Hyperpolarized 13C Pyruvate as a Biomarker in Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a single center prospective imaging study investigating the utility of hyperpolarized 13C-pyruvate/metabolic MR imaging. The current protocol will serve as a companion imaging biomarker study paired with standard of care (SOC) therapeutics, as well as investigational therapies that participants may be scheduled to receive outside of this protocol.

Detailed Description
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PRIMARY OBJECTIVES: Phase I/Part A 1. To optimize the signal-to-noise ratio in detecting intra-tumoral hyperpolarized 13C pyruvate/lactate signal using metabolic MR imaging in participants with advanced solid tumors. Phase II/Part B 1. To determine the mean percent change from baseline in peak intra-tumoral hyperpolarized lactate-to-pyruvate ratio and pyruvate-to-lactate kinetic constant (kPL) after initiation of SOC treatment. SECONDARY OBJECTIVES: Phase I/Part A To further characterize the safety profile of hyperpolarized 13C-pyruvate. To determine the reproducibility of intra-tumoral HP lac/pyr ratio with same-day repeated dose studies. Phase II/Part B To study the association between clinical outcomes and the percent change from baseline in peak intra-tumoral hyperpolarized lactate-to-pyruvate ratio and kPL after initiation of SOC treatment. To further characterize the safety profile of hyperpolarized 13C pyruvate. To determine the reproducibility of intra-tumoral HP lac/pyr ratio with same-day repeated dose studies. OUTLINE: Participants will be enrolled in Part A which is the feasibility, run-in study which includes the iterative adjustment of coil design to optimize imaging parameters within the target tumor lesion(s). If the data from Part A supports further investigation, additional participants will be enrolled in Part B which is a biomarker cohort which includes participants who are planning on being treated with either standard-of-care (SOC) or investigational therapies and will be followed until discontinuation of the treatment regimen outside of this protocol.

Official Title
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A Phase I/II Study of Hyperpolarized 13C Pyruvate as a Biomarker of Aggressiveness & Response to Therapy in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Hyperpolarized 13C-Pyruvate
* Procedure: Magnetic Resonance Imaging (MRI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of at least one target pelvic, abdominal, thoracic, neck or extremity lesion detected by standard staging scans that, in the judgment of study investigator, would be amenable to hyperpolarized C-13 pyruvate/metabolic MR imaging: a. Target lesion must measure at least 1.0 cm in long axis diameter on Computerized tomography (CT) or magnetic resonance imaging (MRI). The participant 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. Adequate renal function defined as creatinine < 1.5 x upper limit of normal (ULN) or estimated creatinine clearance >50 mL/min (by the Cockcroft Gault equation). Participants age 18 and older. Part B only: Planned treatment for disease with either standard of care regimen or an investigational agent. Exclusion Criteria: Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent. Patients with contra- indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular clips. Patients with a metallic implant or device that distorts local magnetic field and compromises the quality of MR imaging. Patients with poorly controlled hypertension, defined as systolic blood pressure at study entry greater than 160mm Hg or diastolic blood pressure greater than 100mm Hg. Note: The addition of anti-hypertensives to control blood pressure is allowed. Patients with congestive heart failure or New York Heart Association (NYHA) status >= 2. Patients who are pregnant or lactating. A history of clinically significant EKG abnormalities or myocardial infarction (MI) within 6 months of study entry. Note: Patients with rate-controlled atrial fibrillation/flutter will be allowed on study. Any condition that, in the opinion of the Principal Investigator,

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A / Phase 1: Feasibility Run-In<br>Participants will undergo MR imaging at a single time point. Imaging will take one day. and no follow up is planned. | Drug: Hyperpolarized 13C-Pyruvate<br>* Given IV<br>* Other names: HP-13C;Procedure: Magnetic Resonance Imaging (MRI)<br>* Imaging procedure<br>* Other names: MRI;|
| Experimental: Part B/ Phase II: Biomarker Cohort<br>Participants will undergo paired hyperpolarized pyruvate/metabolic MR imaging at baseline and again after approximately 21 days of the participants SOC or investigational therapy outside of this protocol. | Drug: Hyperpolarized 13C-Pyruvate<br>* Given IV<br>* Other names: HP-13C;Procedure: Magnetic Resonance Imaging (MRI)<br>* Imaging procedure<br>* Other names: MRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Signal-to-noise ratio (Part A) | Signal-to-noise ratios is defined as a MR/spectroscopy parameter, consisting of the HP C13-Pyruvate or Lactate signal (peak) relative to background noise level (baseline) in MRI spectra of the tissue. For the analysis and interpretation of the HP 13C-pyruvate MR imaging data, DICOM software package (SIVIC) will be used to align, display and quantitatively interrogate serial multi-parametric imaging data. | Day of imaging (1 day) | 
| Mean percent change from baseline in intratumoral HP pyruvate/lactate ratio | Intra-tumoral region of interest (ROI) will be used to quantify peak HP lactate/pyruvate ratio values in the selected volumes of interest. Descriptive statistics will be used to characterize the mean change from baseline in intra-tumoral HP pyruvate/lactate ratio for the study cohort, along with a 95% confidence interval | Up to 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants reporting adverse events (Part A) | Safety analyses will be performed for all patients having received a dose of HP 13C pyruvate. Adverse events will be classified and graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) | Day of imaging (1 day) | 
| Number of participants reporting adverse events (Part B) | Safety analyses will be performed for all patients having received a dose of HP 13C pyruvate. Adverse events will be classified and graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) | Up to 6 months | 
| Median percent change from baseline in peak intratumoral hyperpolarized lactate-to-pyruvate ratio (Part B) | Lactate/pyruvate ratio: hyperpolarized Lactate signal divided by the hyperpolarized pyruvate signal within the tumor region, for each injection/scan on the same day. | Up to 6 months | 
| Objective response rate (ORR) (Part B) | ORR is defined as the proportion of treated patients who experience an objective response (confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 6 months | 
| Clinical benefit rate (CBR) (Part B) | CBR is defined as the proportion of treated patients who experience clinical benefit (confirmed complete response (CR); confirmed partial response (PR); or stable disease (SD) for > 24 weeks per RECIST 1.1 criteria). | Up to 6 months | 
| Radiographic progression-free survival (rPFS) (Part B) | rPFS is defined as the amount of time that elapses between initiation of standard of care treatment and the day of first documented radiographic disease progression per RECIST v.1.1 or death from any cause. | Up to 6 months | 
| Lactate/pyruvate ratio (Part B) | Intra-patient reproducibility of HP lac/pyr ratio and kPL for patients who undergo repeated dose imaging studies will be descriptively reported using summary statistics (mean difference, standard deviation, range). | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarker