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Study of Pamiparib in Newly Diagnosed and rGBM

Primary Purpose

Glioblastoma, Glioblastoma Multiforme, Glioblastoma Multiforme, Adult

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pamiparib
Olaparib
Radiation therapy
Temozolomide
Sponsored by
Nader Sanai
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Participants undergoing resection for a suspected newly diagnosed glioblastoma who are also planned to follow the standard regimen or;
  2. Participants who have had a prior resection of histologically diagnosed glioblastoma (WHO grade IV), defined as participants who have progressed on or following standard therapy, which includes maximal surgical resection, temozolomide, and fractionated radiotherapy. Participants will also need to have radiation planned as part of the post-surgical treatment plan.
  3. Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.
  4. Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable).
  5. Participant has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.
  6. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
  7. Age ≥18 at time of consent
  8. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982)
  9. Ability to swallow oral medications.
  10. Participant has adequate bone marrow and organ function
  11. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause.
  12. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to treatment and agreement to use such a method during study participation and for an additional 6 months after the end of treatment administration.
  13. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner and for an additional 6 months after the end of treatment administration. Avoid sperm donation for duration of the study and for an additional 6 months after the end of treatment administration.
  14. Agreement to adhere to Lifestyle Considerations throughout study duration.
  15. Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A washout period of at least 21 days is required between last chemotherapy dose and Day 1 (provided the participant did not receive radiotherapy).
  16. Females of child-bearing potential must agree not to breastfeed starting at screening, throughout the study period and for 6 months after final study drug administration

Exclusion Criteria:

  1. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise, that cannot be discontinued prior to surgery. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
  2. Pregnancy or lactation.
  3. Known allergic reactions to components of the pamiparib capsule/olaparib.
  4. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal or antiviral therapy within 4 weeks of Day 1.
  5. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis.
  6. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
  7. Any of the following cardiovascular criteria:

    • Current evidence of cardiac ischemia
    • Current symptomatic pulmonary embolism
    • Acute myocardial infarction ≤ 6 months prior to Day 1
    • Heart failure of New York Heart Association Classification III or IV (see Section 13.2) ≤ 6 months prior to Day 1
    • Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1
    • Cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to Day 1
  8. Participant has myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
  9. Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
  10. Prior therapy with PARP inhibitors.
  11. Treatment with another investigational drug or other intervention within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.
  12. For Olaparib participants: Use or anticipated need for food and drugs known to be strong or moderate CYP3A inducers or inhibitors ≤10 days (or ≤5 half-lives, whichever is the shorter) prior to day 1.

Sites / Locations

  • St. Joseph's Hospital and Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Arm A Newly diagnosed glioblastoma treated with pamiparib- ARM CLOSED

Arm B Recurrent glioblastoma treated with pamiparib

Arm C Recurrent glioblastoma treated with olaparib - ARM CLOSED

Arm Description

Participants undergoing resection for a presumed newly diagnosed glioblastoma (nGBM) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Recurrent glioblastoma (rGBM) patients who are scheduled for surgery and expected to receive postoperative fractionated radiotherapy (RT) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Arm C will be an exploratory arm in recurrent glioblastoma patients (rGBM) treated with Olaparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive olaparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Outcomes

Primary Outcome Measures

Systemic plasma PK profile parameters
Total and unbound pamiparib concentration in enhancing and non-enhancing tumor tissue.

Secondary Outcome Measures

Progression-free survival in participants with demonstrated PK effects
6-month progression-free survival (PFS6) rate measured from time of surgery to date of recurrence
Overall survival
Median overall survival
Drug-related toxicity
Incidence of drug-related toxicity
Adverse events
Number of Adverse Events through study completion, assessed up to 24 months
Treatment-emergent adverse events
Number of treatment-emergent adverse events
Deaths
Number and incidence of deaths
Pharmacodynamics (PD) of pamiparib
Quantification of PAR concentration in tumor homogenates

Full Information

First Posted
October 28, 2020
Last Updated
September 15, 2023
Sponsor
Nader Sanai
Collaborators
Barrow Neurological Institute, Ivy Brain Tumor Center, BeiGene
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1. Study Identification

Unique Protocol Identification Number
NCT04614909
Brief Title
Study of Pamiparib in Newly Diagnosed and rGBM
Official Title
A Phase 0/2 Clinical Trial of Pamiparib in Newly-Diagnosed and Recurrent Glioblastoma Patients
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 11, 2021 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Nader Sanai
Collaborators
Barrow Neurological Institute, Ivy Brain Tumor Center, BeiGene

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an open-label, single-center Phase 0/2 study that will enroll up to 30 participants with newly diagnosed (N=12) and recurrent glioblastoma (N=18). The trial will be composed of a Phase 0 component (subdivided into Arm A, Arm B, and Arm C), and an Exploratory Phase 2 component. Participants with tumors demonstrating a PK response in the Phase 0 component of the study will graduate to an exploratory Phase 2 component that combines therapeutic dosing of pamiparib plus fractionated radiotherapy (for unmethylated MGMT promoter newly-diagnosed cases), pamiparib plus fractionated radiotherapy (for recurrent cases) or Olaparib plus fractionated radiotherapy (recurrent cases).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Glioblastoma Multiforme, Glioblastoma Multiforme, Adult

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A Newly diagnosed glioblastoma treated with pamiparib- ARM CLOSED
Arm Type
Experimental
Arm Description
Participants undergoing resection for a presumed newly diagnosed glioblastoma (nGBM) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.
Arm Title
Arm B Recurrent glioblastoma treated with pamiparib
Arm Type
Experimental
Arm Description
Recurrent glioblastoma (rGBM) patients who are scheduled for surgery and expected to receive postoperative fractionated radiotherapy (RT) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.
Arm Title
Arm C Recurrent glioblastoma treated with olaparib - ARM CLOSED
Arm Type
Experimental
Arm Description
Arm C will be an exploratory arm in recurrent glioblastoma patients (rGBM) treated with Olaparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive olaparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.
Intervention Type
Drug
Intervention Name(s)
Pamiparib
Intervention Description
60mg administered orally BID for 4 days prior to surgical resection
Intervention Type
Drug
Intervention Name(s)
Olaparib
Intervention Description
200mg administered orally BID for 4 days prior to surgical resection
Intervention Type
Radiation
Intervention Name(s)
Radiation therapy
Intervention Description
Patients in Phase 2 will receive 6-7 weeks of radiation therapy per standard of care
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Intervention Description
Arm A and Arm B participants after RT is completed, will receive pamiparib in combination with TMZ (newly diagnosed participants). Arm C participants will receive olaparib with TMZ.
Primary Outcome Measure Information:
Title
Systemic plasma PK profile parameters
Description
Total and unbound pamiparib concentration in enhancing and non-enhancing tumor tissue.
Time Frame
Day 4 Intra-operative sample
Secondary Outcome Measure Information:
Title
Progression-free survival in participants with demonstrated PK effects
Description
6-month progression-free survival (PFS6) rate measured from time of surgery to date of recurrence
Time Frame
6 months
Title
Overall survival
Description
Median overall survival
Time Frame
24 months
Title
Drug-related toxicity
Description
Incidence of drug-related toxicity
Time Frame
24 months
Title
Adverse events
Description
Number of Adverse Events through study completion, assessed up to 24 months
Time Frame
24 months
Title
Treatment-emergent adverse events
Description
Number of treatment-emergent adverse events
Time Frame
24 months
Title
Deaths
Description
Number and incidence of deaths
Time Frame
24 months
Title
Pharmacodynamics (PD) of pamiparib
Description
Quantification of PAR concentration in tumor homogenates
Time Frame
Day 4 Intra-operative sample

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants undergoing resection for a suspected newly diagnosed glioblastoma who are also planned to follow the standard regimen or; Participants who have had a prior resection of histologically diagnosed glioblastoma (WHO grade IV), defined as participants who have progressed on or following standard therapy, which includes maximal surgical resection, temozolomide, and fractionated radiotherapy. Participants will also need to have radiation planned as part of the post-surgical treatment plan. Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm. Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable). Participant has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures. Age ≥18 at time of consent Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982) Ability to swallow oral medications. Participant has adequate bone marrow and organ function Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to treatment and agreement to use such a method during study participation and for an additional 6 months after the end of treatment administration. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner and for an additional 6 months after the end of treatment administration. Avoid sperm donation for duration of the study and for an additional 6 months after the end of treatment administration. Agreement to adhere to Lifestyle Considerations throughout study duration. Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A washout period of at least 21 days is required between last chemotherapy dose and Day 1 (provided the participant did not receive radiotherapy). Females of child-bearing potential must agree not to breastfeed starting at screening, throughout the study period and for 6 months after final study drug administration Exclusion Criteria: Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise, that cannot be discontinued prior to surgery. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. Pregnancy or lactation. Known allergic reactions to components of the pamiparib capsule/olaparib. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal or antiviral therapy within 4 weeks of Day 1. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment. Any of the following cardiovascular criteria: Current evidence of cardiac ischemia Current symptomatic pulmonary embolism Acute myocardial infarction ≤ 6 months prior to Day 1 Heart failure of New York Heart Association Classification III or IV (see Section 13.2) ≤ 6 months prior to Day 1 Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1 Cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to Day 1 Participant has myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea). Prior therapy with PARP inhibitors. Treatment with another investigational drug or other intervention within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer. For Olaparib participants: Use or anticipated need for food and drugs known to be strong or moderate CYP3A inducers or inhibitors ≤10 days (or ≤5 half-lives, whichever is the shorter) prior to day 1.
Facility Information:
Facility Name
St. Joseph's Hospital and Medical Center
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Phase 0 Navigator
Phone
602-406-8605
Email
research@ivybraintumorcenter.org
First Name & Middle Initial & Last Name & Degree
Nader Sanai, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Study of Pamiparib in Newly Diagnosed and rGBM

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