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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02913131
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : May 18, 2020
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Rahul Aggarwal, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE September 20, 2016
First Posted Date  ICMJE September 23, 2016
Last Update Posted Date May 18, 2020
Actual Study Start Date  ICMJE October 20, 2016
Estimated Primary Completion Date October 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2020)
  • 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: 1 day ]
  • 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: Up to 24 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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 21, 2016)
  • 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 ]
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2020)
  • Frequency of adverse events as graded by Common Toxicity Criteria version 4.0 [ Time Frame: Up to 24 months ]
    Safety analyses will be performed for all patients having received a dose of HP C-13 pyruvate. The study will use the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 for reporting of adverse events that occur within 3 days of each imaging procedure and any biopsy-related adverse events
  • Association between percent change from baseline in peak intra-tumoral hyperpolarized lactate/pyruvate ratio on metabolic MR imaging with clinical benefit rate (Part B) [ Time Frame: Up to 24 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.
  • Association between percent change from baseline in peak intra-humoral HP lactate/pyruvate ratio on metabolic MR imaging with progression-free survival (Part B) [ Time Frame: Up to 24 months ]
    The log rank test will be used to compare the radiographic progression-free survival between the two groups.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2016)
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: September 21, 2016)
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.
 
Descriptive Information
Brief Title  ICMJE Hyperpolarized C-13 Pyruvate as a Biomarker in Patients With Advanced Solid Tumor Malignancies
Official Title  ICMJE Hyperpolarized C-13 Pyruvate as a Biomarker of PI3K/mTOR Pathway Inhibition in Patients With Advanced Solid Tumor Malignancies
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).
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Prostate Cancer
Intervention  ICMJE
  • Drug: Pyruvate (13C)
    Pyruvate injection followed by an MRI scan.
  • Device: MRI
    MRI scan following the pyruvate (13c) injection
Study Arms  ICMJE
  • 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).
    Interventions:
    • Drug: Pyruvate (13C)
    • Device: MRI
  • 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.
    Interventions:
    • Drug: Pyruvate (13C)
    • Device: MRI
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 14, 2020)
80
Original Estimated Enrollment  ICMJE
 (submitted: September 21, 2016)
40
Estimated Study Completion Date  ICMJE April 1, 2022
Estimated Primary Completion Date October 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rahul Aggarwal, MD 877-827-3222 cancertrials@ucsf.edu
Contact: Lauren Wilch Lauren.Wilch@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02913131
Other Study ID Numbers  ICMJE 159517
R01CA183071 ( U.S. NIH Grant/Contract )
NCI-2017-02190 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Rahul Aggarwal, University of California, San Francisco
Study Sponsor  ICMJE Rahul Aggarwal
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Rahul Aggarwal, MD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP