Clinical trial NCT02296476: A Dose-finding Study of Birabresib (MK-8628) in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)
Official title: A Phase IIa Trial With Dose Optimization of OTX015, a Small Molecule Inhibitor of the Bromodomain and Extra-terminal (BET) Proteins, in Recurrent Glioblastoma Multiforme (GBM) Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Lead sponsor: Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2014-11-20
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Progression-free Survival (PFS) at 6 Months
timeFrame: Month 6
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 6 Months
measure: Duration of Response (DOR)
timeFrame: Up to 6 Months
measure: Overall Survival (OS)
timeFrame: Up to 6 Months
measure: Progression-free Survival
timeFrame: Up to 6 Months
measure: Number of Participants Who Experienced at Least One Adverse Event (AE)
timeFrame: Up to 6 Months
measure: Number of Participants Who Experienced at Least One Toxicity Grade 3-5 AE
timeFrame: Up to 6 Months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to 6 Months
measure: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
timeFrame: Up to Cycle 1 (Up to 28 days)
measure: Observed Maximum Concentration (Cmax) of MK-8628
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours postdose
measure: Time to Maximum Concentration (Tmax) of MK-8628
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours postdose
measure: Apparent Terminal Half-Life (t1/2) of MK-8628
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours
measure: Apparent Total Body Clearance (Cl/F) of MK-8628
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours
measure: Observed Minimum Concentration (Cmin) of MK-8628
timeFrame: Predose on Days 29 and 57
measure: Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
timeFrame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: