Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Diffuse Large B-cell Lymphoma, Multiple Myeloma
Conditions
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.
Interventions
DRUGOTX015/Birabresib
OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally
Sponsors
Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * Adequate liver function tests. * Complete baseline disease assessment workup prior to first study drug administration.
Exclusion criteria
* 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): 1. 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. 2. Existence of significant neurologic or psychiatric disorders impairing the ability to obtain consent. 3. Uncontrolled infection. 4. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | All participants who discontinued study therapy due to an AE at any time during treatment. |
| 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) | 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. |
| 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 | 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. |
| 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 | 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. |
| 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) | 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. |
| Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 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 | 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. |
| Apparent Total Body Clearance (CL/F) 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 | 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. |
| Volume of Distribution at Steady State (Vz/F) 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 | 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. |
| Apparent Terminal Half-Life (t1/2) 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 | 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. |
Participant flow
Recruitment details
80 participants were enrolled in the acute leukemia (AL) cohort and 78 were treated. 61 participants were enrolled in the other hematological malignancies (OHM) cohort and 60 were treated.
Pre-assignment details
The study consisted of a dose escalation phase in participants with AL and OHM followed by and expansion phase in 3 cohorts: de novo acute myelocytic leukemia (AML), myelodysplastic syndrome (MDS) AML, and diffuse large B-cell lymphoma (DLBCL).
Participants by arm
| Arm | Count |
|---|---|
| AL 10 mg QD 14-21 Participants received 10 mg MK-8628/OTX015 administered orally (PO), once daily (QD), in a fasted state on Days 1 to 14 of a 21-day cycle. | 3 |
| AL 20 mg QD 14-21 Participants received 20 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 3 |
| AL 40 mg QD 14-21 Participants received 40 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 4 |
| AL 20 mg BID 21-21 Participants received 20 mg MK-8628/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. | 3 |
| AL 80 mg QD 14-21 Participants received 80 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 4 |
| AL 40 mg BID 14-21 Participants received 40 mg MK-8628/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. | 8 |
| AL 120 mg QD 14-21 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 7 |
| AL 120 mg QD 21-21 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 6 |
| AL 160 mg QD 14-21 Participants received 160 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 6 |
| AML de Novo 80 mg QD 14-21 Participants received 80 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 18 |
| AML/MDS 80 mg QD 14-21 Participants received 80 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 16 |
| OHM 10 mg QD 21-21 Participants received 10 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 5 |
| OHM 20 mg QD 21-21 Participants received 20 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 3 |
