A Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/ Birabresib (MK-8628) in Hematologic Malignancies (MK-8628-001)
A Phase I, Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/MK-8628 in Haematological Malignancies
4 other identifiers
interventional
141
0 countries
N/A
Brief Summary
The primary purpose of this study was to determine the recommended dose (RD) of birabresib (MK-8628) /OTX015 for further phase II studies, in participants with acute leukemia (AL) including acute myeloid leukemia (AML; de novo and secondary to a myelodysplastic syndrome) and acute lymphoblastic leukemia (ALL) or other hematologic malignancies (OHM) including diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). The first phase of the study will be a dose escalation phase to determine the Phase II RD using dose-limiting toxicities (DLTs). Once the RD is determined, participants will be enrolled in an expansion phase at the RD to determine preliminary efficacy in AL and OHM cohorts. Participants received therapy in 21-day cycles until disease progression, intolerable toxicity, or treatment interruption for \>2 weeks due to toxicity.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Dec 2012
Longer than P75 for phase_1
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 22, 2012
CompletedFirst Posted
Study publicly available on registry
October 24, 2012
CompletedStudy Start
First participant enrolled
December 14, 2012
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 20, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
January 20, 2017
CompletedResults Posted
Study results publicly available
October 1, 2018
CompletedJanuary 26, 2021
January 1, 2021
4.1 years
October 22, 2012
January 11, 2018
January 7, 2021
Conditions
Outcome Measures
Primary Outcomes (1)
Number of Participants With Dose Limiting Toxicities (DLTs)
A DLT was graded using the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.02 and defined as any of the following: grade 3 or 4 non-hematologic adverse events unless they were not optimally treated with supportive care; grade 3 or 4 asymptomatic laboratory abnormal values lasting \>7 days; prolonged grade 2 toxicity (lasting more than 2 weeks) leading to treatment interruption and/or dose reduction; pancytopenia with a hypocellular bone marrow and no marrow blasts lasting ≥6 weeks (AL participants); grade 3 neutropenia with fever or infection (OHM participants); grade 3 thrombocytopenia with bleeding (OHM participants); or grade 4 neutropenia or thrombocytopenia, regardless of symptoms and lasting ≥3 days (OHM participants).
Cycle 1 (Up to 21 days)
Secondary Outcomes (9)
Number of Participants Who Experienced at Least One Adverse Event (AE)
Up to 40 days after last dose of study therapy (Up to 28 months)
Number of Participants Who Discontinued Study Therapy Due to AEs
From time of first dose of study therapy until the end of treatment (up to 26 months)
Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR)
From time of first dose of study therapy until the end of treatment (up to 26 months)
Maximum Concentration (Cmax) of MK-8628/OTX015
Cycle 1: Pre-infusion and 20 minutes; 1, 2.25, 3.25, 4, 6, 8, 9, 12, and 24 hours plus one sampling at either 10 hour or 16 hour post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion dependent on dose regimen and enrollment position
Time to Maximum Concentration (Tmax) of MK-8628/OTX015
Cycle 1: Pre-infusion and 20 minutes; 1, 2.25, 3.25, 4, 6, 8, 9, 12, and 24 hours plus one sampling at either 10 hour or 16 hour post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion dependent on dose regimen and enrollment position
- +4 more secondary outcomes
Study Arms (21)
AL 10 mg QD 14-21
EXPERIMENTALParticipants received 10 mg birabresib/OTX015 administered orally (PO), once daily (QD), in a fasted state on Days 1 to 14 of a 21-day cycle.
AL 20 mg QD 14-21
EXPERIMENTALParticipants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AL 40 mg QD 14-21
EXPERIMENTALParticipants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AL 20 mg BID 21-21
EXPERIMENTALParticipants received 20 mg birabresib/OTX015 administered PO, twice a day (BID), with the first daily dose in a fasted state, on Days 1 to 21 of a 21-day cycle.
AL 80 mg QD 14-21
EXPERIMENTALParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AL 40 mg BID 14-21
EXPERIMENTALParticipants received 40 mg birabresib/OTX015 administered PO, twice a day (BID), with the first daily dose in a fasted state, on Days 1 to 14 of a 21-day cycle.
AL 120 mg QD 14-21
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AL 120 mg QD 21-21
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
AL 160 mg QD 14-21
EXPERIMENTALParticipants received 160 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AML de novo 80 mg QD 14-21
EXPERIMENTALParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
AML/MDS 80 mg QD 14-21
EXPERIMENTALParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
OHM 10 mg QD 21-21
EXPERIMENTALParticipants received 10 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
OHM 20 mg QD 21-21
EXPERIMENTALParticipants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
OHM 40 mg QD 21-21
EXPERIMENTALParticipants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
OHM 80 mg QD 21-21
EXPERIMENTALParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
OHM 40 mg BID 21-21
EXPERIMENTALParticipants received 40 mg birabresib/OTX015 administered PO, BID, with the first daily dose in a fasted state, on Days 1 to 21 of a 21-day cycle.
OHM 120 mg QD 21-21
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle.
OHM 120 mg QD 14-21
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
OHM 120 mg QD 5-7
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 5 of a 7-day cycle.
OHM 120 mg QD 7-21
EXPERIMENTALParticipants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 7 of a 21-day cycle
OHM/DLBCL 80 mg QD 14-21
EXPERIMENTALParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
Interventions
OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally
Eligibility Criteria
You may qualify if:
- Histologically or cytologically proven acute leukemias (AML or ALL) or hematologic malignancies (DLBCL or MM) using standard diagnosis criteria. Acute leukemia includes de novo and secondary to a pre-existing myelodysplastic syndrome, according to the World Health Organization 2008 classification. For DLBCL, an archived formaldehyde-fixed paraffin-embedded block must be available.
- Has failed all standard therapies or for whom standard treatments are contra-indicated:
- Acute leukemia participants: \<60 years old in second relapse or relapsing after allogeneic stem cell transplantation (aSCT) regardless of number of relapses; \>60 years old in first relapse with a disease-free interval (DFI) \<12 months or further relapse; irrespective of age, in participants relapsing after aSCT, the time elapsed since aSCT should be \>90 days; participants with B-cell ALL: Philadelphia chromosome positive (Ph+) must have received ≥2 lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only 1 line including 1 TK inhibitor, if the relapse/refractoriness is associated with the detection of a resistance mutation to these inhibitors
- DLBCL participants: Failed 2 standard lines of therapy (≥1 containing an anti-CD20 monoclonal antibody), or for whom such treatment is contra-indicated
- MM participants: Adequately exposed to at least one alkylating agent, one corticosteroid, one immunomodulatory drug (IMiD) and bortezomib, or for whom such treatments are contra-indicated.
- For participants with evaluable disease:
- Advanced leukemia participants must have \>5% bone marrow blasts at study entry, without alternative causality (e.g. bone marrow regeneration)
- DLBCL participants must have ≥1 non-irradiated tumor mass ≥15 mm (long axis of lymph node) or ≥10 mm (short axis of lymph node or extranodal lesions) on spiral computed tomography (CT)-scan.
- MM participants must have ≥1 of the following: serum monoclonal component \>1 g/dL (IgG), or \>0.5 g/dL (IgA), or Bence-Jones (BJ) proteinuria \>200 mg/24h, or measurable plasmacytoma (not previously irradiated).
- Life expectancy ≥3 months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Off previous therapy ≥3 weeks prior to first study drug administration with full recovery from any previous toxicities, except 1) hydroxyurea single agent of in combination (e.g. + 6-Mercaptopurine \[6MP\]) to control hyperleukocytosis, which should be stopped for ≥48 hours, and 2) rituximab, which should be stopped for ≥3 weeks.
- Recovery from the non-hematologic toxic effects of prior treatment to grade ≤1, according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) classification, except alopecia.
- Adequate bone marrow function.
- Adequate calculated creatinine clearance.
- +2 more criteria
You may not qualify if:
- History of prior malignancy other than those previously treated with a curative intent \>3 years ago and without relapse (any tumor) or basal cell skin cancer, in situ cervical cancer, superficial bladder cancer, or high grade intestinal polyps treated adequately, regardless of the DFI.
- Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male participants not using adequate contraception.
- Peripheral cytopenias (i.e. auto-immune hemolytic anemia or thrombocytopenia).
- Acute promyelocytic leukemia or with clinically uncontrolled (i.e. with bleeding) disseminated intravascular coagulation (DIC).
- Chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of GVHD.
- Uncontrolled leptomeningeal disease.
- Other tumor location necessitating an urgent therapeutic intervention (palliative care, surgery or radiation therapy), such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.
- Unable to swallow oral medications, or has gastrointestinal condition (e.g. malabsorption, resection) deemed to jeopardize intestinal absorption.
- Other serious illness or medical conditions, which, in the investigator's opinion could hamper understanding of the study by the participants, participant's compliance to study treatment, participant's safety or interpretation of study results. These conditions include (but are not restricted to):
- Congestive heart failure or angina pectoris except if medically controlled. Previous history of myocardial infarction within 1 year of study entry, uncontrolled hypertension or arrhythmias.
- Existence of significant neurologic or psychiatric disorders impairing the ability to obtain consent.
- Uncontrolled infection.
- Known human immunodeficiency virus (HIV) positivity
- Concurrent treatment with other experimental therapies or participation in another clinical trial within 30 days prior to first study drug administration.
- Concurrent treatment or treatment within 30 days prior to first study drug administration with any other anticancer therapy, except hydroxyurea (+/- 6MP) to control hyperleukocytosis.
- +1 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Related Publications (3)
Odore E, Lokiec F, Cvitkovic E, Bekradda M, Herait P, Bourdel F, Kahatt C, Raffoux E, Stathis A, Thieblemont C, Quesnel B, Cunningham D, Riveiro ME, Rezai K. Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies. Clin Pharmacokinet. 2016 Mar;55(3):397-405. doi: 10.1007/s40262-015-0327-6.
PMID: 26341814RESULTAmorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, Morschhauser F, Karlin L, Broussais F, Rezai K, Herait P, Kahatt C, Lokiec F, Salles G, Facon T, Palumbo A, Cunningham D, Zucca E, Thieblemont C. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016 Apr;3(4):e196-204. doi: 10.1016/S2352-3026(16)00021-1. Epub 2016 Mar 18.
PMID: 27063978DERIVEDBerthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, Taussig DC, Rezai K, Roumier C, Herait P, Kahatt C, Quesnel B, Michallet M, Recher C, Lokiec F, Preudhomme C, Dombret H. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016 Apr;3(4):e186-95. doi: 10.1016/S2352-3026(15)00247-1. Epub 2016 Mar 18.
PMID: 27063977DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Senior Vice President, Global Clinical Development
- Organization
- Merck Sharp & Dohme Corp.
Study Officials
- STUDY DIRECTOR
Medical Director
Merck Sharp & Dohme LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 22, 2012
First Posted
October 24, 2012
Study Start
December 14, 2012
Primary Completion
January 20, 2017
Study Completion
January 20, 2017
Last Updated
January 26, 2021
Results First Posted
October 1, 2018
Record last verified: 2021-01
Data Sharing
- IPD Sharing
- Will share
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf