Acute Myeloid LeukemiaPhase 1NCT01713582
A Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/ Birabresib (MK-8628) in Hematologic Malignancies (MK-8628-001)
A Phase 1 study testing OTX015/Birabresib in people with Acute Myeloid Leukemia and Diffuse Large B-cell Lymphoma, run by Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia, Diffuse Large B-cell Lymphoma, Acute Lymphoblastic Leukemia
- What is being tested?
- OTX015/Birabresib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 141 participants
- Where
- No sites listed yet
- Study dates
- 14 Dec 2012to 20 Jan 2017
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
- Adequate liver function tests.
- Complete baseline disease assessment workup prior to first study drug administration.
Who cannot join
- 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.
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- 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.
- Concomitant treatment with corticosteroids except if chronic treatment with ≤30 mg of methylprednisolone daily or equivalent dose of other corticosteroids.
About this study
Official title: A Phase I, Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/MK-8628 in Haematological Malignancies
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.
- Conditions
- Acute Myeloid Leukemia, Diffuse Large B-cell Lymphoma, Acute Lymphoblastic Leukemia, Multiple Myeloma
- Being tested
- OTX015/Birabresib
- Medical subject headings
- Leukemia, Myeloid, Acute, Lymphoma, Large B-Cell, Diffuse, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OTX015/BirabresibDrug
Also called MK-8628
OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally
| Study group | Role | What they receive |
|---|---|---|
| AL 10 mg QD 14-21 | Experimental | Participants 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. Receives: Drug: OTX015/Birabresib |
| AL 20 mg QD 14-21 | Experimental | Participants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AL 40 mg QD 14-21 | Experimental | Participants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AL 20 mg BID 21-21 | Experimental | Participants 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. Receives: Drug: OTX015/Birabresib |
| AL 80 mg QD 14-21 | Experimental | Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AL 40 mg BID 14-21 | Experimental | Participants 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. Receives: Drug: OTX015/Birabresib |
| AL 120 mg QD 14-21 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AL 120 mg QD 21-21 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AL 160 mg QD 14-21 | Experimental | Participants received 160 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AML de novo 80 mg QD 14-21 | Experimental | Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| AML/MDS 80 mg QD 14-21 | Experimental | Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 10 mg QD 21-21 | Experimental | Participants received 10 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 20 mg QD 21-21 | Experimental | Participants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 40 mg QD 21-21 | Experimental | Participants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 80 mg QD 21-21 | Experimental | Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 40 mg BID 21-21 | Experimental | Participants 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. Receives: Drug: OTX015/Birabresib |
| OHM 120 mg QD 21-21 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 120 mg QD 14-21 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 120 mg QD 5-7 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 5 of a 7-day cycle. Receives: Drug: OTX015/Birabresib |
| OHM 120 mg QD 7-21 | Experimental | Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 7 of a 21-day cycle Receives: Drug: OTX015/Birabresib |
| OHM/DLBCL 80 mg QD 14-21 | Experimental | Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. Receives: Drug: OTX015/Birabresib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Cycle 1 (Up to 21 days)
Secondary outcomes (9)
Number of Participants Who Experienced at Least One Adverse Event (AE)
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. AEs were collected during the entire time frame of treatment plus up to 40 days of follow-up.
Measured: Up to 40 days after last dose of study therapy (Up to 28 months)
Number of Participants Who Discontinued Study Therapy Due to AEs
All participants who discontinued study therapy due to an AE at any time during treatment.
Measured: 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)
Best response was determined from the start of treatment until disease progression, recurrence, or completion of 26 months of treatment. Partial and complete response was assessed by bone marrow aspiration (AL participants); or computed tomography scan, magnetic resonance imaging, positron emission tomography, or X-ray (OHM participants) using standard criteria. Acute leukemia participants were assessed based on the recommendations from the European LeukemiaNet Döhner 2010); lymphoma participants according to Cheson 2007; and MM participants according to Durie 2006.
