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Niraparib/TTFields in GBM

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ClinicalTrials.gov Identifier: NCT04221503
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : July 2, 2020
Sponsor:
Collaborators:
Tesaro, Inc.
NovoCure Ltd.
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
Evaluating the efficacy and safety of niraparib and Tumor-Treating Fields (TTFields) in recurrent glioblastoma (GBM).

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Glioblastoma GBM Drug: Niraparib Device: Optune Procedure: Planned surgical resection Phase 2

Detailed Description:
Tumor-treating fields (TTFields) causes downregulation of BRCA1 signaling and reduced deoxyribonucleic acid (DNA) double-strand break repair capacity. Tumors that are deficient in the homologous recombination DNA damage repair pathway are highly sensitive to blockade of the repair of single strand DNA breaks via poly-ADP ribose polymerase (PARP) inhibition. This is a study of niraparib, a PARP inhibitor, in combination with tumor-treating fields for recurrent glioblastoma. We hypothesize that tumor-treating fields will induce a state of "BRCAness" in the glioma tumor cells, thus sensitizing them to PARP inhibition and resulting in tumor cell death.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating the Efficacy and Safety of Niraparib and Tumor-Treating Fields in Recurrent Glioblastoma
Actual Study Start Date : December 30, 2019
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2025


Arm Intervention/treatment
Experimental: Cohort A
Cohort A is for subjects with recurrent glioblastoma who do not have clinical indication for surgical resection of the recurrent tumor. Subjects in Cohort A will initiate and continue TTFields therapy for 5-7 days prior to starting niraparib.
Drug: Niraparib
Niraparib ([3S]-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl} phenyl] piperidine [tosylate monohydrate salt]) is an orally available, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor. The niraparib drug product is provided as 100-mg capsules filled with a dry blend of niraparib tosylate monohydrate, lactose monohydrate, and magnesium stearate in a hard gelatin capsule.
Other Name: ZEJULA

Device: Optune
Optune, which is manufactured by Novocure, is a portable battery or power supply operated device which produces alternating electrical fields, called tumor treatment fields ("TTFields") within the human body. TTFields are applied to the patient by electrically-insulated surface transducer arrays. TTFields disrupt the rapid cell division exhibited by cancer cells.
Other Name: Tumor Treatment Fields (TTFields)

Active Comparator: Cohort B
Cohort B is for subjects with recurrent glioblastoma who have a clinical indication for surgical resection of the recurrent tumor. Subjects in Cohort B will receive TTFields for 5-7 days prior to planned surgical resection, undergo surgical resection, resume TTFields postoperatively, and initiate niraparib 5- 7 days after starting TTFields postoperatively.
Drug: Niraparib
Niraparib ([3S]-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl} phenyl] piperidine [tosylate monohydrate salt]) is an orally available, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor. The niraparib drug product is provided as 100-mg capsules filled with a dry blend of niraparib tosylate monohydrate, lactose monohydrate, and magnesium stearate in a hard gelatin capsule.
Other Name: ZEJULA

Device: Optune
Optune, which is manufactured by Novocure, is a portable battery or power supply operated device which produces alternating electrical fields, called tumor treatment fields ("TTFields") within the human body. TTFields are applied to the patient by electrically-insulated surface transducer arrays. TTFields disrupt the rapid cell division exhibited by cancer cells.
Other Name: Tumor Treatment Fields (TTFields)

Procedure: Planned surgical resection
Surgery of supratentorial glioblastoma (GBM).
Other Name: Tumor Resection




Primary Outcome Measures :
  1. Disease control, defined as achievement of either CR, PR, or SD, as defined by modified Response Assessment in Neuro-Oncology (mRANO) criteria. [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]

    Complete response (CR) is seen as the disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks.

    Partial response (PR) is ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks.

    Stable disease (SD), must be present on two consecutive MRI scans, with the 2nd/confirmatory MRI performed at least 16 weeks after starting treatment.



