AZD1775 for Advanced Solid Tumors

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01748825
Collaborator
(none)
67
1
10
89
0.8

Study Details

Study Description

Brief Summary

BACKGROUND:
  • Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase.

  • Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts.

  • Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775.

PRIMARY OBJECTIVE:
  • To establish the safety and tolerability of single-agent AZD1775 in patients with refractory solid tumors

  • To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors

SECONDARY OBJECTIVES:
  • To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells

  • To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors

EXPLORATORY OBJECTIVES:

-To identify tumor genomic alterations and gene expression patterns potentially associated with AZD1775 antitumor activity

ELIGIBILITY:
  • Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed, or for which standard therapies do not exist.

  • No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever is shorter) prior to entering the study.

  • Adequate organ function

STUDY DESIGN:
  • This study will follow a traditional 3+3 design.

  • In Arm A starting at dose level 1, AZD1775 will be administered orally, twice a day (BID), for 5 doses (Day (D) 1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling).

  • Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics (PD) endpoints.

  • A further expansion arm of 6 additional patients with documented tumors harboring breast cancer type 1 or 2 (BRCA)-1 or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population.

  • Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, patients without a documented BRCA mutation will be accrued to a once-daily dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1 day for scheduling).

  • During the escalation phase, tumor biopsies will be optional and will be evaluated for pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and apoptosis (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1), Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (pTyr15-Cdk) and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD endpoints.

Condition or Disease Intervention/Treatment Phase
  • Drug: MK-1775 (AZD1775)
Phase 1

Detailed Description

BACKGROUND:
  • Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase.

  • Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts.

  • Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775.

PRIMARY OBJECTIVE:
  • To establish the safety and tolerability of single-agent AZD1775 in patients with refractory solid tumors

  • To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors

SECONDARY OBJECTIVES:

-To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors

EXPLORATORY OBJECTIVES:

-To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor

tissue and circulating tumor cells

  • To assess whether sufficient Wee1 inhibition is maintained throughout the therapeutic regimen

  • To identify tumor genomic alterations and gene expression patterns potentially associated withAZD1775 antitumor activity

ELIGIBILITY:
  • Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed, or for which standard therapies do not exist.

  • No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever is shorter) prior to entering the study.

  • Adequate organ function

STUDY DESIGN:
  • This study will follow a traditional 3+3 design.

  • In Arm A starting at dose level 1, AZD1775 will be administered orally, twice a day (BID), for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling).

  • Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics (PD) endpoints.

  • A further expansion arm of 6 additional patients with documented tumors harboring breast cancer type 1 or 2 (BRCA)-1 or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population.

  • Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, patients without a documented BRCA mutation will be accrued to a once-daily dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1 day for scheduling).

  • During the escalation phase, tumor biopsies will be optional and will be evaluated for pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and apoptosis (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1), Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (pTyr15-Cdk) and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD endpoints.

Study Design

Study Type:
Interventional
Actual Enrollment :
67 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
Actual Study Start Date :
Dec 19, 2012
Actual Primary Completion Date :
May 19, 2020
Actual Study Completion Date :
May 19, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: ARM 1 AZD1775 200 mg Once Daily

Drug: MK-1775 (AZD1775)
MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
Other Names:
  • Adavosertib
  • Experimental: ARM 2 AZD1775 225 mg Once Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 3 AZD1775 225 mg Twice Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing)

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 5 AZD1775 250 mg Once Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 6 AZD1775 300 mg Once Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 7 AZD1775 300 mg Twice Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 8 AZD1775 400 mg Once Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Experimental: ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily

    Drug: MK-1775 (AZD1775)
    MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
    Other Names:
  • Adavosertib
  • Outcome Measures

    Primary Outcome Measures

    1. To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors [Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.]

      Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    2. Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors [Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.]

      Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening.

    3. To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. [Pre-Treatment (Baseline) and Cycle 1 Days 1 and 3 (Arms 3 and 7) or Days 1 and 5 (Arms 1-2, 5-6, and 8)]

      Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration.

    Secondary Outcome Measures

    1. To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors [21 days]

      Objective Response is defined as a Complete Response + Partial Response and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

    Other Outcome Measures

    1. Number of Participants With a Dose-Limiting Toxicity (DLT) [First cycle (21 days) of treatment]

      DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of MK-1775 (Adavosertib (AZD1775). Examples are Grade ≥ 3 non-hematological toxicity, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding, Grade 3 fatigue of greater than 1 week duration, and failure to tolerate 100% of the dosing in the first cycle will be considered a DLT, etc.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 120 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    • ELIGIBILITY CRITERIA:

    • Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed or for which standard therapies do not exist.

