Clinical Trials /

Study of Pamiparib in Newly Diagnosed and rGBM

NCT04614909

Description:

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).

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase 0/2 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

Clinical Trial IDs

  • ORG STUDY ID: 2020-12
  • NCT ID: NCT04614909

Conditions

  • Glioblastoma
  • Glioblastoma Multiforme
  • Glioblastoma Multiforme, Adult

Interventions

DrugSynonymsArms
PamiparibArm A Newly diagnosed glioblastoma treated with pamiparib
OlaparibArm C Recurrent glioblastoma treated with olaparib
TemozolomideArm A Newly diagnosed glioblastoma treated with pamiparib

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm A Newly diagnosed glioblastoma treated with pamiparibExperimentalParticipants 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.
  • Pamiparib
  • Temozolomide
Arm B Recurrent glioblastoma treated with pamiparibExperimentalRecurrent 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.
  • Pamiparib
  • Temozolomide
Arm C Recurrent glioblastoma treated with olaparibExperimentalArm 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.
  • Olaparib
  • Temozolomide

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Systemic plasma PK profile parameters
Time Frame:Day 4 Intra-operative sample
Safety Issue:
Description:Total and unbound pamiparib concentration in enhancing and non-enhancing tumor tissue.

Secondary Outcome Measures

Measure:Progression-free survival in participants with demonstrated PK effects
Time Frame:6 months
Safety Issue:
Description:6-month progression-free survival (PFS6) rate measured from time of surgery to date of recurrence
Measure:Overall survival
Time Frame:24 months
Safety Issue:
Description:Median overall survival
Measure:Drug-related toxicity
Time Frame:24 months
Safety Issue:
Description:Incidence of drug-related toxicity
Measure:Adverse events
Time Frame:24 months
Safety Issue:
Description:Number of Adverse Events through study completion, assessed up to 24 months
Measure:Treatment-emergent adverse events
Time Frame:24 months
Safety Issue:
Description:Number of treatment-emergent adverse events
Measure:Deaths
Time Frame:24 months
Safety Issue:
Description:Number and incidence of deaths
Measure:Pharmacodynamics (PD) of pamiparib
Time Frame:Day 4 Intra-operative sample
Safety Issue:
Description:Quantification of PAR concentration in tumor homogenates

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Nader Sanai

Last Updated

November 4, 2020