| OHM 40 mg QD 21-21 Participants received 40 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 4 |
| OHM 80 mg QD 21-21 Participants received 80 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 7 |
| OHM 40 mg BID 21-21 Participants received 40 mg MK-8628/OTX015 administered PO, BID, with the first daily dose in a fasted state, on Days 1 to 21 of a 21-day cycle. | 6 |
| OHM 120 mg QD 21-21 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. | 7 |
| OHM 120 mg QD 14-21 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 3 |
| OHM 120 mg QD 5-7 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 5 of a 7-day cycle. | 5 |
| OHM 120 mg QD 7-21 Participants received 120 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 7 of a 21-day cycle. | 5 |
| OHM/DLBCL 80 mg QD 14-21 Participants received 80 mg MK-8628/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. | 15 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 | FG020 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse event-related | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Adverse event-unrelated | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 | 1 | 3 | 3 | 2 | 3 | 4 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Disease progression | 3 | 3 | 3 | 2 | 3 | 3 | 3 | 3 | 3 | 11 | 10 | 5 | 3 | 3 | 6 | 6 | 5 | 2 | 3 | 5 | 15 |
| Overall Study | Disease progression and adverse event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Stopped to receive bone marrow graft | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal of consent | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | AL 20 mg QD 14-21 | AL 20 mg BID 21-21 | AL 80 mg QD 14-21 | AL 40 mg BID 14-21 | AL 120 mg QD 14-21 | AL 120 mg QD 21-21 | AL 160 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 20 mg QD 21-21 | OHM 40 mg QD 21-21 | OHM 80 mg QD 21-21 | OHM 40 mg BID 21-21 | OHM 120 mg QD 21-21 | OHM 120 mg QD 14-21 | OHM 120 mg QD 5-7 | OHM 120 mg QD 7-21 | AL 10 mg QD 14-21 | OHM/DLBCL 80 mg QD 14-21 | Total | AL 40 mg QD 14-21 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.7 Years STANDARD_DEVIATION 19.6 | 77.7 Years STANDARD_DEVIATION 2.3 | 70.0 Years STANDARD_DEVIATION 10.6 | 65.8 Years STANDARD_DEVIATION 16.3 | 65.3 Years STANDARD_DEVIATION 13.9 | 58.5 Years STANDARD_DEVIATION 24.1 | 57.8 Years STANDARD_DEVIATION 16.6 | 65.6 Years STANDARD_DEVIATION 10 | 67.2 Years STANDARD_DEVIATION 8.2 | 65.2 Years STANDARD_DEVIATION 15.5 | 74.7 Years STANDARD_DEVIATION 7.4 | 69.0 Years STANDARD_DEVIATION 8.4 | 59.4 Years STANDARD_DEVIATION 18.5 | 54.7 Years STANDARD_DEVIATION 13 | 55.6 Years STANDARD_DEVIATION 19.3 | 66.0 Years STANDARD_DEVIATION 13.2 | 62.4 Years STANDARD_DEVIATION 8.4 | 66.8 Years STANDARD_DEVIATION 8.3 | 67.0 Years STANDARD_DEVIATION 3.5 | 58.5 Years STANDARD_DEVIATION 14.1 | 63.7 Years STANDARD_DEVIATION 13.6 | 73.8 Years STANDARD_DEVIATION 2.1 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 0 Participants | — |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 8 Participants | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 4 Participants | 46 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 6 Participants | 10 Participants | 13 Participants | 5 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 0 Participants | 2 Participants | 11 Participants | 92 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 7 / 8 | 7 / 7 | 6 / 6 | 6 / 6 | 15 / 18 | 15 / 16 | 3 / 5 | 2 / 3 | 2 / 4 | 4 / 6 | 5 / 7 | 1 / 3 | 2 / 5 | 5 / 5 | 9 / 15 | 4 / 7 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 8 / 8 | 7 / 7 | 6 / 6 | 6 / 6 | 18 / 18 | 16 / 16 | 5 / 5 | 3 / 3 | 4 / 4 | 6 / 6 | 7 / 7 | 3 / 3 | 5 / 5 | 5 / 5 | 15 / 15 | 7 / 7 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 3 / 4 | 1 / 3 | 3 / 4 | 7 / 8 | 6 / 7 | 5 / 6 | 4 / 6 | 14 / 18 | 14 / 16 | 3 / 5 | 1 / 3 | 0 / 4 | 5 / 6 | 6 / 7 | 2 / 3 | 2 / 5 | 2 / 5 | 5 / 15 | 4 / 7 |
Outcome results
Primary
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).
Time frame: Cycle 1 (Up to 21 days)
Population: All participants who received at least 85% of the intended dose of study therapy during the first cycle (i.e. \>12 days at full dose for AL and \>18 days at full dose for other hematological malignancies) or discontinued from the study due to a DLT attributable to study therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AL 10 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 20 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 40 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 20 mg BID 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 80 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 40 mg BID 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 120 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 120 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AL 160 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| AML de Novo 80 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| AML/MDS 80 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| OHM 10 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| OHM 20 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| OHM 40 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| OHM 80 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| OHM 40 mg BID 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 5 Participants |
| OHM 120 mg QD 21-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 4 Participants |
| OHM 120 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| OHM 120 mg QD 5-7 | Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
| OHM 120 mg QD 7-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| OHM/DLBCL 80 mg QD 14-21 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 3.65 Hours | Standard Deviation 0.695 |
| AL 20 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.78 Hours | Standard Deviation 1.53 |
| AL 40 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.55 Hours | Standard Deviation 0.533 |
| AL 20 mg BID 21-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.71 Hours | Standard Deviation 1.1 |
| AL 80 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.62 Hours | Standard Deviation 0.673 |
| AL 40 mg BID 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.70 Hours | Standard Deviation 1.19 |
| AL 120 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.49 Hours | Standard Deviation 1.01 |
| AL 120 mg QD 21-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 3.87 Hours | Standard Deviation 0.712 |
| AL 160 mg QD 14-21 | Apparent Terminal Half-Life (t1/2) of MK-8628/OTX015 | 4.27 Hours | Standard Deviation 0.94 |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 9.71 L/hour | Standard Deviation 1.73 |
| AL 20 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 7.67 L/hour | Standard Deviation 2.13 |
| AL 40 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 7.76 L/hour | Standard Deviation 1.38 |
| AL 20 mg BID 21-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 6.53 L/hour | Standard Deviation 1.88 |
| AL 80 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 7.91 L/hour | Standard Deviation 3.04 |
| AL 40 mg BID 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 7.49 L/hour | Standard Deviation 2.18 |
| AL 120 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 8.61 L/hour | Standard Deviation 2.22 |
| AL 120 mg QD 21-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 12.7 L/hour | Standard Deviation 2.8 |
| AL 160 mg QD 14-21 | Apparent Total Body Clearance (CL/F) of MK-8628/OTX015 | 8.87 L/hour | Standard Deviation 2.6 |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 1060 hr*ng/mL | Standard Deviation 191 |
| AL 20 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 2828 hr*ng/mL | Standard Deviation 983 |
| AL 40 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 5301 hr*ng/mL | Standard Deviation 924 |
| AL 20 mg BID 21-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 3947 hr*ng/mL | Standard Deviation 1184 |
| AL 80 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 11910 hr*ng/mL | Standard Deviation 6987 |
| AL 40 mg BID 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 5619 hr*ng/mL | Standard Deviation 1895 |
| AL 120 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 15240 hr*ng/mL | Standard Deviation 6021 |
| AL 120 mg QD 21-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 13190 hr*ng/mL | Standard Deviation 3183 |
| AL 160 mg QD 14-21 | Area Under the Concentration Time Curve of MK-8628/OTX015 From Time 0 to Infinity (AUC 0-inf) | 9833 hr*ng/mL | Standard Deviation 2968 |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 131 ug/L | Standard Deviation 56.5 |
| AL 20 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 275 ug/L | Standard Deviation 104 |
| AL 40 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 627 ug/L | Standard Deviation 328 |
| AL 20 mg BID 21-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 453 ug/L | Standard Deviation 185 |
| AL 80 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 1131 ug/L | Standard Deviation 650 |
| AL 40 mg BID 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 556 ug/L | Standard Deviation 194 |
| AL 120 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 1425 ug/L | Standard Deviation 555 |
| AL 120 mg QD 21-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 1292 ug/L | Standard Deviation 572 |
| AL 160 mg QD 14-21 | Maximum Concentration (Cmax) of MK-8628/OTX015 | 982 ug/L | Standard Deviation 316 |
Secondary
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.
Time frame: From time of first dose of study therapy until the end of treatment (up to 26 months)
Population: All participants who received at least one dose of study therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AL 10 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
| AL 20 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
| AL 40 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| AL 20 mg BID 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| AL 80 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| AL 40 mg BID 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 3 Participants |
| AL 120 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 2 Participants |
| AL 120 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 2 Participants |
| AL 160 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 4 Participants |
| AML de Novo 80 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 7 Participants |
| AML/MDS 80 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 4 Participants |
| OHM 10 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
| OHM 20 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
| OHM 40 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| OHM 80 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| OHM 40 mg BID 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| OHM 120 mg QD 21-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 2 Participants |
| OHM 120 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 1 Participants |
| OHM 120 mg QD 5-7 | Number of Participants Who Discontinued Study Therapy Due to AEs | 2 Participants |
| OHM 120 mg QD 7-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
| OHM/DLBCL 80 mg QD 14-21 | Number of Participants Who Discontinued Study Therapy Due to AEs | 0 Participants |
Secondary
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.
Time frame: Up to 40 days after last dose of study therapy (Up to 28 months)
Population: All participants who received at least one dose of study therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AL 10 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| AL 20 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| AL 40 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| AL 20 mg BID 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| AL 80 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| AL 40 mg BID 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 8 Participants |
| AL 120 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 7 Participants |
| AL 120 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 6 Participants |
| AL 160 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 6 Participants |
| AML de Novo 80 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 18 Participants |
| AML/MDS 80 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 16 Participants |
| OHM 10 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| OHM 20 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| OHM 40 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| OHM 80 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 7 Participants |
| OHM 40 mg BID 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 6 Participants |
| OHM 120 mg QD 21-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 7 Participants |
| OHM 120 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 3 Participants |
| OHM 120 mg QD 5-7 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| OHM 120 mg QD 7-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| OHM/DLBCL 80 mg QD 14-21 | Number of Participants Who Experienced at Least One Adverse Event (AE) | 15 Participants |
Secondary
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.
Time frame: From time of first dose of study therapy until the end of treatment (up to 26 months)
Population: All participants who received one dose of study therapy and had at least one available tumor assessment by the end of Cycle 2 or later or with earlier evidence of response or progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AL 10 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 20 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 40 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| AL 20 mg BID 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 80 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| AL 40 mg BID 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 120 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 120 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AL 160 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| AML de Novo 80 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| AML/MDS 80 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 10 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 20 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 40 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 80 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| OHM 40 mg BID 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 120 mg QD 21-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| OHM 120 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
| OHM 120 mg QD 5-7 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM 120 mg QD 7-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 0 Participants |
| OHM/DLBCL 80 mg QD 14-21 | Number of Participants Whose Best Response Was Partial Response (PR) or Complete Response (CR) | 1 Participants |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 1.78 Hours | Standard Deviation 1.37 |
| AL 20 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 3.03 Hours | Standard Deviation 1.54 |
| AL 40 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 1.75 Hours | Standard Deviation 1.04 |
| AL 20 mg BID 21-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 1.92 Hours | Standard Deviation 0.795 |
| AL 80 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 3.44 Hours | Standard Deviation 1.21 |
| AL 40 mg BID 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 2.73 Hours | Standard Deviation 2.08 |
| AL 120 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 3.48 Hours | Standard Deviation 1.35 |
| AL 120 mg QD 21-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 4.22 Hours | Standard Deviation 2.46 |
| AL 160 mg QD 14-21 | Time to Maximum Concentration (Tmax) of MK-8628/OTX015 | 3.07 Hours | Standard Deviation 1.79 |
Secondary
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.
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
Population: All participants that received at least 1 dose of study therapy and had evaluable data for endpoint. Results were pooled by dose taken and not by disease or regimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AL 10 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 49.6 Liters | Standard Deviation 1 |
| AL 20 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 49.1 Liters | Standard Deviation 3.51 |
| AL 40 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 50.8 Liters | Standard Deviation 10 |
| AL 20 mg BID 21-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 42.4 Liters | Standard Deviation 4.25 |
| AL 80 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 50.4 Liters | Standard Deviation 17.5 |
| AL 40 mg BID 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 48.2 Liters | Standard Deviation 9.22 |
| AL 120 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 54.2 Liters | Standard Deviation 14.4 |
| AL 120 mg QD 21-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 69.3 Liters | Standard Deviation 13.3 |
| AL 160 mg QD 14-21 | Volume of Distribution at Steady State (Vz/F) of MK-8628/OTX015 | 52.0 Liters | Standard Deviation 9.18 |