    • Patients must have measurable disease or evaluable disease for the escalation phase; for the 6 additional patients enrolled at maximum tolerated dose (MTD) for further evaluation of pharmacokinetics (PK) and pharmacodynamics (PD) endpoints (Expansion Cohort A). For the 6-patient breast cancer gene (BRCA)-mutation expansion cohort, patients must have measurable disease; however, tumor biopsies are optional. For Expansion Cohort B, patients must have tumor amenable to biopsy (excisional or incision biopsies of skin or head (H) & neck (N) lesions under visualization) and willingness to undergo a tumor biopsy or patient will be undergoing a procedure due to medical necessity during which the tissue may be collected, or tumor biopsy tissue from a previous research study or medical care is available for submission at registration. Criteria for the submission of tissue are:

    • Tissue must have been collected within 3 months prior to registration

    • Patient has not received any intervening therapy for their cancer since the collection of the tumor sample

    • Tumor tissue must meet the minimum requirements

    • Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic therapy greater than or equal to 3 weeks (or > 5 half-lives, whichever is shorter) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in an exploratory Investigational New Drug (IND)/Phase 0 study or more than or equal to 1 week from palliative radiation therapy. Patients must have recovered to eligibility levels from prior toxicity or adverse events.

    • Age greater than or equal to 18 years of age.

    • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky >60%)

    • Life expectancy of greater than 3 months.

    • Patients must have normal organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL

    • absolute neutrophil count greater than or equal to 1,500/mcL

    • platelets greater than or equal to 100,000/mcL

    • hemoglobin >9 g/dL

    • total bilirubin less than or equal to 1.5 times institutional upper limit of normal

    • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (SGPT) less than or equal to 3 times institutional upper limit of normal

    • creatinine less than or equal to 1.5 times institutional upper limit of normal OR

    • creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

    • The effects of Adavosertib (AZD1775) on the developing human fetus are unknown. For this reason and because molecular inhibitors of Wee1 kinase are known to be teratogenic, women of child-bearing potential (WoCBP) may be included only if acceptable contraception is in place for two weeks before study entry, for the duration of the treatment with the study drug, and for 2 months after the last dose of AZD1775. Male patients who are involved in the study must agree to avoid procreative and unprotected sex (i.e., by using acceptable forms of contraception) and must not donate sperm during the study and for 3 months after the last dose of AZD1775. Where the female partner is pregnant or not using effective birth control, men should be advised to abstain while in the study and for 3 months after the last dose of AZD1775. Female partners, who are of child-bearing potential, of men participating in clinical studies of AZD1775 will also be required to use effective contraceptive measures while their partner is on study drug and for 3 months thereafter. Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children while on AZD1775 or during the 3 months after stopping AZD1775.

    • Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first of study drug and women should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

    • Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube administration is not allowed. Any gastrointestinal disease which would impair ability to swallow, retain, or absorb drug is not allowed.

    • Ability to understand and the willingness to sign a written informed consent document.

    • Patients with prostate cancer can continue to receive treatment with gonadotropin-releasing hormone (GnRH) agonists while on study, as long as there is evidence of disease progression on therapy.

    EXCLUSION CRITERIA:
    • Patients who are receiving any other investigational agents.

    • Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.

    • Eligibility of subjects receiving any medications or substances with the potential to affect the activity or pharmacokinetics of AZD1775 will be determined following review by the principal investigator.

    • Patients receiving any medications or substances that are inhibitors or inducers of Cytochrome P450 3A4 (CYP3A4), or CYP3A4 substrates need to be reviewed by the principal investigator. Continuation of such medications will be at the discretion of the principal investigator. Concomitant use of aprepitant or fosaprepitant is prohibited. As grapefruit and Seville oranges are known to contain moderate inhibitors of CYP3A4, these fruits or their products (including marmalade, juice, etc.) should be avoided while taking AZD1775. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this study. Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to: St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng.

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

    • Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown.

    • Human immunodeficiency virus (HIV) positive patients on antiretroviral therapy are ineligible because of the potential for pharmacokinetics (PK) interactions.

    INCLUSION OF WOMEN AND MINORITIES:

    Both men and women of all races and ethnic groups are eligible for this trial.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Naoko Takebe, M.D., National Cancer Institute (NCI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01748825
    Other Study ID Numbers:
    • 130032
    • 13-C-0032
    First Posted:
    Dec 13, 2012
    Last Update Posted:
    Jul 26, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily
    Period Title: Dose Escalation
    STARTED 6 4 6 3 3 6 3 3 0 0
    COMPLETED 4 2 6 2 2 4 2 3 0 0
    NOT COMPLETED 2 2 0 1 1 2 1 0 0 0
    Period Title: Dose Escalation
    STARTED 0 0 0 0 0 0 0 0 13 20
    COMPLETED 0 0 0 0 0 0 0 0 11 15
    NOT COMPLETED 0 0 0 0 0 0 0 0 2 5

    Baseline Characteristics

    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily Total
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily Total of all reporting groups
    Overall Participants 6 4 6 3 3 6 3 3 13 20 67
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    50%
    2
    50%
    5
    83.3%
    3
    100%
    3
    100%
    4
    66.7%
    2
    66.7%
    2
    66.7%
    12
    92.3%
    8
    40%
    44
    65.7%
    >=65 years
    3
    50%
    2
    50%
    1
    16.7%
    0
    0%
    0
    0%
    2
    33.3%
    1
    33.3%
    1
    33.3%
    1
    7.7%
    12
    60%
    23
    34.3%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58.17
    (19)
    58.13
    (21.56)
    46.18
    (19.26)
    48.4
    (20.88)
    58.33
    (4.1)
    56.97
    (15.39)
    65.07
    (10.51)
    63.13
    (14.74)
    51.49
    (10.82)
    65.59
    (8.57)
    58
    (14.38)
    Sex: Female, Male (Count of Participants)
    Female
    3
    50%
    1
    25%
    1
    16.7%
    3
    100%
    1
    33.3%
    4
    66.7%
    1
    33.3%
    2
    66.7%
    12
    92.3%
    16
    80%
    44
    65.7%
    Male
    3
    50%
    3
    75%
    5
    83.3%
    0
    0%
    2
    66.7%
    2
    33.3%
    2
    66.7%
    1
    33.3%
    1
    7.7%
    4
    20%
    23
    34.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    0
    0%
    2
    3%
    Not Hispanic or Latino
    5
    83.3%
    4
    100%
    6
    100%
    3
    100%
    3
    100%
    6
    100%
    3
    100%
    3
    100%
    12
    92.3%
    19
    95%
    64
    95.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5%
    1
    1.5%
    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%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    16.7%
    1
    25%
    1
    16.7%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    2
    10%
    7
    10.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    3
    15%
    4
    6%
    White
    3
    50%
    3
    75%
    5
    83.3%
    2
    66.7%
    3
    100%
    5
    83.3%
    3
    100%
    3
    100%
    12
    92.3%
    15
    75%
    54
    80.6%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Region of Enrollment (participants) [Number]
    United States
    6
    100%
    4
    100%
    6
    100%
    3
    100%
    3
    100%
    6
    100%
    3
    100%
    3
    100%
    13
    100%
    20
    100%
    67
    100%
    Tumor Type (Count of Participants)
    Ovarian carcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    1
    16.7%
    0
    0%
    2
    66.7%
    4
    30.8%
    6
    30%
    14
    20.9%
    Endometrial carcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    15%
    3
    4.5%
    Mesothelioma
    1
    16.7%
    2
    50%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    6%
    Breast carcinoma
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    2
    33.3%
    0
    0%
    0
    0%
    3
    23.1%
    2
    10%
    8
    11.9%
    Alveolar soft part sarcoma
    1
    16.7%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Colon adenocarcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    1
    5%
    2
    3%
    Leiomyosarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    1
    5%
    2
    3%
    Pancreatic carcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    1
    5%
    2
    3%
    Prostate carcinoma
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Bladder carcinoma
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Cervical carcinoma
    1
    16.7%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Cholangiocarcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5%
    1
    1.5%
    Endometrial carcinosarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Liposarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    1
    5%
    2
    3%
    Pleomorphic sarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5%
    1
    1.5%
    Synovial cell sarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Uterine carcinosarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    10%
    2
    3%
    Non-small cell lung cancer
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    1
    5%
    3
    4.5%
    Papillary serous ovarian carcinoma
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    0
    0%
    2
    3%
    Squamous cell carcinoma
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Synovial cell carcinoma
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Hepatocellular carcinoma
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Malignant fibrous histiocytoma sarcoma
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Salivary adenocarcinoma
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Ewing sarcoma
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Fallopian tube carcinoma
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Sinonasal leiomyosarcoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Atypical granular cell paraspinal
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Peritoneal carcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    1
    7.7%
    0
    0%
    2
    3%
    Embryonal cell
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    0
    0%
    1
    1.5%
    Appendiceal carcinoma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    0
    0%
    1
    1.5%
    Eastern Cooperative Oncology Score (ECOG) (Count of Participants)
    0
    1
    16.7%
    0
    0%
    1
    16.7%
    1
    33.3%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    15%
    7
    10.4%
    1
    5
    83.3%
    4
    100%
    5
    83.3%
    2
    66.7%
    2
    66.7%
    6
    100%
    3
    100%
    3
    100%
    13
    100%
    17
    85%
    60
    89.6%
    Median Number of Prior Therapies (prior therapy) [Median (Full Range) ]
    Median (Full Range) [prior therapy]
    5
    3.5
    7.5
    11
    4
    3
    2
    15
    7
    8
    7

