Hyperpolarized C-13 Pyruvate as a Biomarker in Patients With Advanced Solid Tumor Malignancies

Rahul Aggarwal

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Prostate Cancer

Treatments: Drug: Pyruvate (13C); Device: MRI

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02913131

NCI-2017-02190 (Registry Identifier)

159517

R01CA183071 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 pyruvate as a Biomarker of PI3K/mTOR pathway inhibition in patients with advanced solid tumor malignancies. The current protocol will serve as a companion imaging biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g. CUDC-907, BYL719), as well as a stand-alone protocol for patients treated with standard-of-care therapies inhibiting the PI3K/mTOR signaling pathway (eg. everolimus).

Full description

This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 pyruvate/metabolic magnetic resonance (MR) imaging. The current protocol will serve as a companion imaging biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g. CUDC-907, BYL719), as well as a stand-alone protocol for patients treated with standard-of-care therapies inhibiting the PI3K/mTOR signaling pathway (eg. everolimus).

In Part A (run-in feasibility phase), patients will undergo imaging at a single time point, without paired tumor biopsy. There will be no follow up imaging or requirement for treatment with PI3K/mTOR pathway inhibitor. Iterative adjustment of radiofrequency coil geometry and imaging sequences will be undertaken to optimize intra-tumoral hyperpolarized pyruvate/lactate signal-to-noise ratio.

In Part B, patients will undergo paired baseline hyperpolarized C-13 pyruvate imaging + tumor biopsy,then initiate treatment with agent inhibiting the PI3K/mTOR pathway. After 21 days (+/- 14 days), patients will undergo repeat hyperpolarized C-13 pyruvate MR imaging + tumor biopsy. Patients will subsequently be treated with PI3K/mTOR pathway inhibitor until disease progression, unacceptable toxicity, or patient/physician decision to discontinue therapy.

Enrollment: 23 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Presence of at least one target liver or other intra-abdominal lesion detected by standard staging scans that, in the judgment of Study Investigators, would be amenable to hyperpolarized C-13 pyruvate/metabolic MR imaging: Target lesion must measure >=1.0 cm in long axis diameter on CT or MRI
• 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.
• Adequate organ function, including creatinine < 1.5 x ULN or estimated creatinine clearance >=500 mL/min (by the Cockcroft Gault equation) and total bilirubin <3x upper limit of normal (ULN).

Part B only:

• No prior local therapy to target lesion.

• If patient agrees to optional biopsy:

  • Presence of at least one target lesion amenable to percutaneous tumor biopsy in the judgment of Interventional Radiology
  • No history of bleeding diathesis.
  • Patients on anti-coagulation they must be able to safely stop treatment for purposes of tumor biopsy.

• Planned treatment with agent targeting PI3K/mTOR pathway (either standard of care or investigational agent)

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 MR imaging, including patients with contra-indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular clips.
• Metallic implant or device that distorts local magnetic field and compromises the quality of MR imaging.
• Poorly controlled hypertension, defined as systolic blood pressure at study entry greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg. The addition of anti-hypertensives to control blood pressure is allowed.
• Congestive heart failure or New York Heart Association (NYHA) status ≥ 2.
• A history of clinically significant EKG abnormalities, including QT prolongation (QTcF > 500 ms), a family history of prolonged QT interval syndrome, or myocardial infarction (MI) within 6 months of study entry. Patients with rate-controlled atrial fibrillation/flutter will be allowed on study.
• Any condition that, in the opinion of the Principal Investigator, would impair the patient's ability to comply with study procedures.

Trial design

Primary purpose: Diagnostic

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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23 participants in 2 patient groups

Part A: Feasibility Run-In

Experimental group

Description:

Patients with advanced solid tumor malignancies with at least one liver metastasis will be enrolled with iterative adjustment of coil design to optimize imaging parameters including spatial resolution and signal-to-noise ratio (SNR) of hyperpolarized pyruvate / lactate within the target metastatic lesion(s).

Treatment:

Drug: Pyruvate (13C)

Device: MRI

Part B: Biomarker Cohort

Experimental group

Description:

Patients with advanced solid tumor malignancies and the presence of at least one liver metastasis amenable to hyperpolarized C-13 pyruvate metabolic MR imaging who are planning on being treated with agent targeting PI3K/mTOR pathway will be enrolled.

Treatment:

Drug: Pyruvate (13C)

Device: MRI