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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Oct 2023 → ongoing

Decision date (initial)

2023-06-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fondazione GONO G.I.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgical approach in terms of 12-month progression-free survival (PFS).

Secondary objectives 6

1. To estimate the efficacy of neoadjuvant GAP followed by surgery compared to upfront surgical approach in terms of PFS, EFS, RFS and OS.
2. To evaluate the activity of neoadjuvant GAP followed by surgery as compared to upfront surgical approach in terms of achievement of radical surgery (R0, R0+R1 resection rate).
3. To estimate the impact of neoadjuvant strategy compared to upfront surgical approach on patients' quality of life, as estimated with PRO questionnaires.
4. To evaluate the activity of neoadjuvant GAP in terms of ORR (Overall Response Rate) according to RECIST 1.1 criteria as per investigator assessment and per blinded independent central review (BICR) in the neoadjuvant arm in the subgroup of patients with measurable disease.
5. To retrospectively evaluate the resectability of the primary tumor according to the assessment of a central review committee.
6. To evaluate the safety profile, adverse events and surgical morbidity or mortality of neoadjuvant GAP compared to upfront surgical approach.

Conditions and MedDRA coding

Resectable biliary tract cancers

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures.
2. Estimated life expectancy > 3 months.
3. Adequate baseline hematologic function characterized by the following at screening: a) ANC >=1.5x10^9/L, b) platelets >= 100x10^9/L, c) hemoglobin >=9g/dl. Note: prior transfusions for patients with low hemoglobin are allowed.
4. Adequate liver function characterized by the following at screening: a) Serum total bilitubin <= 1.5xULN and < 2mg/dL.Note: Subjects with Serum total bilirubin >=1.5xULN and conjugated bilirubin <=40% of total bilirubin are allowed. b) Serum transaminases (AST and/or ALT) < 3 x ULN.
5. Adequate renal function, i.e. serum creatinine <= 1.5 institutionalULN and calculated by Cockroft-Gault formula or directly measured creatinine clearance >= 50mL/min
6. 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).
7. No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines
8. 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.
9. 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.
10. Female and male patients >= 18 years and < 75 years.
11. 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.
12. Availability of a tumoral sample
13. ECOG performance status of 0-1.
14. No prior tumor resection for BTC.
15. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax and PET scan.
16. 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..
17. High risk for recurrence defined as the presence of at least one of the following risk features, as evaluated at baseline (pre-surgery)
18. Negative serum pregnancy test within 7 days of starting study treatment in premenopausal 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 19

1. Known allergy or hypersensitivity to cisplatin, gemcitabine, nab-paclitaxel or fluoropyrimidine and their excipients.
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. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
11. Pregnant or breast-feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment.
12. Any other concurrent antineoplastic treatment including radiotherapy.
13. Previous or concurrent systemic (eg cytotoxic or targeted or other experimental drugs) therapy for BTC.
14. Prior surgery or locoregional therapy for BTC.
15. 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).
16. Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
17. Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
18. Presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines.
19. Rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the phase II part is the 12-month progression-free survival (PFS) rate: 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).

Secondary endpoints 11

1. Progression-free survival (PFS), the time from randomization to disease progression, post-resection recurrence or death from any cause
2. Event free survival (EFS): 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.
3. Relapse-free survival (RFS): the time from surgery to disease recurrence or death in patients who undergo to surgery with curative intent.
4. Overall survival (OS): the time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
5. R0 Resection Rate: the percentage of patients, relative to the total of randomized patients, for whom a R0 resection is achieved.
6. R0+R1 resection rate, 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. Note: R0 surgery is defined as microscopically margin free complete surgical removal of all residual disease. R1 resection indicates the removal of all macroscopic disease, but microscopic margins are positive for tumor.
7. Quality of life (QLQ): assessed through Patient Reported Outcome instruments (PROs) distributed by the study staff and completed entirely by the patient. 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 and BIL21 physical functioning, social functioning, and fatigue scores will be compared between the two arms.
8. Overall Response Rate (ORR): is defined as 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. The determination of clinical response will be based on investigator assessment (during study treatment) and it will be retrospectively evaluated as per blinded independent central review (BICR) of CT scan images.
9. Resectability Rate: 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.
10. Toxicity Rate is defined as the percentage of patients, relative to the total of subjects randomized to receive neoadjuvant treatment, experiencing a specific adverse event, according to National Cancer Institute Common Toxicity Criteria
11. Perioperative morbidity and mortality rate is defined as the percentage of patients, with any serious perioperative morbidity or mortality according to Clavien-Dindo classification

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 1

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications