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

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ClinicalTrials.gov Identifier: NCT02913131
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : March 8, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Rahul Aggarwal, University of California, San Francisco

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Pyruvate (13C) Device: MRI Phase 2

Detailed Description:

This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 pyruvate/metabolic 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 with the goal of achieving signal-to-noise ratio of at least 10 in a minimum of 3 patients in order to proceed to Part B of the study.

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Hyperpolarized C-13 Pyruvate as a Biomarker of PI3K/mTOR Pathway Inhibition in Patients With Advanced Solid Tumor Malignancies
Study Start Date : December 2015
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : April 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A: Feasibility Run-In
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). The target SNR of 10 must be achieved in at least 3 patients in order to proceed to part B of the study.
Drug: Pyruvate (13C)
Pyruvate injection followed by an MRI scan.

Device: MRI
MRI scan following the pyruvate (13c) injection

Experimental: Part B: Biomarker Cohort
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.
Drug: Pyruvate (13C)
Pyruvate injection followed by an MRI scan.

Device: MRI
MRI scan following the pyruvate (13c) injection




Primary Outcome Measures :
  1. Part A: Signal-to-noise ratio with respect to intra-tumoral hyperpolarized C-13 lac/pyr ratio detected within target liver metastasis in patients with advanced solid tumor malignancies. [ Time Frame: Baseline ]
  2. Part B: Mean percent change from baseline in peak intra-tumoral hyperpolarized lactate/pyruvate ratio after initiation of treatment with PI3K/mTOR pathway inhibitor. [ Time Frame: Baseline and after approximately 21 days of therapy. Follow-up for approximately 6 months ]
    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 95% confidence interval.


Secondary Outcome Measures :
  1. Frequency of adverse events as graded by Common Toxicity Criteria version 4.0 [ Time Frame: Throughout study - from baseline, after 21 days of therapy, and for duration of follow-up (approximately 6 months) ]
    Safety analyses will be performed for all patients having received a dose of HP C-13 pyruvate. The study will use the NCI CTCAE v4.0.

  2. Association between percent change from baseline in peak intra-tumoral HP lactate/pyruvate ratio on metabolic MR imaging with clinical benefit rate (Part B) [ Time Frame: From baseline to approximately 21 days of therapy. Follow-up for approximately 6 months ]
    For the purposes of analyzing the association between percent change from baseline in intra-tumoral peak lactate/pyruvate ratio on HP MRI with subsequent clinical outcomes, the cohort will be dichotomized by the median percent change. The objective response rate by RECIST 1.1 criteria and clinical benefit rate (response or stable disease for > 24 weeks) will be compared between dichotomized groups using the chi-squared test.

  3. Association between percent change from baseline in peak intra-humoral HP lactrate/pyruvate ratio on metabolic MR imaging with progression-free survival (Part B) [ Time Frame: From baseline to approximately 21 days of therapy. Follow-up for approximately 6 months ]
    The log rank test will be used to compare the radiographic progression-free survival between the two groups.


Other Outcome Measures:
  1. Association between HP peak lactate/pyruvate signal with immunohistochemical expression level of markers of PI3K/mTOR and glycolytic pathway, including LDH, phosphorylated S6, and phosphorylated Akt. (Part B) [ Time Frame: From baseline to approximately 21 days of therapy. Follow-up for approximately 6 months ]
    Analyses will be performed to compare the HP MR markers with immunohistochemical and enzyme expression and activity data from biopsy tissue to investigate the molecular and physiological underpinnings of the HP 13C MR data. When both the HP biomarker and molecular biomarker (LDHA activity) are continuous variables, Spearman's rank correlation coefficient will be used to investigate a possible correlation between them. If the outcome is categorical (e.g. immunohistochemistry score 0-1+ vs 2-3+ for pS6, pAkt, LDHA, and MCT 1/4 expression), the HP biomarker distributions will be compared between the two categories using the Mann-Whitney test.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Presence of at least one target liver 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 1.5 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 50 mL/min (by the Cockcroft Gault equation) and total bilirubin <3x ULN.

Part B only:

  • Presence of at least one target lesion amenable to percutaneous tumor biopsy in the judgment of Interventional Radiology
  • No prior local therapy to target liver lesion.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02913131


Contacts
Contact: Rahul Aggarwal, MD 877-827-3222 cancertrials@ucsf.edu
Contact: Kamran Abri-Lavasani 877-827-3222 cancertrials@ucsf.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Rahul Aggarwal, MD    877-827-3222    cancertrials@ucsf.edu   
Contact: Kamran Abri-Lavasani    877-827-3222    cancertrials@ucsf.edu   
Sponsors and Collaborators
Rahul Aggarwal
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
Principal Investigator: Rahul Aggarwal, MD University of California, San Francisco

Responsible Party: Rahul Aggarwal, Assistant Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02913131     History of Changes
Other Study ID Numbers: 159517
R01CA183071 ( U.S. NIH Grant/Contract )
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: March 8, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No