CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative Chemotherapy Versus Immediate Resection in patIents With resecTable BiliarY Tract Cancers (BTC) at High Risk for Recurrence

Phase 2

Recruiting

• Conditions: Biliary Tract Cancer; Cholangiocarcinoma
• Interventions: Drug: Gemcitabine; Drug: Nab paclitaxel; Drug: Cisplatin; Procedure: Curative Surgery; Drug: Capecitabine

• Registration Number: NCT06037980
• Lead Sponsor: Gruppo Oncologico del Nord-Ovest

Brief Summary

PURITY is a multicentre, randomized adaptive phase II/III trial aimed at comparing the triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment (ARM A) versus standard upfront surgery (ARM B) in terms of 12-month PFS rate (phase II part) and PFS (phase III part) in patients with resectable BTC at high risk for recurrence.

Detailed Description

PURITY is a multicentre, randomized adaptive phase II/III trial aimed at comparing the triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment (ARM A) versus standard upfront surgery (ARM B) in terms of 12-month PFS rate (phase II part) and PFS (phase III part) in patients with resectable BTC at high risk for recurrence.

High risk for recurrence, for which patients will be eligible for study, is defined by the presence of at least one of the following risk features, as evaluated at baseline (pre-surgery):

1. For cholangiocarcinoma:

* Suspected or definite locoregional lymph node involvement in the absence of jaundice (at least one of the following):

* positive FNA cytology (obtained by EUS).

* positive locoregional lymph nodes at PET-CT.

* suspected positive locoregional lymph nodes at imaging (CT or MRI scan) according to local MTD discussion (eg. short axis \> 1.5 cm, contrast enhancement uptake, round shape, restriction at DWI).

* Macrovascular invasion at preoperative CT scan.

* Expected R1 resection due to proximity to major intrahepatic vascular and biliary structures.

* For iCCA, presence of satellitosis or multifocal disease or radiological suspicion of tumoral diaphragmatic adhesion.

* For iCCA, size of the liver lesion \>5 cm.

* For eCCA, size of the primary lesion \> 3cm.

* Ca19.9 \>100 U/mL.

2. For GBC:

* Incidentally Detected Gallbladder Carcinoma (IGBC) After Simple Cholecystectomy with indication for radical second surgery (\>pT2) or newly diagnosed GBC.

Study Timeline

• Study First Submitted: 2023-08-09
• Study First Submitted QC: 2023-09-07
• Study First Posted: 2023-09-14
• Study Start: 2023-11-07
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-13
• Last Update Posted: 2025-03-25
• Primary Completion: 2028-12
• Study Completion: 2029-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures.

2. Female and male patients ≥18 years and <75 years.

3. Histologically or cytologically confirmed non metastatic resectable carcinoma of biliary tract (BTC), including gallbladder carcinoma (GBC), intrahepatic, periperihilar or distal Cholangiocarcinoma (CCA). Mixed tumor entities with hepatocellular carcinoma and ampullary cancers are excluded.

4. Availability of a tumoral sample

5. ECOG performance status of 0-1.

6. No prior tumor resection for BTC.

7. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax and PET scan.

8. Technically resectable BTC as per local Multidisciplinary Team (MDT) assessment, including a core team with at least one medical oncologist, one surgeon, one radiologist, one endoscopist/gastroenterologist and one pathologist, all with expertise > 3 years on biliary tract cancer and hepatobiliary oncology.

9. High risk for recurrence defined as the presence of at least one of the following risk features, as evaluated at baseline (pre-surgery):

   1. For cholangiocarcinoma:

      • Suspected or definite locoregional lymph node involvement (at least one of the following):

        • positive FNA cytology (obtained by EUS).
        • positive locoregional lymph nodes at PET-CT.
        • suspected positive locoregional lymph nodes at imaging (CT or MRI scan) according to local MDT discussion (eg. short axis > 1.5 cm, contrast enhancement uptake, round shape, restriction at DWI).

      • Macrovascular invasion at preoperative CT scan.

      • Expected R1 resection due to proximity to major intrahepatic vascular and biliary structures.

      • For iCCA, presence of satellitosis or multifocal disease or radiological suspicion of tumoral diaphragmatic adhesion.

      • For iCCA, size of the liver lesion >5 cm.

      • For eCCA, size of the primary lesion > 3cm.

      • Ca19.9 >100 U/mL.

   2. For GBC:

      • Incidentally Detected Gallbladder Carcinoma (IGBC) after simple cholecystectomy with indication for radical second surgery (>pT2) or newly diagnosed GBC.

10. Estimated life expectancy > 3 months.

11. Adequate baseline hematologic function characterized by the following at screening:

    1. ANC ≥ 1.5 × 109/L
    2. platelets ≥ 100 × 109/L
    3. hemoglobin ≥ 9 g/dl. Note: prior transfusions for patients with low hemoglobin are allowed.

12. Adequate liver function characterized by the following at screening:

    1. 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.
    2. Serum transaminases (AST and/or ALT) < 3 x ULN.

13. 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

14. 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).

15. No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines

16. Females 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.

17. Males must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in APPENDIX V of the full protocol.

18. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause.

19. A participant 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

1. Known allergy or hypersensitivity to any of the study drugs.
2. Any known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer.
3. Locally unresectable tumor according to local MDT (including radiological evidence suggesting inability to resect with curative intent whilst maintaining adequate vascular inflow and outflow, and sufficient future liver remnant).
4. Evidence of distant metastases at any site.
5. Tumors requiring multi-step surgical procedures such as two-stage hepatectomy or Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) due to liver volumetry-based assessment of anticipated inadequate future liver remnant.
6. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic decompensation in the year before enrolment.
7. 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.
8. Chronic or current active infectious disease requiring systemic antibiotics or antifungal treatment within 2 weeks prior to enrollment.
9. 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.
10. Pregnant or breast-feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment.
11. Any other concurrent antineoplastic treatment including radiotherapy.
12. Previous or concurrent systemic (eg cytotoxic or targeted or other experimental drugs) therapy for BTC.
13. Prior surgery or locoregional therapy for BTC.
14. Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last three months, significant arrhythmia).
15. Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
16. Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial.
17. Presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines.
18. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Preoperative chemotherapy	Nab paclitaxel	Triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment followed by surgery and adjuvant chemotherapy
Preoperative chemotherapy	Cisplatin	Triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment followed by surgery and adjuvant chemotherapy
Preoperative chemotherapy	Curative Surgery	Triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment followed by surgery and adjuvant chemotherapy
Upfront surgery	Curative Surgery	Standard upfront surgery and adjuvant chemotherapy
Preoperative chemotherapy	Gemcitabine	Triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment followed by surgery and adjuvant chemotherapy
Preoperative chemotherapy	Capecitabine	Triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment followed by surgery and adjuvant chemotherapy
Upfront surgery	Capecitabine	Standard upfront surgery and adjuvant chemotherapy

Primary Outcome Measures

Name	Time	Method
12-month progression-free survival (PFS) rate	12 months	the proportion of patients alive and free from progression/post-resection recurrence by 12-months timepoint from randomization (to be considered as primary endpoint in the phase II part of the study and as secondary endpoint in the phase III part of the study).
median PFS	From date of randomization until the date of first documented progression (as assessed by radiological evaluation and clinical examination) or date of death from any cause, whichever came first, assessed up to 120 months	i.e. the time from randomization to disease progression, post-resection recurrence or death from any cause (to be considered as secondary endpoint in the phase II part of the study and as primary endpoint in the phase III part of the study).

Secondary Outcome Measures

Name	Time	Method
Median relapse free survival	from date of surgery to date of disease recurrence or date of death, whichever came first, in patients who undergo surgery with curative intent, assessed up to 120 months.	i.e. the time from surgery to disease recurrence or death in patients who undergo to surgery with curative intent.
Toxicity rates	Through study completion, an average of 1 year for each patient	.e. the percentage of patients, relative to the total of subjects randomized to neoadjuvant treatment, experiencing a specific adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0).
Median event free survival	from date of randomization to disease progression that precludes definitive surgery, treatment discontinuation for any reason, post-resection recurrence, diagnosis of second cancer, or death from any cause, assessed up to 120 months	i.e. the time from randomization to disease progression that precludes definitive surgery, treatment discontinuation for any reason, post-resection recurrence, a second primary cancer, or death from any cause.
Median Overall survival	from date of randomization to date of death (or last follow up for alive patients), assessed up to 120 months.	i.e. the time from randomization to death or last follow-up for alive patients.
R0 resection rate	At surgery	i.e. the percentage of patients, relative to the total of randomized patients, for whom a R0 resection is achieved.
Resectability rate of primary tumor	Resectability rate will be assessed before surgery (after the 3 cycles of neoadjuvant chemotherapy for the experimental treatment arm)	i.e. the retrospective evaluation of patients with unresectable disease, as assessed by the central review committee, in the two arms, and of the rate of conversion to resectability in the neoadjuvant arm.
R0+R1 resection rate	At surgery	i.e. the percentage of patients, relative to the total of randomized patients, for whom the tumor was macroscopically removed and the intent of surgery is considered curative.
Quality of life EORTC QLQ-C30 scores	Quality of life questionnaires will be compiled during screening (28 days before randomisation) and at restaging before (week 8 to 10 after randomisation) and after surgery (week 6 to 16 after surgery)	QoL will be estimated with EORTC QLQ-C30; mean score changes from baseline, proportion of patients with improved, stable, or deteriorated scores from baseline and time to deterioration in the EORTC QLQ-C30 scores will be compared between the two arms. Time to deterioration will be defined as the time from baseline to the first onset of a 10-point or greater decrease (for functional scales)/increase (for symptoms scale) from baseline, with confirmation under the right-censoring rule. All available observations will be used to calculate time to deterioration.
Quality of life BIL21 scores	Quality of life questionnaires will be compiled during screening (28 days before randomisation) and at restaging before (week 8 to 10 after randomisation) and after surgery (week 6 to 16 after surgery)	QoL will be estimated with the module BIL21; mean score changes from baseline, proportion of patients with improved, stable, or deteriorated scores from baseline and time to deterioration in the BIL21 physical functioning, social functioning, and fatigue scores will be compared between the two arms. Time to deterioration was defined as the time from baseline to the first onset of a 10-point or greater decrease from baseline for functional scales or a 10-point or greater increase for symptom scales, with confirmation under the right-censoring rule. All available observations will be used to calculate time to deterioration.
Overall response rate	At radiological evaluation as performed at restaging before surgery (week 8 to 10 after randomisation)	of neoadjuvant therapy as per investigator assessment and central review, i.e. the percentage of patients, relative to the total of enrolled subjects receiving neoadjuvant treatment, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria.
Perioperative morbidity and mortality	At surgery	i.e. the percentage of patients, relative to the total of enrolled subjects undergoing surgery, with any serious perioperative morbidity or mortality according to Clavien-Dindo classification.

Trial Locations

Locations (19)

Humanitas Cancer Center; 🇮🇹 Milan, Italy

Azienda Ospedaliera Universitaria Pisa; 🇮🇹 Pisa, Italy

ASST Spedali Civili; 🇮🇹 Brescia, Italy

Ospedale San Raffaele; 🇮🇹 Milano, Italy

Ospedale S. Gerardo; 🇮🇹 Monza, Italy

IOV; 🇮🇹 Padova, Italy

Oncologia Medica Policlinico Sant'Orsola - Malpighi; 🇮🇹 Bologna, Italy

AOUI Verona - Policlinico "G.B. Rossi"; 🇮🇹 Verona, Italy

Policlinico Gemelli; 🇮🇹 Rome, Italy

IRST (Cesena-Forlì-Meldola); 🇮🇹 Ravenna, Italy

Ospedali Riuniti di Ancona; 🇮🇹 Ancona, Italy

Azienda Ospedaliera S. Croce e Carle; 🇮🇹 Cuneo, Italy

IRST Dino Amadori; 🇮🇹 Meldola, Italy

ASST Papa Giovanni XXIII; 🇮🇹 Bergamo, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori; 🇮🇹 Milan, Italy

Università di Modena; 🇮🇹 Modena, Italy

Ospedale Niguarda Cancer Center; 🇮🇹 Milan, Italy

Policlinico San Matteo; 🇮🇹 Pavia, Italy

Azienda Ospedaliera Ordine Mauriziano; 🇮🇹 Turin, Italy