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A Dose-finding Study of MK-8628 in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)

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ClinicalTrials.gov Identifier: NCT02296476
Recruitment Status : Terminated (This study was terminated due to lack of clinical activity and not due to safety reasons.)
First Posted : November 20, 2014
Results First Posted : May 17, 2018
Last Update Posted : July 2, 2018
Sponsor:
Information provided by (Responsible Party):
Oncoethix GmbH

Tracking Information
First Submitted Date  ICMJE October 3, 2014
First Posted Date  ICMJE November 20, 2014
Results First Submitted Date  ICMJE February 13, 2018
Results First Posted Date  ICMJE May 17, 2018
Last Update Posted Date July 2, 2018
Actual Study Start Date  ICMJE October 29, 2014
Actual Primary Completion Date October 20, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2018)
Progression-free Survival (PFS) at 6 Months [ Time Frame: Month 6 ]
Progression-free survival was the time from the start of study treatment to the date of clinical or radiographic evidence of progressive disease according to Response Assessment in Neuro-Oncology (RANO) 2010 criteria or death. Progression, as assessed by RANO 2010, was defined as a ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. PFS at 6 months was measured as the percentage of participants who were alive and progression-free at Month 6. PFS at 6 months was calculated for all participants who were actively enrolled in the study at the 6-month time point.
Original Primary Outcome Measures  ICMJE
 (submitted: November 17, 2014)
Progression-free Survival at 6 months [ Time Frame: after 6 months of OTX015 treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2018)
  • Objective Response Rate (ORR) [ Time Frame: Up to 6 Months ]
    ORR was defined as the number of participants in the analysis population who experienced a Complete Response (CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically) or a Partial Response (PR: ≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically) and was assessed using RANO 2010.
  • Duration of Response (DOR) [ Time Frame: Up to 6 Months ]
    DOR was the time from the first documented CR (complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically)or PR (≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically), as assessed by RANO 2010, until documentation of disease progression, or the date of the last tumor assessment (if there was no documented progression), or the last tumor assessment before the start of further antitumor therapy. DOR was calculated for all participants who experienced a CR or PR.
  • Overall Survival (OS) [ Time Frame: Up to 6 Months ]
    OS was the time from the start of study treatment to the date of death. Participants were to be censored at their last contact if they were still alive at the cut-off date. OS was calculated for all participants who did not discontinue from the study due to disease progression.
  • Progression-free Survival [ Time Frame: Up to 6 Months ]
    Progression-free survival was the time from the start of study treatment to the date of clinical or radiographic evidence of progressive disease according to RANO 2010 criteria or death. Progression, as assessed by RANO 2010, was defined as a ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. PFS was measured as the number of participants who were alive and progression-free for up to 6 months.
  • Number of Participants Who Experienced at Least One Adverse Event (AE) [ Time Frame: Up to 6 Months ]
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced at least one AE is presented.
  • Number of Participants Who Experienced at Least One Toxicity Grade 3-5 AE [ Time Frame: Up to 6 Months ]
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced ≥1 Grade 3-5 AE per National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 criteria is presented. Grade 3 was classified as severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care; Grade 4 was classified as potentially life-threatening or disabling; and Grade 5 was an AE resulting in death.
  • Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to 6 Months ]
    The number of participants who discontinued study treatment due to an AE is presented.
  • Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 [ Time Frame: Up to Cycle 1 (Up to 28 days) ]
    A DLT was defined as any of the following toxicities that were considered by the investigator to be related to MK-8628: Hematologic toxicity: Grade 4 hematologic toxicity or febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with bleeding or lasting >7 days; Non-hematologic toxicity: Grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed with supportive care, Grade 3 or 4 laboratory abnormality lasting >7 days, or intolerable Grade 2 non-hematologic toxicity resulting in study treatment discontinuation or delay >7 days with or without dose reduction.
  • Observed Maximum Concentration (Cmax) of MK-8628 [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours postdose ]
    Blood samples were obtained at specified time points for the pharmacokinetic (PK) analysis of Cmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry and Cmax was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Cmax of MK-8628 after oral administration is presented.
  • Time to Maximum Concentration (Tmax) of MK-8628 [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours postdose ]
    Blood samples were obtained at specified time points for the PK analysis of Tmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry and Tmax was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Tmax of MK-8628 after oral administration is presented.
  • Apparent Terminal Half-Life (t1/2) of MK-8628 [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours ]
    Blood samples were obtained at specified time points for the PK analysis of t1/2 of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry and t1/2 was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The t1/2 of MK-8628 after oral administration is presented.
  • Apparent Total Body Clearance (Cl/F) of MK-8628 [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours ]
    Blood samples were obtained at specified time points for the PK analysis of Cl/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry and Cl/F was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Cl/F of MK-8628 after oral administration is presented.
  • Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628 [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours ]
    Blood samples were obtained at specified time points for the PK analysis of Vz/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry and Vz/F was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Vz/F of MK-8628 after oral administration is presented.
  • Observed Minimum Concentration (Cmin) of MK-8628 [ Time Frame: Predose on Days 29 and 57 ]
    Blood samples were obtained at specified time points for the PK analysis of Cmin of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. A single Cmin value for MK-8628 was estimated using dose and steady-state predose concentrations of MK-8628 on Days 29 and 57. The Cmin of MK-8628 after oral administration is presented.
  • Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞) [ Time Frame: Day 1: Predose and 0.25, 1, 2, 3, 7, and 8 hours ]
    Blood samples were obtained at specified time points for the PK analysis of AUC 0-∞ of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The AUC 0-∞ was estimated indirectly using the dose and CL/F values. The AUC 0-∞ of MK-8628 after oral administration is presented.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2014)
  • Efficacy: objective response rate [ Time Frame: Every 8 weeks from inclusion date to first observed disease progression (expected average 6 months) ]
  • Efficacy: Response duration [ Time Frame: Every 8 weeks from inclusion date to first observed disease progression (expected average 6 months) ]
  • Efficacy: Progression Free Survival (PFS) [ Time Frame: Every 8 weeks from inclusion date to first observed disease progression (expected average 6 months) ]
  • Efficacy: Overall Survival (OS) [ Time Frame: Every 4 weeks from inclusion date to first observed disease progression (expected average 6 months) ]
  • Safety : incidence of Adverse Events (AE) [ Time Frame: Every 4 weeks from inclusion date to last treatment intake (expected average 6 months) ]
  • Safety : severity of Adverse Events (AE) [ Time Frame: Every 4 weeks from inclusion date to last treatment intake (expected average 6 months) ]
  • Safety : Dose Limiting Toxicities (DLT) occurrence [ Time Frame: First 4 weeks of treatment ]
  • Pharmacokinetics : Cmax [ Time Frame: at day 1 ]
  • Pharmacokinetics : Area Under Curve (AUC) [ Time Frame: at day 1, day 29, day 57 ]
  • Pharmacokinetics : Clearance [ Time Frame: at day 1, day 29, day 57 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Dose-finding Study of MK-8628 in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)
Official Title  ICMJE 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
Brief Summary

A study of single-agent 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE Drug: MK-8628
Administered orally in a fasted state once daily.
Other Name: OTX015
Study Arms  ICMJE
  • Experimental: MK-8628 80 mg
    Participants received 80 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.
    Intervention: Drug: MK-8628
  • Experimental: MK-8628 120 mg
    Participants received 120 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.
    Intervention: Drug: MK-8628
  • Experimental: MK-8628 160 mg
    Participants received 160 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.
    Intervention: Drug: MK-8628
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 17, 2015)
12
Original Estimated Enrollment  ICMJE
 (submitted: November 17, 2014)
51
Actual Study Completion Date  ICMJE October 20, 2015
Actual Primary Completion Date October 20, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries France,   Switzerland
 
Administrative Information
NCT Number  ICMJE NCT02296476
Other Study ID Numbers  ICMJE 8628-002
OTX015_107 ( Other Identifier: OncoEthix Protocol Number )
MK-8628-002 ( Other Identifier: Merck Protocol Number )
2014-001469-28 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Oncoethix GmbH
Study Sponsor  ICMJE Oncoethix GmbH
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Oncoethix GmbH
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP