Clinical trial NCT06037980: 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
Official title: A Phase II/III Randomized Clinical Trial of 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: PURITY Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Biliary Tract Cancer
Cholangiocarcinoma
Keywords: Biliary Tract Cancers
Cholangiocarcinoma
Neoadjuvant Chemotherapy
Cisplatin Gemcitabine Nabpaclitaxel
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
First posted: 2023-09-14
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, open-label, multicenter, randomized phase II-III study
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 12-month progression-free survival (PFS) rate
timeFrame: 12 months
measure: median PFS
timeFrame: 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
Secondary outcomes:
measure: Median event free survival
timeFrame: 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
measure: Median relapse free survival
timeFrame: 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.
measure: Median Overall survival
timeFrame: from date of randomization to date of death (or last follow up for alive patients), assessed up to 120 months.
measure: R0 resection rate
timeFrame: At surgery
measure: R0+R1 resection rate
timeFrame: At surgery
measure: Quality of life EORTC QLQ-C30 scores
timeFrame: 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)
measure: Quality of life BIL21 scores
timeFrame: 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)
measure: Overall response rate
timeFrame: At radiological evaluation as performed at restaging before surgery (week 8 to 10 after randomisation)
measure: Resectability rate of primary tumor
timeFrame: Resectability rate will be assessed before surgery (after the 3 cycles of neoadjuvant chemotherapy for the experimental treatment arm)
measure: Toxicity rates
timeFrame: Through study completion, an average of 1 year for each patient
measure: Perioperative morbidity and mortality
timeFrame: At surgery
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: Ospedali Riuniti di Ancona
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Oncologia Medica Policlinico Sant'Orsola - Malpighi
city: Brescia
country: Italy
facility: ASST Spedali Civili
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce e Carle
city: Meldola
country: Italy
facility: IRST Dino Amadori
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milan
country: Italy
facility: Humanitas Cancer Center
city: Milan
country: Italy
facility: Ospedale Niguarda Cancer Center
city: Modena
country: Italy
facility: Università di Modena
city: Monza
country: Italy
facility: Ospedale S. Gerardo
city: Padova
country: Italy
facility: IOV
city: Pavia
country: Italy
facility: Policlinico San Matteo
city: Pisa
country: Italy
facility: Azienda Ospedaliera Universitaria Pisa
city: Ravenna
country: Italy
facility: IRST (Cesena-Forlì-Meldola)
city: Rome
country: Italy
facility: Policlinico Gemelli
city: Turin
country: Italy
facility: Azienda Ospedaliera Ordine Mauriziano
city: Verona
country: Italy
facility: AOUI Verona - Policlinico "G.B. Rossi"
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
name: Monica Niger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 02 2390 2919
name: Monica Niger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yadav S, Xie H, Bin-Riaz I, Sharma P, Durani U, Goyal G, Borah B, Borad MJ, Smoot RL, Roberts LR, Go RS, McWilliams RR, Mahipal A. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: A propensity score matched analysis. Eur J Surg Oncol. 2019 Aug;45(8):1432-1438. doi: 10.1016/j.ejso.2019.03.023. Epub 2019 Mar 21.
citation: Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, Borad MJ. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 2019 Jun 1;5(6):824-830. doi: 10.1001/jamaoncol.2019.0270.
citation: Maithel SK, Keilson JM, Cao HST, Rupji M, Mahipal A, Lin BS, Javle MM, Cleary SP, Akce M, Switchenko JM, Rocha FG. NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2023 Oct;30(11):6558-6566. doi: 10.1245/s10434-023-13809-5. Epub 2023 Jun 27.