The PLATINUM Trial: Optimizing Chemotherapy For The Second-Line Treatment Of Metastatic BRCA1/2 Or PALB2-Associated Metastatic Pancreatic Cancer

Study Overview

The PLATINUM Trial: Optimizing Chemotherapy for the Second-Line Treatment of Metastatic BRCA1/2 or PALB2-Associated Metastatic Pancreatic Cancer

This phase II/III trial compares the effect of the 3-drug chemotherapy combination of nab-paclitaxel, gemcitabine, plus cisplatin versus the 2-drug chemotherapy combination of nab-paclitaxel plus gemcitabine for the treatment of patients with pancreatic cancer that has spread to other places in the body (metastatic) and a known genetic mutation in the BRCA1, BRCA2, or PALB2 gene.

PRIMARY OBJECTIVES: I. To evaluate and compare overall response rate (ORR) in patients with BRCA1/2 or PALB2 mutant pancreas cancer whose disease has progressed on front-line fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX) treated with nab-paclitaxel, gemcitabine, and cisplatin (NABPLAGEM) = nab-paclitaxel, gemcitabine, and cisplatin (arm 1) versus nab-paclitaxel and gemcitabine (arm 2). (Phase II) II. To evaluate and compare overall survival (OS) time in patients with BRCA1/2 or PALB2 mutant whose disease has progressed on front-line FOLFIRINOX treated with 1) NABPLAGEM = nab-paclitaxel, gemcitabine, and cisplatin (arm 1) versus nab-paclitaxel and gemcitabine (arm 2). (Phase III) SECONDARY OBJECTIVES: I. To evaluate and compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) criteria between 2 treatment arms. II. To evaluate and compare duration of response (DoR) between 2 treatment arms. III. To evaluate and compare CA19-9 response (defined as patients with a baseline CA19-9 >= 2x upper limit of normal (ULN) who demonstrate a minimum 25% decrease in CA19-9 at any time point) between 2 treatment arms. IV. To evaluate and compare toxicity profile as assessed by treating clinicians between 2 treatment arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive nab-paclitaxel intravenously (IV) over 30-40 minutes, gemcitabine IV over 30-40 minutes, and cisplatin IV over 30-60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) or computed tomography (CT) throughout the trial. Patients may optionally undergo blood sample collection at baseline and on study. ARM II: Patients receive nab-paclitaxel IV over 30-40 minutes and gemcitabine IV over 30-40 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT throughout the trial. Patients may optionally undergo blood sample collection at baseline and on study. After completion of study treatment, patients are followed up within 30 days and then every 3 months for 2 years or until death, whichever comes first.

Pancreatic Acinar Cell Carcinoma
Pancreatic Adenocarcinoma
Pancreatic Adenosquamous Carcinoma
Pancreatic Carcinoma
Pancreatic Ductal Adenocarcinoma
Pancreatic Squamous Cell Carcinoma
Stage IV Pancreatic Cancer AJCC v8

DRUG: Nab paclitaxel
DRUG: Gemcitabine
DRUG: Cisplatin
PROCEDURE: Magnetic Resonance Imaging
PROCEDURE: Computed Tomography
PROCEDURE: Biospecimen Collection

A022106
NCI-2023-06547 (OTHER Identifier) (OTHER: NCI Clinical Trial Reporting Program)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2023-10-30	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-03-28
First Submitted that Met QC Criteria 2023-10-30	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-04-02
First Posted (ACTUAL) 2023-11-03	Results First Posted N/A	Last Verified 2025-03

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm I (nab-paclitaxel, gemcitabine, cisplatin) Patients receive nab-paclitaxel IV over 30-40 minutes, gemcitabine IV over 30-40 minutes, and cisplatin IV over 30-60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patie	DRUG: Nab paclitaxel Given IV DRUG: Gemcitabine Given IV DRUG: Cisplatin Given IV PROCEDURE: Magnetic Resonance Imaging Undergo MRI PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Biospecimen Collection Undergo blood sample collection
ACTIVE_COMPARATOR: Arm II (nab-paclitaxel, gemcitabine) Patients receive nab-paclitaxel IV over 30-40 minutes and gemcitabine IV over 30-40 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT through	DRUG: Nab paclitaxel Given IV DRUG: Gemcitabine Given IV PROCEDURE: Magnetic Resonance Imaging Undergo MRI PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Biospecimen Collection Undergo blood sample collection

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm I (nab-paclitaxel, gemcitabine, cisplatin)

Patients receive nab-paclitaxel IV over 30-40 minutes, gemcitabine IV over 30-40 minutes, and cisplatin IV over 30-60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patie

DRUG: Nab paclitaxel

Given IV

DRUG: Gemcitabine

Given IV

DRUG: Cisplatin

Given IV

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

ACTIVE_COMPARATOR: Arm II (nab-paclitaxel, gemcitabine)

Patients receive nab-paclitaxel IV over 30-40 minutes and gemcitabine IV over 30-40 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT through

DRUG: Nab paclitaxel

Given IV

DRUG: Gemcitabine

Given IV

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

Primary Outcome Measures	Measure Description	Time Frame
Overall response rate (ORR) (Phase II)	Will be assessed by the proportion of patients who achieve complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) during the protocol treatment. Fisher's exact test will be conducted based on the first 32 patients in each arm who meet PP population criteria.	Up to 12 months
Overall Survival (OS) (Phase III)	Will be conducted on modified intention-to-treat population. Stratified Cox model will be constructed to compare OS in the experimental arm to OS in the control arm.	From the date of randomization to the date of death due to all causes, assessed up to 5 years

Secondary Outcome Measures	Measure Description	Time Frame
Progression-free survival	Will be assessed per RECIST 1.1. Will be estimated, in each arm, using the method of Kaplan-Meier and compared by stratified Cox regression model.	From the date of randomization to the date of first documented disease progression or death due to all causes, whichever occurs first, assessed up to 5 years
Incidence of adverse events	The maximum grade for each type of adverse events that are possibly, probably, or definitely related to study treatments will be recorded for each patient.	Up to 30 days after the last dose of study treatment

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Jamie Crawley, MA

Phone Number: 773-702-9934

Email: jcrawley@bsd.uchicago.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Metastatic pancreatic adenocarcinoma. Adenosquamous carcinoma, squamous carcinoma, acinar cell carcinoma, and carcinoma not otherwise specified are also acceptable
BRCA1/2 or PALB2 mutation (somatic or germline) identified on any Clinical Laboratory Improvement Amendments (CLIA)-certified gene panel. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org. (Submission of mutation report will be required)
Measurable disease
Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment
Clinical or radiographic progression on first-line FOLFIRINOX (or nanoliposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin [NALIRIFOX]) for metastatic disease

Patients whose front-line chemotherapy was required to be simplified due to toxicity associated with any of the constituent components of FOLFIRINOX/NALIRIFOX (e.g. simplified to leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX], leucovorin calcium, fluorouracil, and irinotecan [FOLFIRI], fluorouracil [5-FU] [including capecitabine]) will be eligible
Patients with progressive disease while on maintenance PARP inhibitor treatment after FOLFIRINOX (or NALIRIFOX), irrespective of how long ago they received FOLFIRINOX/NALIRIFOX, will also be eligible
Patients who develop metastatic disease during or within 6 months after completing FOLFIRINOX/NALIRIFOX in either the locally advanced or adjuvant/neoadjuvant settings will be eligible
Patients may not have received prior cisplatin for their pancreatic cancer in any setting

Note: Patients may have previously received gemcitabine +/- nab-paclitaxel for resectable (neoadjuvant/adjuvant) or locally advanced disease if (1) treatment was completed > 1 year ago and (2) in the opinion of the treating provider, re-treatment with gemcitabine/nab-paclitaxel is appropriate
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky performance status >= 60)
Absolute neutrophil count >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 8.0 g/dL
Creatinine =< 1.8 x institutional upper limit of normal (ULN) or calculated creatinine clearance (Calc. CrCl) > 40 mL/min
Total bilirubin =< 2.0 x institutional ULN

Any elevated bilirubin should be asymptomatic at enrollment (except for participants with documented Gilbert's syndrome who may only be included if the total bilirubin =< 3 x ULN or direct bilirubin =< 1.5 x ULN)
Aspartate transaminase (AST)/alanine transaminase (ALT) =< 3 x institutional ULN

AST/ALT of =< 5 x ULN if liver metastases are present
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
Patients with > grade 2 peripheral sensory neuropathy are not eligible
Patients with a 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 are eligible for this trial
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for at least 8-weeks.

Patients with known, new or progressive brain metastases (active brain metastases) or leptomeningeal disease are ineligible
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load anytime within 6 months prior to registration are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Concomitant chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

Publications

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