Hyperpolarized 13C Pyruvate MRI for Treatment Response Assessment in Pancreatic Ductal Adenocarcinoma

PRIMARY OBJECTIVES:

I. To determine the signal-to-noise ratio of 13C pyruvate metabolism (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate area-under-the-curve (AUC) ratio, and apparent rate constant for pyruvate-to-lactate conversion, kPL) in the target tumor (primary tumor and/or abdominal metastases) in Cohort A.

II. To determine the percent changes in the target tumor (primary tumor and/or abdominal metastases) 13C pyruvate metabolism (peak 13C lactate/pyruvate ratio, 13C lactate/pyruvate AUC ratio, and kPL) between pre-treatment scan and scan obtained at 4-week (+/-2 weeks) following treatment initiation in Cohort B.

SECONDARY OBJECTIVES:

I. To determine the repeatability of 13C pyruvate metabolism measures in the target tumor (primary tumor and/or abdominal metastasis) in patients with same-day repeated dose in Cohort A and B.

II. To determine whether the baseline or the changes in the target tumor (primary tumor and/or abdominal metastases) 13C pyruvate metabolism at 4 weeks following treatment initiation are associated with the best objective response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria on subsequent clinical computed tomography (CT) scans in Cohort B.

EXPLORATORY OBJECTIVE:

I. To explore 13C pyruvate metabolism between the primary tumor and abdominal metastases (when present) both at baseline and following treatment in both Cohort A and B.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive hyperpolarized carbon C 13 pyruvate intravenously (IV) over less than one minute then undergo MRI over 5 minutes at baseline in the absence of unacceptable toxicity.

COHORT B: Patients receive hyperpolarized carbon C 13 pyruvate IV over less than one minute then undergo MRI over 5 minutes at baseline and 4 weeks after beginning treatment in the absence of unacceptable toxicity.

In both cohorts, patients may receive an optional second hyperpolarized carbon C 13 pyruvate dose and undergo MRI within 15 to 60 minutes following the completion of the first scan.

After completion of study treatment, patients are followed up every 2-3 months

• Hyperpolarized Carbon C 13 Pyruvate (Drug), also known as Hyperpolarized 13C Pyruvate: Given IV prior to imaging
• Magnetic Resonance Imaging (MRI) (Procedure), also known as MRI, Magnetic Resonance Imaging Scan, MR Imaging: Undergo MRI

Primary outcomes

• Cohort A: Signal-to-noise Ratio of the Target Lesion 13C Pyruvate Metabolism Measures Will be Determined for Each Patient [Baseline]: Descriptive statistics will be used to summarize the mean, standard deviation, and 95% confidence interval of the measurements.
• Cohort B: Target Tumor Metabolism [Up to 4 weeks]: Paired t-test or Wilcoxon signed rank test will be used to compare the target tumor Hyperpolarized (HP) 13C pyruvate metabolism pre- and 4-week (+/- 2 weeks) post treatment initiation.

Secondary outcomes

• Cohort A: Intraclass Correlation Coefficient (ICC) [Up to 6 months]: ICC will be used to estimate the intra-subject agreement to assess repeatability of tumor HP 13C pyruvate metabolism in patients with same-day repeated dose. ICC will also be used to estimate agreement obtained from a one-way analysis of variance model based on 2 measurements per subject. The result will be presented with a 95% confidence interval
• Cohort B: Best Objective Response [Up to 4 weeks after treatment initiation]: Objective response for patients in Cohort B will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on subsequent clinical CT scans. For the purpose of response assessment in this pilot study, we will group patients either as having disease control when the best response is complete response (CR), partial response (PR), or stable disease (SD) on subsequent clinical CT scans, or having disease progression when the best response is progressive disease (PD) on subsequent CT scans. Comparisons the baseline or changes in the target tumor 13C pyruvate metabolism at 4 weeks (+/-2 weeks) after treatment initiation between the disease control group and disease progression group (as defined by RECIST on subsequent clinical CT scans) will be made using the Mann-Whitney tests.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Locally advanced or metastatic pancreatic ductal adenocarcinoma, with at least one target lesion in the abdomen measuring >= 1 cm
* The subject is able and willing to comply with study procedures and provide signed and dated informed consent
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

* Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent
* Patients unwilling or unable to undergo magnetic resonance (MR) imaging, including patients with contraindications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular clips
* Poorly controlled hypertension, defined as either systolic > 170 or diastolic > 110. The addition of anti-hypertensives to control blood pressure is allowed for eligibility determination
* Congestive heart failure >= class III
* Myocardial infarction within the past year
* History of QT prolongation on electrocardiogram (EKG), defined as pretreatment QTs > 440 msec in males or > 460 msec in females
* Pregnant and lactating females

Participant flow

Outcome results

• Cohort A: Signal-to-noise Ratio of the Target Lesion 13C Pyruvate Metabolism Measures Will be Determined for Each Patient (Primary)
• Cohort B: Target Tumor Metabolism (Primary)
• Cohort A: Intraclass Correlation Coefficient (ICC) (Secondary)
• Cohort B: Best Objective Response (Secondary)

Adverse events

Time frame: Up to 4 weeks

Limitations and caveats: Study closed earlier than expected due to slow accrual

• Results publication: Gordon JW, Chen HY, Nickles T, Lee PM, Bok R, Ohliger MA, Okamoto K, Ko AH, Larson PEZ, Wang ZJ. Hyperpolarized 13C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma. J Magn Reson Imaging. 2024 Aug;60(2):741-749. doi: 10.1002/jmri.29162. Epub 2023 Dec 2. PMID 38041836

• Study Protocol and Statistical Analysis Plan (PDF, 2022-07-29)

• Zhen Wang, MD, Principal investigator, University of California, San Francisco