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Magnetic Resonance (MR) Imaging With Hyperpolarized Pyruvate (HP) (13C) in Castration-Resistant Prostate Cancer (MR)

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ClinicalTrials.gov Identifier: NCT02911467
Recruitment Status : Recruiting
First Posted : September 22, 2016
Last Update Posted : November 13, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This is a prospective imaging study evaluating the utility of baseline metabolic MR imaging with Hyperpolarized Pyruvate (HP) (13C) as a predictive response biomarker to androgen signaling inhibition in patients with castration-resistant prostate cancer.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Pyruvate (13C) Device: MRI Phase 1

Detailed Description:
This is a prospective imaging study evaluating the utility of baseline metabolic MR imaging as a predictive response biomarker to androgen signaling inhibition in patients with castration-resistant prostate cancer. Patients with a target lesion that is amenable for metabolic MR imaging will be eligible for study participation. Patients will undergo baseline metabolic MR imaging with Hyperpolarized Pyruvate C-13 pyruvate followed by initiation of androgen signaling inhibition (either as standard of care or as part of clinical trial; including abiraterone and/or enzalutamide treatment). Patient will subsequently undergo repeat metabolic MR scan after 28 days (+/- 7 days) of therapy. For those without primarily refractory disease, a third metabolic MR scan will be completed at the time of radiographic disease progression by The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria. MR- or CT-guided tumor biopsies are optional at baseline and at the time of disease progression.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Magnetic Resonance (MR) Imaging With Hyperpolarized Pyruvate (13C) as a Predictive Biomarker of Response to Androgen Signaling Inhibitors in Castration-Resistant Prostate Cancer
Actual Study Start Date : November 8, 2016
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MR imaging with hyperpolarized 13C pyruvate of men with CRPC
75 men with castration-resistant prostate cancer (CRPC) will undergo MR imaging with hyperpolarized 13C pyruvate of a pre-selected target lesion at baseline and after 1 month of treatment with an androgen signaling inhibitor. Patients with CRPC that is not primarily refractory (defined as disease progression by PCWG2 criteria within 6 months of treatment initiation) to Androgen Signaling Inhibitors (ASI) treatment will undergo a third metabolic MR scan at the time of disease progression. Patients may undergo optional MR- or CT-guided tumor biopsies at baseline and at the time of disease progression.
Drug: Pyruvate (13C)
Pyruvate injection followed by an MRI scan.

Device: MRI
MRI scan following the Pyruvate injection




Primary Outcome Measures :
  1. Mean difference in baseline intra-tumoral peak lac/pyr ratio on HP C-13 MRI in ASI-refractory versus ASI-responsive CRPC tumors [ Time Frame: Baseline to within 6 months since treatment initiation ]
    ASI-refractory disease is defined as progression by PCWG2 criteria within 6 months of treatment initiation. ASI-responsive disease includes all other tumors not meeting this criterion.


Secondary Outcome Measures :
  1. Association between change from baseline in peak intra-tumoral HP lac/pyr ratio after 28 days of ASI treatment with subsequent clinical outcomes on ASI treatment [ Time Frame: Baseline and after 28 days ]
    Association between change from baseline in peak intra-tumoral HP lac/pyr ratio after 28 days of ASI treatment with subsequent clinical outcomes on ASI treatment including Prostate Specific Antigen (PSA) response rate and radiographic progression-survival by PCWG2 criteria.

  2. Mean percent change from baseline in peak intra-tumoral HP lac/pyr ratio on repeat metabolic MRI obtained at the time of radiographic disease progression by PCWG2 criteria. [ Time Frame: Baseline and the time of radiographic disease progression by PCWG2 ]
  3. Baseline peak intra-tumoral HP lac/pyr ratio cut-point that most accurately predicts for response versus refractoriness to subsequent ASI treatment [ Time Frame: Baseline ]
  4. Assessment of the occurrence of clinically significant changes in safety variables from baseline [ Time Frame: Baseline and to end of treatment ]
    Assessment of the occurrence of clinically significant changes in safety variables from baseline. Safety endpoints include monitoring for the occurrence of treatment-emergent AEs. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology (Toxicity) Criteria for Adverse Events (CTCAE) version 4.0


Other Outcome Measures:
  1. Correlation between intra-tumoral peak lac/pyr ratio and lactate area under the curve (AUC) with immunohistochemical markers [ Time Frame: Baseline, 28 days, and then 18-20 months ]
    Correlation between intra-tumoral peak lac/pyr ratio and lactate AUC with immunohistochemical markers including LDHA, Ki-67, MYC (myelocytomatosis oncogene), and MCT (Monocarboxylate transporter) 1/MCT 4 expression.

  2. Association between intra-tumoral peak lac/pyr ratio and histologic subtype of prostate cancer [ Time Frame: Baseline, 28 days, and then 18-20 months ]
    Association between intra-tumoral peak lac/pyr ratio and histologic subtype of prostate cancer (adenocarcinoma versus neuroendocrine prostate cancer)

  3. Mean difference in change from baseline in peak intra-tumoral HP lac/pyr ratio between patients treated with abiraterone-based versus enzalutamide-based therapy [ Time Frame: Baseline, 28 days, and then 18-20 months ]
  4. Mean, standard deviation, and range in intra-tumoral peak HP lac/pyr ratio between metastatic lesions for an individual patient [ Time Frame: Baseline, 28 days, and then 18-20 months ]
  5. Optional tumor biopsies: compare the HP MR markers with immunohistochemical and enzyme expression and activity data from biopsy tissue [ Time Frame: Baseline, 28 days, and then 18-20 months ]
    For patients who undergo optional tumor biopsies, 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 MYC, LDHA, and MCT 1/4 expression), the HP biomarker distributions will be compared between the two categories using the Mann-Whitney test.

  6. Optional baseline tumor biopsy: compare the difference in baseline peak intra-tumoral lac/pyr ratio on metabolic MR between adenocarcinoma and neuroendocrine prostate cancer [ Time Frame: Baseline, 28 days, and then 18-20 months ]
    For patients who undergo baseline tumor biopsy, patients will be dichotomized on the basis of histologic classification: adenocarcinoma versus neuroendocrine differentiation, using standard pathologic assessment from a pathologist blinded to radiologic findings. The difference in baseline peak intra-tumoral lac/pyr ratio on metabolic MR between adenocarcinoma and neuroendocrine prostate cancer will be compared 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:

  1. Biopsy-proven prostate cancer.
  2. Progressive, castration-resistant disease according to PCWG2 criteria.
  3. Planned treatment with an androgen signaling inhibitor (e.g., abiraterone, enzalutamide, apalutamide (ARN-509)). Patients must not be receiving androgen signaling inhibitor at the time of the baseline MR scan. Combination treatment (e.g., androgen signaling inhibitor in conjunction with another systemic treatment) is allowed.
  4. Presence of at least one target lesion detected by standard staging scans that, in the judgment of Study Investigators, would be amenable to hyperpolarized C-13 pyruvate/metabolic MR imaging:

    • Soft tissue/visceral organ target lesions must measure at 1.5 cm in long axis diameter on CT or MRI.
    • Target lesions in the bone must be visualized by CT or MRI (lesions present only on bone scan do not qualify).
    • For patients with target lesion in prostate/prostatic bed:

      i. No contra-indications to endorectal coil insertion (e.g., patients with a prior abdominoperineal resection of the rectum or latex allergy).

    ii. No prior local treatment to the selected lesion. Patients who have received prior radiation or ablative therapy to the prostate will be required to have biopsy-proven evidence of disease recurrence following completion of local therapy.

  5. The subject is able and willing to comply with study procedures and provide signed and dated informed consent.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  7. Adequate organ function, including absolute neutrophil count (ANC) ≥ 1500 cells/µL, hemoglobin ≥ 9.0 gm/dL, platelets ≥ 75,000 cells/µL, creatinine < 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min (by the Cockcroft Gault equation), bilirubin <1.5x ULN (unless Gilbert's is suspected in which case total bilirubin < 3 x ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5x ULN.
  8. For patients undergoing optional tumor biopsy:

    • No history of bleeding diathesis.
    • Patients on anti-coagulation they must be able to safely stop treatment for purposes of tumor biopsy.
  9. For patients with partners of childbearing potential, willing to use adequate contraception for one month after undergoing HP pyruvate infusion.
  10. Patients must have prior bilateral orchiectomy or be on continuous luteinizing-hormone releasing hormone (LHRH) analogue therapy for the duration of study.
  11. Castrate level of serum testosterone (< 50 ng/dL) at study entry.

Exclusion Criteria:

  1. Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent.
  2. 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.
  3. Metallic hip implant or any other metallic implant or device that distorts local magnetic field and compromises the quality of MR imaging.
  4. 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.
  5. Congestive heart failure or New York Heart Association (NYHA) status ≥ 2.
  6. 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.
  7. 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): NCT02911467


Contacts
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Contact: Rahul Aggarwal, MD (415) 353-9278 Rahul.Aggarwal@ucsf.edu
Contact: Paula Dutton (415) 885-7871 Paula.Dutton@ucsf.edu

Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Rahul Aggarwal, MD    415-353-9278    Rahul.Aggarwal@ucsf.edu   
Contact: Paula Dutton, BS    415-885-7871    Paula.Dutton@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rahul Aggarwal, MD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02911467    
Other Study ID Numbers: 15559
P0048644 ( Other Identifier: UCSF - NIH Natl Cancer Institute )
First Posted: September 22, 2016    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases