function: i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × institutional upper limit of normal (ULN); if liver metastases, then ≤ 5 × the institutional ULN; ii. Serum Bilirubin ≤ 1.5 × institutional ULN or if known Gilbert’s syndrome then ≤ 3 × institutional ULN; iii. Serum albumin ≥ 30 g/L (3 g/dL) and iv. INR ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT)≤1.5 x ULN. This applies to participants who are not receiving therapeutic anticoagulation, participants receiving therapeutic anticoagulation should be on a stable dose. c. Renal Function: i. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min using the Cockcroft-Gault formula.
- Have an Eastern Oncology Group (ECOG) performance status of 0 or 1.
- Have a life expectancy of ≥ 6 months.
- Have measurable disease per RECIST v1.1 meeting the following criteria: a. At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST v1.1 using conventional CT and/or MRI. • Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show subsequent evidence of substantial size increase to be deemed a target lesion.
- For Phase 2 only: Have cytologically or histologically and radiologically confirmed recurrent or metastatic disease as outlined below: a. Pancreatic Cancer monotherapy group: i. Pancreatic ductal adenocarcinoma (ductal adenocarcinoma and related subtypes eligible; endocrine and neuroendocrine tumors excluded) ii. Participants must have progressed after at least 1, but no more than two prior chemotherapy regimens for locally advanced unresectable or metastatic disease. Criteria b through h removed during Protocol amendment 7. i. Pancreatic Cancer combination group (with mFOLFIRINOX) i. Pancreatic ductal adenocarcinoma (ductal adenocarcinoma and related subtypes eligible; endocrine and neuroendocrine tumors excluded); ii. Participants have not received prior systemic therapy for metastatic disease. v. Participants must not have received prior taxane therapy either as monotherapy or in combination.
- For Phase 2 only: Have cytologically or histologically and radiologically confirmed recurrent or metastatic disease as outlined below: j. Non-small cell lung cancer monotherapy group i. Non-small cell lung cancer (adenocarcinoma and squamous eligible; endocrine, neuroendocrine and small cell tumors are excluded) ii. Participants must have progressed after at least 1 but not more than 2 prior systemic regimens including chemotherapy and immunotherapy, if eligible. Participants with NSCLC and targeted therapy treatment options, are eligible for the clinical trial as long as they meet these criteria (progression after 1 or 2 prior therapies). Note: Participants with NSCLC harbouring mutations amenable to targeted therapy treatment are eligible if received targeted therapy as single agent or in combination in 1st or 2nd line of treatment; participants not eligible to receive such therapies in 1 or 2L are also eligible to participate to the study. iii. Participants who have received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and an immune checkpoint inhibitor and developed recurrent or metastatic disease while on or within 12 months of completing therapy are eligible iv. Participants with recurrent disease > 12 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum-doublet regimen and an immune checkpoint (given either together or sequentially to treat the recurrence), are eligible v. Participants must have received platinum-based chemotherapy for advanced or metastatic disease and immune checkpoint inhibitor either together (in the same line of treatment) or sequentially (two different lines of treatment) and then progressed. k. Non small cell lung cancer combination group i. Non-small cell lung cancer (adenocarcinoma and squamous eligible; endocrine, neuroendocrine and small cell tumors are excluded) ii. Participants must have progressed after at least 1 but not more than 2 prior systemic regimens including chemotherapy and immunotherapy, if eligible. Participants with NSCLC and targeted therapy treatment options, are eligible for the clinical trial as long as they meet these criteria (progression after 1 or 2 prior therapies). Note: Participants with NSCLC harbouring mutations amenable to targeted therapy treatment are eligible if received targeted therapy as single agent or in combination in 1st or 2nd line of treatment; participants not eligible to receive such therapies in 1 or 2L are also eligible to participate to the study. iii. Participants who have received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and an immune checkpoint inhibitor and developed recurrent or metastatic disease while on or within 12 months of completing therapy are eligible iv. Participants with recurrent disease > 12 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum-doublet regimen and an immune checkpoint (given either together or sequentially to treat the recurrence), are eligible v. Participants must not have received prior taxane therapy either as monotherapy or in combination.
- For Phase 2 only: Have cytologically or histologically and radiologically confirmed recurrent or metastatic disease as outlined below: l. Breast cancer monotherapy group i. Hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative • Participant has a histologically and/or cytologically documented diagnosis of HR positive HER2 negative metastatic breast cancer (based on the most recently analyzed tissue sample tested by a local laboratory). • Participants must have progressed on at least one line of hormone-based therapy (either alone or in combination) and at least one, but not more than two lines of chemotherapy (including cytotoxic, targeted and/or anti-drug conjugate therapies) for metastatic disease. ii. HER2 positive • Participant has a histologically and/or cytologically documented diagnosis of HER2 positive metastatic breast cancer (based on the most recently analyzed tissue sample tested by a local laboratory). • Participant must have progressed on at least two lines of HER2 targeted therapy for metastatic disease. iii. Triple negative breast cancer (TNBC) • Participant has a histologically and/or cytologically documented diagnosis of TNBC (based on the most recently analyzed tissue sample tested by a local laboratory). • Participants must have progressed on at least two lines of cytotoxic chemotherapy (including cytotoxic, anti-drug conjugate, targeted therapies and/or IO) for metastatic disease.
Exclusion Criteria
- Active malignancy except for the specific cancer under investigation in this study, ie, participant known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment with the following exceptions: a. History of second malignancy that has been successfully treated, with no evidence of active cancer for 3 years prior to enrollment; b. Surgically cured low-risk tumors, such as early-stage cervical or endometrial cancer, any cancer in situ, or non-melanoma skin cancers; and c. Prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.
- Received prior radiopharmaceutical therapy (eg, radium 223 223Ra-dichloride, [177Lu]Lu-DOTA-TATE, [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617, actinium 225 [225Ac]Ac-PSMA-617, etc.) or prior EBRT to more than 25% of the bone marrow or received any prior EBRT directly to kidney, or received any EBRT within 2 weeks prior to administration of [177Lu]Lu-FAP-2286. • Prior administration of a radiopharmaceutical unless 10 or more half-lives have elapsed before injection/infusion of [68Ga]Ga-FAP-2286 or [177Lu]Lu-FAP-2286.
- Ongoing adverse effects from anticancer treatment NCI-CTCAE v5.0 (or higher) Grade 1, with the exception for alopecia and vitiligo.
- Impaired cardiac function or clinically significant cardiac diseases, including any of the following: a. Clinically significant and/or uncontrolled cardiac disease such as congestive heart failure requiring treatment (New York Heart Association > Class 2), uncontrolled hypertension, clinically significant arrhythmia, or congenital prolonged QT syndrome; b. Corrected QT interval (Fridericia’s formula) > 450 msec for males or > 470 msec for females at Screening; or c. Acute coronary syndrome or acute myocardial infarction ≤ 6 months prior to administration of [177Lu]Lu-FAP-2286.
- Inability to complete the needed investigational and standard imaging examinations due to any reason (e.g., severe claustrophobia, inability to lie still for the entire imaging time).
- Active severe urinary incontinence, severe voiding dysfunction, or urinary obstruction requiring an indwelling/condom catheter that, in the judgment of the investigator, could prevent adhering to radiation safety instructions.
- Severe chronic or active HIV infection: a. Participants on effective antiretroviral therapy with undetectable viral load within 6 months prior to the first dose of [177Lu]Lu-FAP-2286 are eligible.
- Presence of any other condition that may increase the risk associated with study participation or interfere with the interpretation of study results, and, in the opinion of the investigator, would make the participant inappropriate for entry into the study.
- Non–study-related minor surgical procedure ≤ 5 days, or major surgical procedure ≤ 21 days, prior to the administration of [177Lu]Lu-FAP-2286; in all cases, the participant must be sufficiently recovered and stable before treatment administration.
- Significant weight loss (> 10% of body weight) within 28 days prior to providing informed consent for this study.
- The following are exclusion criteria, as applicable: a. Female participants of childbearing potential: i. Refusal to use a highly effective method of contraception or to practice true abstinence during treatment and for 6 months following the last dose of investigational product; ii. Pregnant, suspected pregnancy, or breast feeding; iii. Planning on getting pregnant during treatment and for 6 months following the last dose of investigational product. b. Male participants with female partners of childbearing potential: i. Refusal to use a highly effective method of contraception or to practice true abstinence during treatment and for 6 months following the last dose of investigational product. c. All male participants: i. Refusal to use condoms during sex. ii. Planning to make semen donations during treatment and for 6 months following the last dose of investigational product.
- Symptomatic and/or untreated CNS metastases or leptomeningeal disease or with primary tumor of CNS origin. a. Participants with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks and have completed RT> 2 weeks prior to treatment. Participants may be on corticosteroids if on a stable dose equivalent to prednisone 10 mg daily or less.
- Received anticancer treatment with chemotherapy, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs ≤ 14 days prior (≤ 28 days prior in case of checkpoint inhibitor therapy and other antibody therapies) to the administration of [177Lu]Lu-FAP-2286.
- Participants with known hypersensitivity to the active agent or excipients.
- Severe chronic or active infections (including active tuberculosis, HBV, or HCV infection) requiring systemic antibacterial, antifungal or antiviral therapy within 2 weeks before enrollment. Note: Antiviral therapy is permitted for participants with chronic HBV or HCV infection. Participants receiving antivirals at Screening should have been treated for > 2 weeks before enrollment. Inactive hepatitis B surface antigen (HbsAg) carriers treated and stable hepatitis B participants (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Participants with detectable hepatitis B surface antigen (HbsAg) or detectable HBV DNA should be managed per treatment guidelines. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 31 Jul 2025 | 7 |
 France | Recruiting | 31 Jul 2025 | 10 |
 Italy | Not Yet Recruiting | 31 Jul 2025 | 9 |
 Spain | Recruiting | 31 Jul 2025 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AAA614 | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS INFUSION | 00 | 24 | PRD11548042 |
Abraxane | Test | POWDER FOR SUSPENSION FOR INJECTION | INTRAVENOUS USE | 100 | 60 | PRD12989983 |
CALCIUM FOLINATE | Test | — | INTRAVENOUS INJECTION | 400 | 60 | SUB06052MIG |
PACLITAXEL ALBUMIN-BOUND | Test | — | INTRAVENOUS USE | 100 | 60 | SUB127678 |
CAAA614A12101 | Test | POWDER FOR SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 400 | 60 | PRD13013564 |
IRINOTECAN | Test | — | INTRAVENOUS USE | 150 | 60 | SUB08295MIG |
FLUOROURACIL | Test | — | INTRAVENOUS USE | 2400 | 60 | SUB07721MIG |
AAA514 | Test | KIT FOR RADIOPHARMACEUTICAL PREPARATION | INTRAVENOUS INJECTION | 00 | 1 | PRD11636664 |
OXALIPLATIN | Test | — | INTRAVENOUS USE | 85 | 60 | SUB09490MIG |