Measured: From time of first dose of study therapy until the end of treatment (up to 26 months)
Maximum Concentration (Cmax) of MK-8628/OTX015
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24 hours (h) + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for Cmax were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24h + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for Tmax were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24h + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for t1/2 were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf)
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24h + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for AUC 0-first were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Apparent Total Body Clearance (CL/F) of MK-8628/OTX015
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24h + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for CL/F were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015
Data were collected in Cycle 1 according to dosing regimen and enrollment position at the following sampling schedules: 1) Complete QD for the first 3 participants per dose level: Pre-infusion and 1, 4, 8, 12, and 24h + 1 sampling at either 10h or 16h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 2) Limited QD for participants 4 and higher: Pre-infusion and 1, 4, 6, and 8h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level; 3) BID: Pre-infusion and at 20 minutes and 1, 2.25, 3.25. 9, 12, and 24h post-infusion on Days 1 and 2 and on Days 8, 15, and 22 pre-infusion per dose level.
Blood samples for Vz/F were measured using liquid chromatography-tandem mass spectrometry and analyzed using a nonlinear mixed-effects modelling software program Monolix version 4.3.2. Results for each dose level and method of administration included participants from both AL and OHM cohorts and different regimen frequencies.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Oct 2012 (estimated)
- Study start14 Dec 2012
- Primary completion20 Jan 2017
- Study completion20 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 141 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01713582
- Sponsor's protocol ID
- 8628-001
- Other IDs
- OTX015_104, 2012-003380-22, MK-8628-001
- Status last verified
- Jan 2021
- First submitted
- 22 Oct 2012
- Last updated
- 26 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
Publications
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.
PubMed 26341814Amorim 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.
PubMed 27063978Berthon 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.
PubMed 27063977
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/MK-8628 in Haematological Malignancies
- ClinicalTrials.gov ID
- NCT01713582
- Acronym / sponsor ID
- 8628-001
- Conditions
- Acute Myeloid Leukemia, Diffuse Large B-cell Lymphoma, Acute Lymphoblastic Leukemia, Multiple Myeloma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 141 participants (actual)
- Lead sponsor
- Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)Industry (pharma, biotech, devices)
- Study start
- 14 Dec 2012 (actual)
- Primary completion
- 20 Jan 2017 (actual)
- Study completion
- 20 Jan 2017 (actual)
- First posted
- 24 Oct 2012 (estimated)
- Results
- Posted 1 Oct 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 21
| Arm | Type | Receives |
|---|---|---|
| AL 10 mg QD 14-21 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants 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 | Experimental | Drug: OTX015/BirabresibParticipants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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:
- For participants with evaluable disease:
- Life expectancy ≥3 months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OTX015/BirabresibAlso: MK-8628OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally | Drug | AL 10 mg QD 14-21, AL 120 mg QD 14-21, AL 120 mg QD 21-21, AL 160 mg QD 14-21, AL 20 mg BID 21-21, AL 20 mg QD 14-21, AL 40 mg BID 14-21, AL 40 mg QD 14-21, AL 80 mg QD 14-21, AML de novo 80 mg QD 14-21, AML/MDS 80 mg QD 14-21, OHM 10 mg QD 21-21, OHM 120 mg QD 14-21, OHM 120 mg QD 21-21, OHM 120 mg QD 5-7, OHM 120 mg QD 7-21, OHM 20 mg QD 21-21, OHM 40 mg BID 21-21, OHM 40 mg QD 21-21, OHM 80 mg QD 21-21, OHM/DLBCL 80 mg QD 14-21 |
Primary outcome
Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Cycle 1 (Up to 21 days)
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).
9 secondary outcomes
Number of Participants Who Experienced at Least One Adverse Event (AE)
Time frame: Up to 40 days after last dose of study therapy (Up to 28 months)
Number of Participants Who Discontinued Study Therapy Due to AEs
Time frame: 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)
Time frame: From time of first dose of study therapy until the end of treatment (up to 26 months)
Maximum Concentration (Cmax) of MK-8628/OTX015
Time frame: 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
Time frame: 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
Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015
Time frame: 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
Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf)
Time frame: 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
Apparent Total Body Clearance (CL/F) of MK-8628/OTX015
Time frame: 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
Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 26341814Odore 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.
- Derived from this study: PubMed 27063978Amorim 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.
- Derived from this study: PubMed 27063977Berthon 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.
- Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing OTX015/Birabresib in people with Acute Myeloid Leukemia and Diffuse Large B-cell Lymphoma, run by Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose Limiting Toxicities (DLTs) (time frame: Cycle 1 (Up to 21 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01713582, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2021.