Phase III Trial of Gemcitabine and Nab-Paclitaxel Switch Maintenance Versus Modified FOLFIRINOX Continuation in Advanced Pancreatic Cancer
- Trial ID
- 2024-515214-41-00
- Protocol
- PANThEON
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the PANThEON phase III trial is to evaluate the **efficacy** of switch maintenance therapy with Gemcitabine plus nab-Paclitaxel (Gem-NabP) following a 3-month induction with modified FOLFIRINOX (mFOLFIRINOX) compared to the continuation of mFOLFIRINOX in patients with advanced pancreatic cancer. This is assessed in terms of overall survival (OS), which is a critical endpoint in determining the potential benefit of a treatment regimen in extending the life expectancy of patients with this aggressive malignancy.
Secondary objectives include:
- Estimating the efficacy of the switch maintenance strategy in terms of progression-free survival (PFS) and time to treatment failure (TTF).
- Assessing the activity of the switch maintenance approach by evaluating the objective response rate (ORR) and disease control rate (DCR).
- Evaluating the impact of the switch maintenance strategy on patients' quality of life.
- Determining the safety profile of the switch maintenance regimen compared to mFOLFIRINOX continuation.
- Evaluating the proportion of patients who start induction chemotherapy but are not eligible for randomization due to early disease progression or other causes.
- Estimating the impact of the switch maintenance strategy on subsequent treatment lines.
Participants
The clinical trial involves participants diagnosed with **advanced pancreatic cancer**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for those under 70 years, and 0 for those aged 70 and above. Participants are required to have histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma, eligible for first-line treatment. The trial includes individuals with adequate renal, coagulation, hematologic, and liver function, as well as an estimated life expectancy of more than three months. The trial population was selected based on these criteria, and the sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use effective contraceptive methods and refrain from donating eggs or sperm during and after the study period. The trial also involves a vulnerable population, although specific details are not disclosed by the sponsor.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **gemcitabine** plus **nab-paclitaxel** as switch maintenance therapy compared to the continuation of modified **FOLFIRINOX** in patients with advanced pancreatic cancer. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to assess overall survival as the primary endpoint, with secondary endpoints including progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life, and treatment toxicity. The trial is expected to commence recruitment on December 16, 2024, and conclude by December 16, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate renal and liver function, absence of complete dihydropyrimidine dehydrogenase enzyme deficiency, and an ECOG performance status of 0-1. Following successful screening, participants will be randomized to receive either the switch maintenance therapy or the continuation of modified FOLFIRINOX. Study visits will include regular follow-up assessments to monitor treatment efficacy and safety, with the end-of-study visit marking the conclusion of the participant's involvement.
The expected duration of participant involvement is contingent upon the treatment arm and individual response, with a maximum treatment period of 28 days for certain medications. Conditions that may lead to early termination from the study include clinical deterioration, treatment toxicity, withdrawal of consent, or disease progression. Participants are required to comply with study protocols, including the use of effective contraceptive methods and agreement not to donate eggs or sperm during and after the study period.
Treatment
The clinical trial involves the administration of several **antineoplastic** agents, each with specific dosing regimens and administration routes. **Fluorouracil** is administered in the form of an infusion. The maximum daily dose is 2400 mg/m², with a total maximum dose of 33600 mg/m² over a treatment period of 28 days. This chemical substance is classified under the ATC code L01BC02 and is used as an antimetabolite in cancer treatment.
**Paclitaxel** is also administered via infusion, with a maximum daily dose of 125 mg/m² and a total maximum dose of 1500 mg/m² over a 16-day treatment period. It is categorized as an anti-cancer chemotherapeutic agent under the ATC code L01CD01.
**Irinotecan Hydrochloride** is delivered through infusion, with a maximum daily dose of 150 mg/m² and a total maximum dose of 2100 mg/m² over a 28-day treatment period. It is classified under the ATC code L01XX19 as an antineoplastic agent.
**Gemcitabine Hydrochloride** is administered by infusion, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 12000 mg/m² over a 16-day treatment period. It is an antimetabolite used in cancer therapy, classified under the ATC code L01BC05.
**Oxaliplatin** is given via infusion, with a maximum daily dose of 85 mg/m² and a total maximum dose of 1190 mg/m² over a 28-day treatment period. It is an anti-cancer chemotherapeutic agent, classified under the ATC code L01XA03.
**Calcium Folinate**, also known as **Leucovorin Calcium**, is administered through injection. The maximum daily dose is 400 mg/m², with a total maximum dose of 5600 mg/m² over a 28-day treatment period. It serves as a detoxifying substance for antineoplastic treatments and is classified under the ATC code V03AF04.
All substances are of chemical origin and are not formulated for pediatric use. The trial aims to evaluate the efficacy of these treatments in patients with advanced pancreatic cancer, comparing the switch maintenance of Gemcitabine plus nab-Paclitaxel against the continuation of modified FOLFIRINOX.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)**, defined as the time from randomization to death or last follow-up for patients who are still alive. This primary endpoint will provide a direct measure of the treatment's impact on patient longevity. Secondary endpoints will include Progression-Free Survival (PFS), which measures the time from randomization to disease progression or death from any cause, and Time to Treatment Failure (TTF), which is the time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, or death.
Additional secondary endpoints will evaluate the Objective Response Rate (ORR), which is the percentage of patients achieving a complete or partial response according to RECIST 1.1 criteria, and the Disease Control Rate (DCR), which includes patients achieving a complete response, partial response, or stable disease. Quality of Life (QoL) will be assessed using the EORTC QLQ-C30 and its modules, providing insights into the patient's well-being and treatment impact. Toxicity will be monitored by the percentage of patients experiencing specific adverse events, classified according to the National Cancer Institute Common Toxicity Criteria (version 5.0).
The trial will also track the proportion of patients not eligible for randomization due to clinical deterioration, treatment toxicity, withdrawal of consent, or disease progression. The frequency of subsequent treatment lines will be recorded, indicating the percentage of patients who undergo systemic treatment after progression in both trial arms. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment's impact on advanced pancreatic cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient able and willing to provide written informed consent and to comply with the study protocol.
- Subjects must be ≥18 years.
- Histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma eligible for treatment in the first-line setting.
- Presence of measurable or non-measurable disease assessed by CT scan and/or MRI according to RECIST 1.1 (Appendix I of the protocol). Note: any lesion which has been subjected to percutaneous therapies or radiotherapy should not be considered measurable, unless the lesion has clearly progressed since the procedure.
- Availability of archival tumor sample (primary tumor or metastatic site) for biomarker analysis.
- ECOG performance status of 0-1 (if age < 70 years). If age ≥70 years, ECOG PS must be 0.
- Estimated life expectancy > 3 months.
- Adequate baseline hematologic function characterized by the following at screening: a. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L b. platelets count ≥ 100 × 109/L c. hemoglobin ≥ 9 g/dl. Note: prior transfusions for patients with low hemoglobin are allowed.
- Adequate liver function characterized by the following at screening:a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note: Subjects with Serum total bilirubin ≥ 1.5 × ULN and conjugated bilirubin ≤ ULN or < 40% of total bilirubin are allowed. b. Serum transaminases (AST and/or ALT) < 3 x ULN (< 5 x ULN in presence of liver metastasis). In participants with elevated AST or ALT, the values must be stable for at least 2 week and with no evidence of biliary obstruction by imaging.
- Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN and calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min.
- Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
- No presence of complete dihydropyrimidine dehydrogenase (DPYD) enzyme deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT) with DPYD gene testing mandatory at screening as per national guidelines. UDP-glucuronosyltransferase 1A1 (UGT1A1) testing is not mandatory. However, if UGT test is routinely performed in the participating centers, enrolment of patients carriers of variants of DPYD and homozygous variant UGT1A1 [7/7] has to be discussed with the Sponsor. See Appendix VI of the full protocol for details.
- Women of childbearing potential must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in Appendix V of the full protocol, during the treatment period and for at least 7 months after the last administration of study treatments.
- Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause.
- Men must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in Appendix V of the full protocol, during the treatment period and for at least 7 months after the last administration of study treatments.
- Participants must agree not to donate eggs/sperm for future use for the purposes of assisted reproduction during the study and for a period of 7 months after receiving the last dose of study treatment. Female and male participants should consider preservation of eggs/sperm prior to study treatment as anti-cancer treatments may impair fertility.
Exclusion Criteria
- Pancreatic neuroendocrine, acinar, squamous/adenosquamous, or islet tumors.
- Previous or concurrent systemic (eg cytotoxic or targeted or other experimental drugs) therapy for advanced pancreatic adenocarcinoma. Note: previous (neo)adjuvant or perioperative anti-cancer therapy for non-metastatic, resectable or borderline resectable PDAC, associated with surgery on the primary tumor, is allowed if ≥ 9 months have elapsed from the last dose of therapy and documented disease progression or relapse.
- Major surgery or radiation therapy performed within ≤4 weeks before randomization. Palliative radiotherapy to bone lesions is allowed if performed ≥ 2 weeks prior to start of study treatment. Patients must have recovered from any effect from major surgery.
- Known allergy or hypersensitivity to study drugs and/or their excipients.
- Unresolved toxicity ≥ CTCAE grade 2 attributed to any prior therapies (e.g. grade ≥2 peripheral neurotoxicity), excluding anemia or alopecia.
- Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that requires directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study entry.
- Any known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years prior to study entry except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer.
- Know active uncontrolled hepatitis B or hepatitis C. Patients with a past or resolved HBV infection are eligible. Patients with chronic disease controlled by antiviral therapy or requiring prophylactic treatment are eligible.
- Chronic or current active infectious disease requiring systemic antibiotics or antifungal treatment within 2 weeks prior to enrollment.
- Known uncontrolled HIV infection. HIV-positive patients are eligible if their CD4+ cell count amounts to 300 cells per μL or more; HIV viral load must be undetectable per standard of care assay, and they must be compliant with antiretroviral treatment.
- Pregnant or breast-feeding patient, or patient planning to become pregnant within 7 months after the end of treatment.
- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA > II, unstable angina pectoris, history of myocardial infarction within 3 months before study entry, significant arrhythmia).
- Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
- Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 16 Dec 2024 | 340 |
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 |
|---|---|---|---|---|---|---|
PACLITAXEL | Test | PHF00230MIG | INFUSION | 125 | 16 | SCP129816 |
GEMCITABINE | Test | PHF00230MIG | INFUSION | 1000 | 16 | SCP1128788 |
IRINOTECAN | Comparator | PHF00230MIG | INFUSION | 150 | 28 | SCP139021 |
FLUOROURACIL | Comparator | PHF00231MIG | INFUSION | 2400 | 28 | SCP1165178 |
OXALIPLATIN | Comparator | PHF00230MIG | INFUSION | 85 | 28 | SCP128961 |
CALCIUM LEVOFOLINATE | Comparator | PHF00231MIG | INJECTION | 400 | 28 | SCP139914 |