Secondary Outcome Measures :
  1. Number of AEs (Adverse Events) [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, all events will be recorded from the time a subject has signed the informed consent form.

  2. Duration of disease control. [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Achieving a confirmed best response to treatment of stable disease (SD), partial response (PR), or complete response (CR).

  3. Objective radiographic response (ORR) [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    ORR is defined by mRANO criteria, and duration of response.

  4. Progression-free survival (PFS) [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Progression-free survival (PFS) is defined as the time from date of enrollment until the earliest date of disease progression (as determined by mRANO criteria) or death due to any cause.

  5. Overall survival (OS) [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Overall survival (OS) is defined as the time from date of enrollment until death from any cause.


Other Outcome Measures:
  1. Objective response rate (ORR) associations. [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Association between pre-treatment tumor genomics, transcriptomics, proteomics, and prior bevacizumab use and ORR.

  2. Progression-free survival (PFS) associations [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Association between pre-treatment tumor genomics, transcriptomics, proteomics, and prior bevacizumab use and PFS.

  3. Overall survival (OS) associations [ Time Frame: When termination of the study or 5 years after removal from protocol therapy, whichever occurs first. ]
    Association between pre-treatment tumor genomics, transcriptomics, proteomics, and prior bevacizumab use and OS.



Information from the National Library of Medicine

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Ages Eligible for Study:   22 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histopathologically or molecularly (per c-IMPACT NOW criteria) proven diagnosis of glioblastoma which is recurrent following radiation therapy (prior dose must have been between 40 and 75 Gy).
  • Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen.
  • Patients must have measurable contrast-enhancing disease (defined by at least 1cm x 1cm) by magnetic resonance imaging (MRI) imaging within 28 days of starting study treatment.
  • Patients may have had treatment for an unlimited number of prior relapses.
  • Patients must have recovered from severe toxicity of prior therapy.
  • Patients must be able to swallow oral medications.
  • Karnofsky performance status >= 60.
  • Life expectancy >3 months.
  • Adequate hematologic parameters.
  • Adequate hepatic function within 7 days prior to start of study treatment.
  • Adequate renal function within 7 days prior to start of study treatment.
  • Reproductive Status
  • Women - negative serum or urine pregnancy test
  • Men and Women - must agree to an adequate method to avoid pregnancy
  • Participant must agree to not donate blood during the study or for 90 days after the last dose of niraparib.
  • Participant must, in the opinion of the Investigator, be able to comply with study procedures, including use of the Optune device.
  • Cohort B (surgical) patients only: patients must be undergoing surgery that is clinically indicated as determined by their care providers.
  • Cohort B (surgical) patients only: patients must have a tumor tissue form indicating availability of archived tissue from a previous surgery for glioblastoma, completed and signed by a pathologist.
  • Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent (or have legally authorized representative sign on patient's behalf if patient physically unable to sign consent due to neurologic deficit).

Exclusion Criteria:

  • Age < 22 years.
  • Prior treatment with tumor-treating fields therapy (Optune) within the past 6 months.
  • Prior treatment with a PARP inhibitor.
  • Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
  • Patients with infratentorial tumor.
  • Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
  • Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection.
  • Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain.
  • Skull defects.
  • Known hypersensitivity to conductive hydrogels or known hypersensitivity to niraparib components or excipients.
  • Patients with gastrointestinal disorders or abnormalities that would interfere with absorption of study treatment.
  • Prisoners or subjects who are involuntarily incarcerated.
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
  • Participant must not be simultaneously enrolled in any interventional clinical trial.

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): NCT04221503


Contacts
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Contact: Maikel Mansour 2156624000 NCRD-BTC@uphs.upenn.edu

Locations
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United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Stephen Bagley, MD       NCRD-BTC@uphs.upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
Tesaro, Inc.
NovoCure Ltd.
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04221503    
Other Study ID Numbers: 03319
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: July 2, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents