A Dose-finding Study of Birabresib (MK-8628) in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: Birabresib
Intervention description: Administered orally in a fasted state once daily.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      A study of single-agent birabresib (MK-8628) (formerly known as OTX015) in recurrent GBM
      after standard front-line therapy failure.

      The first phase of the study (dose escalation) will determine the maximum tolerated dose
      (MTD). MTD assessment will be based using dose-limiting toxicities (DLTs) observed during the
      first 28 days of treatment.

      The second phase of the study (expansion cohort) will assess efficacy as measured by the
      progression-free survival rate at 6 months (PFS-6) as determined by an independent central
      review committee.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has signed informed consent obtained prior to initiation of any study-specific
             procedures and treatment. Participants registered for this trial must be treated and
             followed at the participating centers

          -  Has a histologically confirmed diagnosis of de novo glioblastoma multiforme (World
             Health Organization grade IV astrocytoma) with unequivocal tumor recurrence by
             magnetic resonance imaging (MRI) scan (performed on a stable steroid dosage received
             for at least 5 days) following front-line treatment with surgical resection, cranial
             radiotherapy and temozolomid. Participants who do not undergo surgical resection as
             part of front-line therapy due to anatomical location based on neurosurgeon's
             assessment will be permitted if a confirmatory tumor biopsy was performed

          -  Has at least one measurable and/or non-measurable lesion as per Response Assessment in
             Neuro-Oncology (RANO) criteria (Wen et al., 2010)

          -  Is at least 18 years old

          -  Has a life expectancy >3 months;

          -  Has a Karnofsky performance status (KPS) ≥70%

          -  Has adequate bone marrow reserve, renal and liver function as demonstrated by the
             following: absolute neutrophil count ≥1.5 x109/L; platelet count ≥150 x109/L;
             hemoglobin ≥10 g/dL; creatinine 2 x the upper limit of normal (ULN) or calculated
             creatinine clearance ≥30 mL/min (Cockroft and Gault formula or Modification of Diet in
             Renal Disease [MDRD] formula for participants aged >65 years); alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN, and total
             bilirubin ≤ULN

          -  Has an interval of ≥2 weeks since surgical resection, ≥4 weeks since chemotherapy (≥6
             weeks for nitrosoureas), and ≥12 weeks since radiotherapy completion when starting
             study treatment. Participants with recent tumor resection must have an MRI within 48
             hours post-surgery

          -  Has archived tumor pathology specimen (paraffin-embedded or frozen block)

        Exclusion Criteria:

          -  Has had prior antineoplastic treatment for recurrent disease including vascular
             endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)
             inhibitors and cytotoxic agents

          -  Is unable to undergo MRI because of non-compatible devices

          -  Is unable to swallow oral medications or presence of a gastrointestinal disorder (e.g.
             malabsorption, resection) deemed to jeopardize intestinal absorption

          -  Has persistent grade >1 clinically significant toxicities related to prior
             antineoplastic therapies

          -  Has a history of prior or concomitant malignancies within 5 years of study entry
             (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma).
             Male participants with concurrent controlled hormone dependent prostate cancer are
             allowed

          -  Has other serious illness or medical conditions which in the investigator's opinion
             could hamper understanding of the study by the participant, the participant's
             compliance to study treatment, participant's safety, or interpretation of study
             results. These include (but are not restricted to) existence of significant neurologic
             or psychiatric disorders impairing the ability to obtain consent, uncontrolled
             infection and known HIV positivity

          -  Is taking enzyme-inducing antiepileptic drug (EIAED)

          -  Is taking strong CYP3A4 interacting drugs

          -  Is participating in another clinical trial or treatment with any investigational drug
             within 4 weeks prior to first study treatment administration, or 5 half-lives of
             previously administered drugs, whichever is longer

          -  Is pregnant or breast feeding

          -  Is not using effective contraception while on study treatment if a participant of
             child-bearing potential