Safety, Tolerability, and Efficacy of TAK-659 in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (AML)

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT02323113
Collaborator
(none)
43
17
2
41.2
2.5
0.1

Study Details

Study Description

Brief Summary

The purpose of the Phase 1b dose finding phase is to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 in participants with relapsed or refractory AML. The purpose of the Phase 2 expansion phase is to evaluate preliminary efficacy of TAK-659 in relapsed or refractory AML as measured by overall response rate (ORR).

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

The drug being tested in this study is TAK-659. TAK-659 is being tested to treat people who have relapsed or refractory acute myelogenous leukemia (AML). This study will be conducted in 2 phases. The first phase will determine a safe and well-tolerated dose of TAK-659 to be used in the second phase, and the second phase will look at response to treatment in people who take TAK-659.

The study will enroll approximately 106 participants (approximately 40 in the first phase and 66 in the second phase). There will be two separate cohorts during Phase 2 portion of the study, one for participants with FLT-3 internal tandem duplication (ITD) mutations and the other for FLT-3 wild-type participants.

Phase 1b:

• TAK-659 60 milligram (mg) tablet starting dose escalated in 20 mg or higher increments to a maximum tolerated dose or RP2D

Phase 2:

• TAK-659 tablet at the maximum tolerated dose or RP2D determined in Phase 1b.

All participants will be asked to take their prescribed tablets at the same time each day throughout the study.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 24 months (12 months of treatment and 12 months of follow up) unless the treating physician believes the participant would continue to derive benefit from the study drug.

Study Design

Study Type:
Interventional
Actual Enrollment :
43 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)
Actual Study Start Date :
Mar 9, 2015
Actual Primary Completion Date :
Jun 8, 2018
Actual Study Completion Date :
Aug 15, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1b: TAK-659

TAK-659 tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage of TAK-659 may increase in 20 mg increments using a 3 + 3 dose escalation design to determine a MTD and/or RP2D.

Drug: TAK-659
TAK-659 tablets.

Experimental: Phase 2: TAK-659

TAK-659, tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage for this phase will be determined from results of Phase 1b MTD/RP2D.

Drug: TAK-659
TAK-659 tablets.

Outcome Measures

Primary Outcome Measures

  1. Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) [From the first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)]

    AE meant any untoward medical occurrence in a participant or participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose may result in death, life-threatening, required in participant hospitalization or prolongation of an existing hospitalization or can be a medically important event. TEAEs were defined as any AE that occurs after administration of the first dose of study treatment and up through 28 days after the last dose of study medication, or until the start of subsequent antineoplastic therapy, whichever occurs first.

  2. Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) [Up to Cycle 1 (28 days)]

    Toxicity was evaluated according to the NCI CTCAE, v4.03. DLT was defined as any of the following considered related to any of the treatment, by investigator: Prolonged myelosuppression with persistence of Grade ≥4 neutropenia or thrombocytopenia in absence of leukemia (blast count <5% in bone marrow) ≥42 days after initiation of Cycle 1 therapy; Any Grade ≥3 nonhematologic toxicity with exceptions- Grade 3 nausea or emesis resolved to Grade ≤1 or baseline in a week after use of optimal antiemetic regimen. Grade 3 diarrhea that resolved to Grade ≤1 or baseline in a week after receiving maximal supportive therapy, Brief (<1 week) Grade 3 fatigue, Asymptomatic Grade 3 laboratory abnormalities that were not clinically significant; Failure to administer ≥75% of planned doses of study drug due to TAK-659 -related or possibly related hematological or nonhematologic toxicities; related Grade ≥2 nonhematologic toxicities that required dose reduction or discontinuation of therapy.

  3. Phase 1b: Number of Participants With Clinically Significant Laboratory Findings Reported as TEAEs [From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)]

    Clinical laboratory evaluations were performed locally for Hematology, Serum Chemistry, Urinalysis. Any abnormal laboratory values were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline.

  4. Phase 1b: Number of Participants With Clinically Significant Vital Sign Findings Reported as TEAEs [From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)]

    Vital signs measurement (blood pressure, heart rate, and temperature) were performed before dosing on visit days and as clinically indicated. Any vital sign finding were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline.

  5. Phase 2: Overall Response Rate (ORR) [Up to 13 months]

    ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate.

Secondary Outcome Measures

  1. Phase 2: Duration of Response (DOR) [Up to 13 months]

    DOR was defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD). PD was defined as >50% increase in bone marrow blasts from baseline value.

  2. Phase 2: Time to Progression (TTP) [Up to 13 months]

    TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value.

  3. Phase 2: Mortality Rate at Months 3 and 6 [Months 3 and 6]

    Percentage of participants who died at Months 3 and 6.

  4. Phase 2: Overall Survival (OS) [Up to 13 months]

    OS was defined as the time from the date of study entry to the date of death.

  5. Phase 2: Overall Response Rate (ORR) in FLT-3-internal Tandem Duplication (ITD) Mutant Versus Wild Type (WT) Populations [Days 22 to 28 of Cycles 1, 2, 4 and 5 (each cycle was of 28-days)]

    ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate.

  6. Phase 2: Duration of Response (DOR) in FLT-3-ITD Mutant Versus WT Populations [Up to 13 months]

    DOR was defined as the time from the date of first documentation of a response to the date of first documented PD. PD was defined as >50% increase in bone marrow blasts from baseline value.

  7. Phase 2: Time to Progression (TTP) in FLT-3-ITD Mutant Versus WT Populations [Up to 13 months]

    TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value.

  8. Phase 2: Mortality Rate in FLT-3-ITD Mutant Versus WT Populations [Months 3 and 6]

    Number of participants who died at Months 3 and 6.

  9. Phase 2: Overall Survival (OS) in FLT-3-ITD Mutant Versus WT Populations [Cycle 1 (28-day Cycle), Day 1 to 12 months]

    OS was defined as the time from the date of study entry to the date of death.

  10. Phase 1: Cmax: Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose]

  11. Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose]

  12. Phase 1: AUC0-24: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose]

    AUC0-24 was analyzed in the QD arms/cohorts as their sampling was done up to 24 hours.

  13. Phase 1: AUC0-8: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 8 hours for BID arms) post-dose]

    AUC0-8 was analyzed in the BID arms/cohorts as their sampling was done up to 8 hours.

  14. Phase 1: CL/Fss: Apparent Clearance After Extravascular Administration at Steady State After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose]

  15. Phase 1: Rac(AUC0-24): Accumulation Ratio Based on AUC0-24 After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 24 hours for QD arms) post-dose]

    Accumulation ratio (based on AUC0-24), calculated as AUC0-24 after multiple dosing (at steady state)/AUC0-24 after a single dose.

  16. Phase 1: Rac(AUC0-8): Accumulation Ratio Based on AUC0-8 After Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 8 hours for BID arms) post-dose]

    Accumulation ratio (based on AUC0-8), calculated as AUC0-8 after multiple dosing (at steady state)/AUC0-8 after a single dose.

  17. Phase 1: PTR: Peak Trough Ratio After Multiple Dose (Day 15) for TAK-659 [Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose]

    The ratio of the maximum observed plasma concentration to the observed trough plasma concentration, where trough concentration is the concentration at the end of the dosing interval at steady-state before the next dose is administered.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. Male or female participants 18 years or older.

  2. Must have a histopathologically documented diagnosis of primary or secondary AML (excluding acute promyelocytic leukemia), as defined by World Health Organization (WHO) criteria (Jaffe et al, 2001), for whom no standard therapies are anticipated to result in a durable remission according to the clinical judgment of the principal investigator, or who refuses standard therapies (phase 1b and 2).

  3. Participants for the phase 2 portion of the study must, in addition, meet the following:

o Must be refractory to or relapsed after no more than 2 prior chemotherapy regimens. Re-induction with the same regimen or stem cell transplant will not be considered a separate regimen.

  1. Eastern Cooperative Oncology Group performance status of 0 to 1.

  2. Female participants who:

  • Are postmenopausal for at least 1 year before the screening visit, or

  • Are surgically sterile, or

  • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or

  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or

  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

  1. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

  2. In the absence of rapid progressive disease, the interval from prior systemic anticancer treatment to time of TAK-659 administration should be at least 2 weeks for cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for noncytotoxic agents, and participants have to have recovered from acute toxicities of these therapies. Participants who are on hydroxyurea may be included in the study and may continue on hydroxyurea for the first 28 days while participating in this study.

  3. Suitable venous access for the study-required blood sampling, including pharmacokinteic (PK) and pharmacodynamic (PD) sampling and blood transfusion support.

  4. Clinical laboratory values as specified in the following:

  • Total bilirubin must be less than or equal to (<=) 1.5* the upper limit of normal (ULN).

  • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be less than or equal to (<=) 2.5*the ULN.

  • Lipase <=1.5ULN and amylase <=1.5ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis.

  • Creatinine clearance greater than or equal to (>=) 60 milliliter per minute (mL/min) either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours).

Exclusion Criteria:
  1. Clinically active central nervous system leukemia.

  2. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

  3. Any serious medical or psychiatric illness, including drug or alcohol abuse that could, in the investigator's opinion, potentially jeopardize the safety of the participant or interfere with the objectives of the study.

  4. Systemic anti-cancer treatment (including investigational agents) <=21 days or <= 5their half-lives before the first dose of study treatment. (For example, if the 5the half-life is shorter than 21 days, 5*half-life should be used as the washout period. However, a minimum of 10 days should elapse from prior therapy to initiating protocol therapy).

  5. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (v4.03).

  6. Receipt of hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of TAK-659; clinically significant graft-versus-host disease (GVHD) requiring ongoing immunosuppressive therapy post HSCT at the time of screening (use of topical steroids for ongoing skin GVHD is permitted).

  7. Active, systemic infection requiring intravenous (IV) antibiotic, antifungal, or antiviral therapy or other serious infection within 14 days before the first dose of study drug.

  8. Major surgery within 14 days before the first dose of study drug and have not recovered fully from any complications from surgery.

  9. Radiotherapy less than 2 weeks before the first dose of study treatment or have not recovered from acute toxic effects from radiotherapy.

  10. Known human immunodeficiency virus (HIV) positive (testing not required).

  11. Known hepatitis B surface antigen-positive, known or suspected active hepatitis C infection (testing not required).

  12. Evidence of currently uncontrolled cardiovascular conditions as listed in the protocol; acute myocardial infarction with 6 months before starting study drug; baseline QT interval (QTcF) greater than (>) 450 milliseconds (msec) (males) or > 475 msec (females); or abnormalities on baseline 12-lead electrocardiogram (ECG) that are considered clinically significant per investigator.

  13. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea > Grade 1 despite supportive therapy.

  14. Use or consumption of any of the following substances:

  • Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) or strong inhibitors or inducers of Cytochrome (CY) P3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first dose of study drug. In general, the use of these agents is not permitted during the study except for AE management.

  • Medications or supplements that are known to be strong CYP3A mechanism based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drug. In general, the use of these agents is not permitted during the study except for AE management.

  • Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study.

  1. White blood cell count > 50,000 per micro liter (/µL); hydroxyurea may be used to control the level of circulating leukemic blast cell counts prior to study entry and, if needed, concomitantly while on TAK-659 treatment during the first 28 days of the study. Hydroxyurea can be used up to a maximum dose of 5 gram per (g/) day.

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama at Birmingham Birmingham Alabama United States 35233
2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago Illinois United States 60611
3 Oncology Specialists, S.C. Niles Illinois United States 60714
4 Johns Hopkins Hospital Baltimore Maryland United States 21287
5 Dana Farber Cancer Institute Boston Massachusetts United States 02215
6 University of Michigan Comprehensive Cancer Center Ann Arbor Michigan United States 48109
7 Karmanos Cancer Center Detroit Michigan United States 48201
8 Henry Ford Health System Detroit Michigan United States 48202
9 Mayo Clinic Rochester Minnesota United States 55905
10 North Shore Long Island Jewish Medical Center New York New York United States 10024
11 University of North Carolina Hospital Chapel Hill North Carolina United States 27514
12 UC Health Clinical Trials Office Cincinnati Ohio United States 45206
13 Baylor University Medical Center Dallas Texas United States 75204
14 Medical College of Wisconsin, Inc. Milwaukee Wisconsin United States 53266
15 Queen Elizabeth II Health Sciences Centre Halifax Nova Scotia Canada B3H 3A7
16 Princess Margaret Hospital Toronto Ontario Canada M5G 2M9
17 Wake Forest University Baptist Medical Center Toronto Ontario Canada M5G 2M9

Sponsors and Collaborators

  • Millennium Pharmaceuticals, Inc.

Investigators

  • Study Director: Study Director, Takeda

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02323113
Other Study ID Numbers:
  • C34002
  • U1111-1163-2185
First Posted:
Dec 23, 2014
Last Update Posted:
May 11, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Millennium Pharmaceuticals, Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Participants took part in the study at 7 investigative sites in United States from 09 March 2015 to study end date:15 August 2018. An additional 8 sites were activated to participate in the Phase 2 expansion phase of the study, however, the Phase 2 portion of the study was not opened for enrollment.
Pre-assignment Detail Participants with relapsed or refractory acute myelogenous leukemia(AML)were enrolled in dose escalation phase of study to receive TAK-659 to determine maximum tolerated dose/recommended phase 2 dose. In dose expansion phase(Phase 2), participants refractory to or relapsed after <=2 prior chemotherapy regimens and with no prior exposure to any investigational FLT-3 inhibitors were to be enrolled, however, as per Sponsor's decision, the study terminated before initiation of the Phase 2.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Period Title: Overall Study
STARTED 4 7 4 5 9 8 6 0
COMPLETED 0 0 0 0 0 0 0 0
NOT COMPLETED 4 7 4 5 9 8 6 0

Baseline Characteristics

Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID Total
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. Total of all reporting groups
Overall Participants 4 7 4 5 9 8 6 43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
62.3
(19.62)
59.3
(16.40)
56.0
(18.89)
60.0
(20.30)
68.0
(7.35)
50.3
(14.69)
58.5
(13.98)
59.4
(15.30)
Sex: Female, Male (Count of Participants)
Female
0
0%
4
57.1%
1
25%
3
60%
5
55.6%
3
37.5%
4
66.7%
20
46.5%
Male
4
100%
3
42.9%
3
75%
2
40%
4
44.4%
5
62.5%
2
33.3%
23
53.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
2.3%
Not Hispanic or Latino
3
75%
7
100%
4
100%
5
100%
9
100%
6
75%
6
100%
40
93%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
0
0%
2
25%
0
0%
2
4.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Asian
0
0%
1
14.3%
0
0%
0
0%
0
0%
0
0%
0
0%
1
2.3%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
1
14.3%
1
25%
2
40%
0
0%
2
25%
2
33.3%
8
18.6%
White
3
75%
5
71.4%
3
75%
3
60%
9
100%
6
75%
3
50%
32
74.4%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
2
4.7%
Region of Enrollment (Count of Participants)
United States
4
100%
7
100%
4
100%
5
100%
9
100%
8
100%
6
100%
43
100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]
166.9
(6.80)
168.1
(15.15)
169.2
(6.35)
170.4
(15.06)
168.8
(11.75)
176.8
(10.29)
169.6
(13.49)
170.4
(11.49)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]
63.30
(10.692)
77.16
(18.963)
79.48
(13.133)
75.62
(15.049)
78.48
(27.515)
90.41
(23.728)
89.82
(24.609)
80.41
(21.645)

Outcome Measures

1. Primary Outcome
Title Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Description AE meant any untoward medical occurrence in a participant or participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose may result in death, life-threatening, required in participant hospitalization or prolongation of an existing hospitalization or can be a medically important event. TEAEs were defined as any AE that occurs after administration of the first dose of study treatment and up through 28 days after the last dose of study medication, or until the start of subsequent antineoplastic therapy, whichever occurs first.
Time Frame From the first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)

Outcome Measure Data

Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9 8 6
TEAEs
4
100%
7
100%
4
100%
5
100%
9
100%
8
100%
6
100%
SAEs
4
100%
6
85.7%
4
100%
5
100%
9
100%
7
87.5%
6
100%
2. Primary Outcome
Title Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
Description Toxicity was evaluated according to the NCI CTCAE, v4.03. DLT was defined as any of the following considered related to any of the treatment, by investigator: Prolonged myelosuppression with persistence of Grade ≥4 neutropenia or thrombocytopenia in absence of leukemia (blast count <5% in bone marrow) ≥42 days after initiation of Cycle 1 therapy; Any Grade ≥3 nonhematologic toxicity with exceptions- Grade 3 nausea or emesis resolved to Grade ≤1 or baseline in a week after use of optimal antiemetic regimen. Grade 3 diarrhea that resolved to Grade ≤1 or baseline in a week after receiving maximal supportive therapy, Brief (<1 week) Grade 3 fatigue, Asymptomatic Grade 3 laboratory abnormalities that were not clinically significant; Failure to administer ≥75% of planned doses of study drug due to TAK-659 -related or possibly related hematological or nonhematologic toxicities; related Grade ≥2 nonhematologic toxicities that required dose reduction or discontinuation of therapy.
Time Frame Up to Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description
DLT-evaluable population include all participants in the phase 1b portion of the study at each dose cohort who either experienced a DLT during Cycle 1 or completed at least 75% of planned doses of TAK-659 and had sufficient follow-up data to allow both the sponsor and investigators to determine whether a DLT occurred.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 3 6 3 3 6 7 6
Count of Participants [Participants]
0
0%
0
0%
0
0%
0
0%
1
11.1%
0
0%
3
50%
3. Primary Outcome
Title Phase 1b: Number of Participants With Clinically Significant Laboratory Findings Reported as TEAEs
Description Clinical laboratory evaluations were performed locally for Hematology, Serum Chemistry, Urinalysis. Any abnormal laboratory values were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline.
Time Frame From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)

Outcome Measure Data

Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9 8 6
Febrile neutropenia
0
0%
3
42.9%
3
75%
4
80%
5
55.6%
5
62.5%
6
100%
Anaemia
0
0%
1
14.3%
1
25%
1
20%
4
44.4%
2
25%
3
50%
Thrombocytopenia
1
25%
3
42.9%
1
25%
0
0%
0
0%
0
0%
0
0%
Pancytopenia
0
0%
1
14.3%
0
0%
0
0%
2
22.2%
0
0%
0
0%
Leukocytosis
1
25%
1
14.3%
0
0%
0
0%
0
0%
0
0%
0
0%
Leukopenia
0
0%
0
0%
0
0%
0
0%
1
11.1%
0
0%
0
0%
Neutropenia
0
0%
0
0%
0
0%
1
20%
0
0%
0
0%
0
0%
Thrombocytosis
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
Aspartate aminotransferase increased
0
0%
5
71.4%
2
50%
3
60%
5
55.6%
3
37.5%
4
66.7%
Amylase increased
0
0%
4
57.1%
1
25%
2
40%
4
44.4%
3
37.5%
2
33.3%
Alanine aminotransferase increased
0
0%
3
42.9%
2
50%
2
40%
3
33.3%
1
12.5%
3
50%
Lipase increased
0
0%
2
28.6%
1
25%
2
40%
4
44.4%
3
37.5%
2
33.3%
Platelet count decreased
0
0%
0
0%
0
0%
1
20%
3
33.3%
1
12.5%
4
66.7%
Blood lactate dehydrogenase increased
1
25%
1
14.3%
0
0%
2
40%
1
11.1%
0
0%
2
33.3%
White blood cell count decreased
0
0%
0
0%
0
0%
0
0%
2
22.2%
3
37.5%
2
33.3%
Neutrophil count decreased
0
0%
0
0%
0
0%
1
20%
1
11.1%
1
12.5%
3
50%
Gamma-glutamyltransferase increased
1
25%
0
0%
1
25%
1
20%
1
11.1%
1
12.5%
0
0%
Blood alkaline phosphatase increased
0
0%
0
0%
1
25%
0
0%
1
11.1%
1
12.5%
1
16.7%
Blood creatinine increased
0
0%
1
14.3%
1
25%
0
0%
0
0%
1
12.5%
1
16.7%
Blood calcium decreased
0
0%
0
0%
0
0%
0
0%
0
0%
3
37.5%
0
0%
Blood phosphorus decreased
0
0%
0
0%
0
0%
1
20%
0
0%
2
25%
0
0%
Blood bilirubin increased
0
0%
0
0%
1
25%
0
0%
1
11.1%
0
0%
0
0%
Blood creatine phosphokinase increased
0
0%
0
0%
0
0%
0
0%
1
11.1%
0
0%
1
16.7%
Blood potassium decreased
0
0%
0
0%
0
0%
1
20%
0
0%
0
0%
0
0%
Blood uric acid increased
0
0%
0
0%
0
0%
1
20%
0
0%
0
0%
0
0%
Haemoglobin decreased
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
Lymphocyte count increased
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
Transaminases increased
0
0%
0
0%
0
0%
1
20%
0
0%
0
0%
0
0%
Hypophosphataemia
1
25%
1
14.3%
2
50%
1
20%
2
22.2%
0
0%
4
66.7%
Hypocalcaemia
0
0%
0
0%
1
25%
4
80%
1
11.1%
1
12.5%
2
33.3%
Hypokalaemia
0
0%
3
42.9%
1
25%
1
20%
1
11.1%
1
12.5%
1
16.7%
Hypomagnesaemia
1
25%
1
14.3%
1
25%
3
60%
0
0%
0
0%
1
16.7%
Hyperkalaemia
0
0%
0
0%
0
0%
1
20%
0
0%
1
12.5%
0
0%
Hyperuricaemia
0
0%
0
0%
0
0%
0
0%
1
11.1%
0
0%
1
16.7%
Hyponatraemia
0
0%
0
0%
0
0%
0
0%
1
11.1%
1
12.5%
0
0%
Hyperamylasaemia
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hyperglycaemia
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hyperlipasaemia
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hypernatraemia
0
0%
0
0%
1
25%
0
0%
0
0%
0
0%
0
0%
Hyperphosphataemia
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
Hypoglycaemia
0
0%
0
0%
0
0%
0
0%
0
0%
1
12.5%
0
0%
4. Primary Outcome
Title Phase 1b: Number of Participants With Clinically Significant Vital Sign Findings Reported as TEAEs
Description Vital signs measurement (blood pressure, heart rate, and temperature) were performed before dosing on visit days and as clinically indicated. Any vital sign finding were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline.
Time Frame From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)

Outcome Measure Data

Analysis Population Description
Safety population included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9 8 6
Weight Increased
0
0%
1
14.3%
0
0%
0
0%
0
0%
0
0%
0
0%
Tachycardia
0
0%
1
14.3%
1
25%
0
0%
1
11.1%
0
0%
1
16.7%
Hypertension
1
25%
0
0%
2
50%
0
0%
1
11.1%
0
0%
0
0%
Hypotension
0
0%
0
0%
0
0%
0
0%
2
22.2%
1
12.5%
0
0%
Pyrexia
1
25%
2
28.6%
1
25%
1
20%
4
44.4%
0
0%
2
33.3%
5. Primary Outcome
Title Phase 2: Overall Response Rate (ORR)
Description ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and the planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
6. Secondary Outcome
Title Phase 2: Duration of Response (DOR)
Description DOR was defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD). PD was defined as >50% increase in bone marrow blasts from baseline value.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and the planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
7. Secondary Outcome
Title Phase 2: Time to Progression (TTP)
Description TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
8. Secondary Outcome
Title Phase 2: Mortality Rate at Months 3 and 6
Description Percentage of participants who died at Months 3 and 6.
Time Frame Months 3 and 6

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
9. Secondary Outcome
Title Phase 2: Overall Survival (OS)
Description OS was defined as the time from the date of study entry to the date of death.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and the planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
10. Secondary Outcome
Title Phase 2: Overall Response Rate (ORR) in FLT-3-internal Tandem Duplication (ITD) Mutant Versus Wild Type (WT) Populations
Description ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate.
Time Frame Days 22 to 28 of Cycles 1, 2, 4 and 5 (each cycle was of 28-days)

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and the planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
11. Secondary Outcome
Title Phase 2: Duration of Response (DOR) in FLT-3-ITD Mutant Versus WT Populations
Description DOR was defined as the time from the date of first documentation of a response to the date of first documented PD. PD was defined as >50% increase in bone marrow blasts from baseline value.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
12. Secondary Outcome
Title Phase 2: Time to Progression (TTP) in FLT-3-ITD Mutant Versus WT Populations
Description TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value.
Time Frame Up to 13 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
13. Secondary Outcome
Title Phase 2: Mortality Rate in FLT-3-ITD Mutant Versus WT Populations
Description Number of participants who died at Months 3 and 6.
Time Frame Months 3 and 6

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as the expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
14. Secondary Outcome
Title Phase 2: Overall Survival (OS) in FLT-3-ITD Mutant Versus WT Populations
Description OS was defined as the time from the date of study entry to the date of death.
Time Frame Cycle 1 (28-day Cycle), Day 1 to 12 months

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed as expansion phase 2 portion of the study was not opened for enrollment and planned analyses were not conducted due to early termination of study.
Arm/Group Title Phase 2 (Dose Expansion Phase)
Arm/Group Description TAK-659 tablets at the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) determined from dose escalation phase, orally, QD or BID on Days 1 to 28 in each 28-day Cycle, for up to 12 cycles or until disease progression in participants who were to be entered in Phase 2.
Measure Participants 0
15. Secondary Outcome
Title Phase 1: Cmax: Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659
Description
Time Frame Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose

Outcome Measure Data

Analysis Population Description
PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number analyzed is the number of participants with data available for analysis at the given timepoint.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9 8 6
Cycle 1 Day 1
74.39
(32.27)
157.21
(41.54)
211.32
(41.98)
310.76
(30.13)
322.32
(68.92)
87.86
(96.10)
122.59
(42.81)
Cycle 1 Day 15
188.48
(46.25)
256.10
(44.58)
213.13
(35.55)
574.23
(25.98)
404.07
(53.48)
120.39
(60.27)
299.01
(43.89)
16. Secondary Outcome
Title Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659
Description
Time Frame Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose

Outcome Measure Data

Analysis Population Description
PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number analyzed is the number of participants with data available for analysis at the given timepoint.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9 8 6
Cycle 1 Day 1
2.41
2.08
2.53
3.03
1.17
2.63
2.08
Cycle 1 Day 15
1.97
2.00
2.10
2.04
2.97
2.17
1.48
17. Secondary Outcome
Title Phase 1: AUC0-24: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Once-Daily (QD) Multiple Dose (Day 15) for TAK-659
Description AUC0-24 was analyzed in the QD arms/cohorts as their sampling was done up to 24 hours.
Time Frame Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose

Outcome Measure Data

Analysis Population Description
Participants from PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters who received QD dosing of TAK-659. Number analyzed is the number of participants with data available for analysis at the given timepoint.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 4 7 4 5 9
Cycle 1 Day 1
796.8688
(29.8559)
1244.4982
(32.8536)
2072.1874
(55.3105)
2563.5593
(21.0820)
3188.8032
(59.6781)
Cycle 1 Day 15
1767.7607
(41.9029)
2368.2318
(43.8496)
2535.7901
(19.5210)
4636.1667
(23.7653)
4390.3805
(42.5850)
18. Secondary Outcome
Title Phase 1: AUC0-8: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659
Description AUC0-8 was analyzed in the BID arms/cohorts as their sampling was done up to 8 hours.
Time Frame Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 8 hours for BID arms) post-dose

Outcome Measure Data

Analysis Population Description
Participants from PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters who received BID dosing of TAK-659. Number analyzed is number of participants with data available for analysis at the given time point.
Arm/Group Title TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 8 6
Cycle 1 Day 1
369.3765
(65.9672)
519.9999
(44.9975)
Cycle 1 Day 15
718.2914
(47.5599)
1239.4346
(31.9812)
19. Secondary Outcome
Title Phase 1: CL/Fss: Apparent Clearance After Extravascular Administration at Steady State After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659
Description
Time Frame Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose

Outcome Measure Data

Analysis Population Description
PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number analyzed is the number of participants with data available for analysis at the given timepoint. Only QD dosing Cohorts were analyzed for this outcome measure.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 3 5 2 3 4
Geometric Mean (Geometric Coefficient of Variation) [L/h]
33.9412
(41.9029)
42.2256
(43.8496)
47.3225
(19.5210)
30.1974
(23.7653)
36.4433
(42.5850)
20. Secondary Outcome
Title Phase 1: Rac(AUC0-24): Accumulation Ratio Based on AUC0-24 After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659
Description Accumulation ratio (based on AUC0-24), calculated as AUC0-24 after multiple dosing (at steady state)/AUC0-24 after a single dose.
Time Frame Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 24 hours for QD arms) post-dose

Outcome Measure Data

Analysis Population Description
Participants from PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters who received QD dosing of TAK-659. Overall number analyzed are the number of participants with data available for analysis.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 2 5 2 3 4
Geometric Mean (Geometric Coefficient of Variation) [ratio]
2.7001
(20.7227)
1.7936
(32.6687)
1.5697
(11.4956)
1.9398
(7.1129)
2.0033
(28.3167)
21. Secondary Outcome
Title Phase 1: Rac(AUC0-8): Accumulation Ratio Based on AUC0-8 After Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659
Description Accumulation ratio (based on AUC0-8), calculated as AUC0-8 after multiple dosing (at steady state)/AUC0-8 after a single dose.
Time Frame Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 8 hours for BID arms) post-dose

Outcome Measure Data

Analysis Population Description
Participants from PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters who received BID dosing of TAK-659. Overall number analyzed are the number of participants with data available for analysis.
Arm/Group Title TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 5 3
Geometric Mean (Geometric Coefficient of Variation) [ratio]
2.3819
(45.4917)
2.6371
(36.8694)
22. Secondary Outcome
Title Phase 1: PTR: Peak Trough Ratio After Multiple Dose (Day 15) for TAK-659
Description The ratio of the maximum observed plasma concentration to the observed trough plasma concentration, where trough concentration is the concentration at the end of the dosing interval at steady-state before the next dose is administered.
Time Frame Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose

Outcome Measure Data

Analysis Population Description
PK-evaluable population included all participants in the acute myelogenous leukemia dose escalation cohorts who had sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number analyzed are the number of participants with data available for analysis.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
Measure Participants 3 5 2 4 5 5 4
Geometric Mean (Geometric Coefficient of Variation) [ratio]
4.8957
(21.1877)
6.1564
(56.0024)
4.1585
(24.0807)
6.7852
(35.6808)
4.7045
(24.8880)
1.8886
(31.4783)
2.6415
(27.6855)

Adverse Events

Time Frame From the first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Arm/Group Description TAK-659, 60 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 100 mg tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 120 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 140 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 160 mg, tablets, orally, QD on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 60 mg, tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles. TAK-659, 80 mg tablets, orally, BID on Days 1 to 28 in each 28-day Cycle until disease progression or occurrence of unacceptable drug-related toxicities or discontinuation or up to 12 cycles.
All Cause Mortality
TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/4 (25%) 3/7 (42.9%) 3/4 (75%) 4/5 (80%) 7/9 (77.8%) 4/8 (50%) 4/6 (66.7%)
Serious Adverse Events
TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/4 (100%) 6/7 (85.7%) 4/4 (100%) 5/5 (100%) 9/9 (100%) 7/8 (87.5%) 6/6 (100%)
Blood and lymphatic system disorders
Febrile neutropenia 0/4 (0%) 1/7 (14.3%) 3/4 (75%) 3/5 (60%) 4/9 (44.4%) 3/8 (37.5%) 5/6 (83.3%)
Anaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 2/6 (33.3%)
Pancytopenia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 0/6 (0%)
Leukocytosis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Neutropenia 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Thrombocytopenia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Cardiac disorders
Cardiac arrest 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Atrial fibrillation 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Cardiac failure 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Cardiac failure congestive 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Cardio-respiratory arrest 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Cardiogenic shock 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Myocardial infarction 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Tachycardia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Gastrointestinal disorders
Gastric haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 4/6 (66.7%)
Gastrointestinal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Anal fistula 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Diarrhoea haemorrhagic 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Enteritis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Gastritis 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Gastritis haemorrhagic 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Haematemesis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Haematochezia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lower gastrointestinal haemorrhage 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Nausea 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pancreatitis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Rectal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Stomatitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Upper gastrointestinal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Vomiting 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
General disorders
Pyrexia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 1/6 (16.7%)
Death 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Fatigue 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Multiple organ dysfunction syndrome 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Infections and infestations
Pneumonia 0/4 (0%) 0/7 (0%) 1/4 (25%) 3/5 (60%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Bronchopulmonary aspergillosis 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Enterococcal bacteraemia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Enterococcal infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Sepsis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Adenovirus infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Anal abscess 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Bacterial sepsis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Clostridium bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Clostridium difficile infection 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Device related infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Fungaemia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Fungal infection 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Fusarium infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Infection 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Klebsiella infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Lung infection 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Parainfluenzae virus infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Periodontitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Periorbital cellulitis 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pneumocystis jirovecii pneumonia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pneumonia escherichia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pneumonia fungal 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Pneumonia klebsiella 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pneumonia necrotising 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pneumonia staphylococcal 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pulmonary mycosis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Staphylococcal infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Staphylococcal sepsis 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Streptococcal sepsis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Injury, poisoning and procedural complications
Subdural haematoma 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Subarachnoid haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Investigations
Amylase increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Aspartate aminotransferase increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lactobacillus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Lipase increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Neutrophil count decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Respiratory syncytial virus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Transaminases increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Metabolism and nutrition disorders
Dehydration 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Hyperkalaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hypocalcaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Hypoglycaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Hypophosphataemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Musculoskeletal and connective tissue disorders
Arthritis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Back pain 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Haemarthrosis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Muscular weakness 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia 0/4 (0%) 0/7 (0%) 2/4 (50%) 1/5 (20%) 3/9 (33.3%) 2/8 (25%) 0/6 (0%)
Nervous system disorders
Encephalopathy 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Cerebrovascular accident 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Dizziness 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Haemorrhage intracranial 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Psychiatric disorders
Mental status changes 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Renal and urinary disorders
Acute kidney injury 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 2/5 (40%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pulmonary oedema 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 0/6 (0%)
Respiratory failure 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Acute respiratory distress syndrome 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Acute respiratory failure 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Dyspnoea 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Epistaxis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Haemoptysis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Pharyngeal stenosis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pneumonia aspiration 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pneumonitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Skin and subcutaneous tissue disorders
Erythema 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Other (Not Including Serious) Adverse Events
TAK-659 60 mg QD TAK-659 100 mg QD TAK-659 120 mg QD TAK-659 140 mg QD TAK-659 160 mg QD TAK-659 60 mg BID TAK-659 80 mg BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/4 (100%) 7/7 (100%) 4/4 (100%) 5/5 (100%) 9/9 (100%) 8/8 (100%) 6/6 (100%)
Blood and lymphatic system disorders
Anaemia 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 4/9 (44.4%) 2/8 (25%) 2/6 (33.3%)
Febrile neutropenia 0/4 (0%) 2/7 (28.6%) 0/4 (0%) 2/5 (40%) 1/9 (11.1%) 3/8 (37.5%) 1/6 (16.7%)
Thrombocytopenia 1/4 (25%) 2/7 (28.6%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lymphadenopathy 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Increased tendency to bruise 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Leukocytosis 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Leukopenia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pancytopenia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Splenic lesion 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Thrombocytosis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Cardiac disorders
Tachycardia 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Pericardial effusion 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Angina pectoris 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Atrial fibrillation 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Bundle branch block left 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Cardiomyopathy 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Supraventricular extrasystoles 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Ventricular tachycardia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Ear and labyrinth disorders
Deafness 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Ear pain 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vertigo 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Endocrine disorders
Adrenal insufficiency 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Hypothyroidism 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Eye disorders
Periorbital oedema 0/4 (0%) 2/7 (28.6%) 2/4 (50%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Eyelid oedema 1/4 (25%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Retinal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 2/6 (33.3%)
Vision blurred 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Cataract 0/4 (0%) 2/7 (28.6%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Dry eye 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Eye swelling 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Conjunctival haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Macular fibrosis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Ocular hyperaemia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Scleral hyperaemia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Scleral oedema 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vitreous floaters 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Gastrointestinal disorders
Diarrhoea 0/4 (0%) 5/7 (71.4%) 2/4 (50%) 2/5 (40%) 3/9 (33.3%) 4/8 (50%) 1/6 (16.7%)
Nausea 1/4 (25%) 0/7 (0%) 1/4 (25%) 3/5 (60%) 2/9 (22.2%) 2/8 (25%) 1/6 (16.7%)
Stomatitis 1/4 (25%) 3/7 (42.9%) 1/4 (25%) 2/5 (40%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Constipation 2/4 (50%) 2/7 (28.6%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Vomiting 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 1/5 (20%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Dry mouth 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Gastrointestinal haemorrhage 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Gingival bleeding 1/4 (25%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Melaena 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Mouth haemorrhage 1/4 (25%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Rectal haemorrhage 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Abdominal discomfort 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Abdominal distension 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Abdominal pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Abdominal pain upper 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Haematochezia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Oral pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Abdominal pain lower 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Angina bullosa haemorrhagica 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Dysphagia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Faeces discoloured 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Frequent bowel movements 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Glossodynia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Haemorrhoids 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Hypoaesthesia oral 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Ileus 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Large intestine polyp 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lip pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Lower gastrointestinal haemorrhage 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Oesophageal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Oral mucosa haematoma 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
General disorders
Fatigue 1/4 (25%) 4/7 (57.1%) 2/4 (50%) 0/5 (0%) 3/9 (33.3%) 3/8 (37.5%) 1/6 (16.7%)
Chills 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 1/5 (20%) 2/9 (22.2%) 2/8 (25%) 1/6 (16.7%)
Pyrexia 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 1/5 (20%) 3/9 (33.3%) 0/8 (0%) 1/6 (16.7%)
Oedema peripheral 1/4 (25%) 1/7 (14.3%) 1/4 (25%) 1/5 (20%) 1/9 (11.1%) 1/8 (12.5%) 1/6 (16.7%)
Pain 1/4 (25%) 1/7 (14.3%) 0/4 (0%) 2/5 (40%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Asthenia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Face oedema 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Chest discomfort 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Facial pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Feeling abnormal 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Influenza like illness 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Malaise 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Swelling 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Unevaluable event 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hepatobiliary disorders
Hepatic lesion 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Hyperbilirubinaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Infections and infestations
Clostridium difficile infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Cytomegalovirus infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Oral candidiasis 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Upper respiratory tract infection 1/4 (25%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Acinetobacter bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Adenovirus infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Alpha haemolytic streptococcal infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Appendicitis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Cellulitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Chronic sinusitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Device related infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Diverticulitis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Escherichia bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Fungal infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Fungal skin infection 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Osteomyelitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Sepsis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Sinusitis fungal 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Streptococcal bacteraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Tonsillitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Viral upper respiratory tract infection 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Urinary tract infection bacterial 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Injury, poisoning and procedural complications
Contusion 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 2/5 (40%) 2/9 (22.2%) 1/8 (12.5%) 1/6 (16.7%)
Laceration 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 1/8 (12.5%) 1/6 (16.7%)
Fall 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Infusion related reaction 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Muscle strain 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Post procedural contusion 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Procedural pain 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Procedural site reaction 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Wound 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Investigations
Aspartate aminotransferase increased 0/4 (0%) 5/7 (71.4%) 2/4 (50%) 3/5 (60%) 5/9 (55.6%) 3/8 (37.5%) 4/6 (66.7%)
Amylase increased 0/4 (0%) 4/7 (57.1%) 1/4 (25%) 2/5 (40%) 4/9 (44.4%) 3/8 (37.5%) 2/6 (33.3%)
Alanine aminotransferase increased 0/4 (0%) 3/7 (42.9%) 2/4 (50%) 2/5 (40%) 3/9 (33.3%) 1/8 (12.5%) 3/6 (50%)
Lipase increased 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 2/5 (40%) 4/9 (44.4%) 3/8 (37.5%) 2/6 (33.3%)
Platelet count decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 3/9 (33.3%) 1/8 (12.5%) 4/6 (66.7%)
Blood lactate dehydrogenase increased 1/4 (25%) 1/7 (14.3%) 0/4 (0%) 2/5 (40%) 1/9 (11.1%) 0/8 (0%) 2/6 (33.3%)
White blood cell count decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 3/8 (37.5%) 2/6 (33.3%)
Gamma-glutamyltransferase increased 1/4 (25%) 0/7 (0%) 1/4 (25%) 1/5 (20%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Neutrophil count decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 3/6 (50%)
Blood alkaline phosphatase increased 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 1/6 (16.7%)
Blood creatinine increased 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Blood calcium decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 3/8 (37.5%) 0/6 (0%)
Blood phosphorus decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Blood bilirubin increased 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Blood creatine phosphokinase increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Ejection fraction decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Troponin increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Blood potassium decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Blood uric acid increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Clostridium test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Electrocardiogram QT prolonged 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Enterococcus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Haemoglobin decreased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Human rhinovirus test positive 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
International normalised ratio increased 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lymphocyte count increased 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Pseudomonas test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Respirovirus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Staphylococcus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Streptococcus test positive 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Urine output increased 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Weight increased 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Metabolism and nutrition disorders
Hypophosphataemia 1/4 (25%) 1/7 (14.3%) 2/4 (50%) 1/5 (20%) 2/9 (22.2%) 0/8 (0%) 4/6 (66.7%)
Hypocalcaemia 0/4 (0%) 0/7 (0%) 1/4 (25%) 4/5 (80%) 0/9 (0%) 1/8 (12.5%) 2/6 (33.3%)
Hypokalaemia 0/4 (0%) 3/7 (42.9%) 1/4 (25%) 1/5 (20%) 1/9 (11.1%) 1/8 (12.5%) 1/6 (16.7%)
Hypomagnesaemia 1/4 (25%) 1/7 (14.3%) 1/4 (25%) 3/5 (60%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Decreased appetite 1/4 (25%) 1/7 (14.3%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Fluid overload 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Hyperuricaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Hyponatraemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Dehydration 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Hyperamylasaemia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hyperglycaemia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hyperkalaemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Hyperlipasaemia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hypernatraemia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Hyperphosphataemia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Hypervolaemia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Malnutrition 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vitamin D deficiency 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 1/4 (25%) 3/7 (42.9%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Back pain 1/4 (25%) 3/7 (42.9%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Myalgia 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Pain in extremity 0/4 (0%) 2/7 (28.6%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Muscular weakness 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 2/8 (25%) 0/6 (0%)
Musculoskeletal pain 2/4 (50%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Bone cyst 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Bone pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Chest wall haematoma 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Flank pain 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Intervertebral disc protrusion 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Joint range of motion decreased 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Joint swelling 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Kyphosis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Muscle spasms 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Musculoskeletal stiffness 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Myopathy 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Pain in jaw 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Spinal osteoarthritis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Spinal pain 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Squamous cell carcinoma of skin 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Nervous system disorders
Headache 0/4 (0%) 2/7 (28.6%) 2/4 (50%) 0/5 (0%) 3/9 (33.3%) 4/8 (50%) 2/6 (33.3%)
Dizziness 1/4 (25%) 1/7 (14.3%) 1/4 (25%) 1/5 (20%) 4/9 (44.4%) 0/8 (0%) 2/6 (33.3%)
Dysgeusia 0/4 (0%) 0/7 (0%) 1/4 (25%) 1/5 (20%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Neuropathy peripheral 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Seizure 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Tremor 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 0/6 (0%)
Amnesia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Cerebral haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Encephalopathy 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Haemorrhage intracranial 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Paraesthesia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Presyncope 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Sinus headache 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Syncope 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Hypogeusia 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Psychiatric disorders
Insomnia 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 2/6 (33.3%)
Anxiety 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 2/6 (33.3%)
Confusional state 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 1/8 (12.5%) 0/6 (0%)
Mental status changes 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 1/6 (16.7%)
Agitation 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Depression 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Disorientation 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Mental fatigue 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Sleep disorder 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Renal and urinary disorders
Acute kidney injury 0/4 (0%) 1/7 (14.3%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Haematuria 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 2/6 (33.3%)
Urinary retention 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Dysuria 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Nocturia 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pollakiuria 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Proteinuria 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Reproductive system and breast disorders
Acquired hydrocele 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Testicular oedema 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vulvovaginal discomfort 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vulvovaginal erythema 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Cough 1/4 (25%) 1/7 (14.3%) 1/4 (25%) 1/5 (20%) 4/9 (44.4%) 1/8 (12.5%) 1/6 (16.7%)
Epistaxis 1/4 (25%) 3/7 (42.9%) 0/4 (0%) 1/5 (20%) 1/9 (11.1%) 3/8 (37.5%) 1/6 (16.7%)
Dyspnoea 0/4 (0%) 2/7 (28.6%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 2/8 (25%) 1/6 (16.7%)
Hypoxia 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 4/9 (44.4%) 0/8 (0%) 1/6 (16.7%)
Oropharyngeal pain 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 2/6 (33.3%)
Dyspnoea exertional 1/4 (25%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pulmonary mass 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Sinus congestion 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Haemoptysis 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Pharyngeal haemorrhage 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 1/6 (16.7%)
Pneumonitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Rhinorrhoea 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 0/6 (0%)
Upper-airway cough syndrome 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Dysphonia 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Lung infiltration 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Nasal congestion 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Nasal dryness 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Nasal oedema 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Paranasal sinus discomfort 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pharyngeal ulceration 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Productive cough 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Pulmonary hypertension 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pulmonary oedema 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Respiratory failure 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Respiratory tract congestion 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Sneezing 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Tachypnoea 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Wheezing 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Skin and subcutaneous tissue disorders
Petechiae 0/4 (0%) 3/7 (42.9%) 1/4 (25%) 2/5 (40%) 3/9 (33.3%) 1/8 (12.5%) 2/6 (33.3%)
Night sweats 0/4 (0%) 0/7 (0%) 2/4 (50%) 0/5 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/6 (0%)
Swelling face 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 1/6 (16.7%)
Purpura 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 0/8 (0%) 0/6 (0%)
Rash 0/4 (0%) 0/7 (0%) 0/4 (0%) 1/5 (20%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Rash maculo-papular 0/4 (0%) 0/7 (0%) 1/4 (25%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Rash pruritic 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Blister 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Dermatitis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Dermatitis exfoliative generalised 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Dry skin 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Ecchymosis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Eczema 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Erythema 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Hypersensitivity vasculitis 1/4 (25%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Pruritus 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Rash generalised 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Rash macular 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Urticaria 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)
Vascular disorders
Hypertension 1/4 (25%) 0/7 (0%) 2/4 (50%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Hypotension 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 2/9 (22.2%) 1/8 (12.5%) 0/6 (0%)
Flushing 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 1/8 (12.5%) 0/6 (0%)
Deep vein thrombosis 0/4 (0%) 0/7 (0%) 0/4 (0%) 0/5 (0%) 1/9 (11.1%) 0/8 (0%) 0/6 (0%)
Pallor 0/4 (0%) 1/7 (14.3%) 0/4 (0%) 0/5 (0%) 0/9 (0%) 0/8 (0%) 0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In general, investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.

Results Point of Contact

Name/Title Study Director
Organization Takeda
Phone +1-877-825-3327
Email TrialDisclosures@takeda.com
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02323113
Other Study ID Numbers:
  • C34002
  • U1111-1163-2185
First Posted:
Dec 23, 2014
Last Update Posted:
May 11, 2021
Last Verified:
Apr 1, 2021