    Outcome Measures

    1. Primary Outcome
    Title To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors
    Description Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
    Time Frame Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily
    Measure Participants 6 4 6 3 3 6 3 3 13 20
    Count of Participants [Participants]
    6
    100%
    4
    100%
    6
    100%
    3
    100%
    3
    100%
    6
    100%
    3
    100%
    3
    100%
    13
    100%
    20
    100%
    2. Primary Outcome
    Title Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors
    Description Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening.
    Time Frame Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily
    Measure Participants 6 4 6 3 3 6 3 3 13 20
    Grade 1-2 Anemia
    50
    833.3%
    75
    1875%
    50
    833.3%
    67
    2233.3%
    33
    1100%
    67
    1116.7%
    67
    2233.3%
    100
    3333.3%
    69
    530.8%
    60
    300%
    Grade 3 Anemia
    33
    550%
    25
    625%
    17
    283.3%
    67
    2233.3%
    0
    0%
    33
    550%
    33
    1100%
    67
    2233.3%
    15
    115.4%
    30
    150%
    Grade 1-2 Lymphopenia
    50
    833.3%
    75
    1875%
    67
    1116.7%
    67
    2233.3%
    33
    1100%
    67
    1116.7%
    67
    2233.3%
    67
    2233.3%
    54
    415.4%
    80
    400%
    Grade 3 Lymphopenia
    50
    833.3%
    25
    625%
    17
    283.3%
    33
    1100%
    33
    1100%
    17
    283.3%
    33
    1100%
    67
    2233.3%
    8
    61.5%
    25
    125%
    Grade 4 Lymphopenia
    0
    0%
    0
    0%
    0
    0%
    33
    1100%
    0
    0%
    0
    0%
    33
    1100%
    0
    0%
    0
    0%
    10
    50%
    Grade 1-2 Neutropenia
    17
    283.3%
    25
    625%
    17
    283.3%
    0
    0%
    33
    1100%
    17
    283.3%
    33
    1100%
    100
    3333.3%
    23
    176.9%
    25
    125%
    Grade 3 Neutropenia
    17
    283.3%
    25
    625%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    33
    1100%
    67
    2233.3%
    8
    61.5%
    30
    150%
    Grade 4 Neutropenia
    17
    283.3%
    0
    0%
    0
    0%
    33
    1100%
    0
    0%
    0
    0%
    33
    1100%
    33
    1100%
    0
    0%
    20
    100%
    3. Primary Outcome
    Title To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors.
    Description Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration.
    Time Frame Pre-Treatment (Baseline) and Cycle 1 Days 1 and 3 (Arms 3 and 7) or Days 1 and 5 (Arms 1-2, 5-6, and 8)

    Outcome Measure Data

    Analysis Population Description
    Participants are grouped by dose level. Arm 3 represents combined data for patients receiving 225 mg twice daily on days 1-2 and once on day 3 of each 21-day cycle and for patients receiving 225 mg twice daily on days 1-2 and 8-9 and once on days 3 and 10 (the latter includes both dose escalation and expansion phase patients); these data are combined because all of these patients received the same dose over the pharmacokinetic analysis period (cycle 1 days 1-3).
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily
    Arm/Group Description Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 200 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 225 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 225 mg twice daily on cycle 1 days 1-2, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 250 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 300 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 300 mg twice daily on cycle 1 days 1-2, during which the plasma concentrations of AZD1775 were evaluated. Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 400 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.
    Measure Participants 4 3 15 3 6 3 3
    Pre-Treatment (Baseline)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    Cycle 1 Day 1, 1 hour post-dose
    135
    (230)
    577
    (248)
    262
    (257)
    539
    (236)
    426
    (377)
    452
    (402)
    641
    (452)
    Cycle 1 Day 1, 2 hours post-dose
    402
    (327)
    1017
    (442)
    592
    (354)
    766
    (36)
    997
    (703)
    878
    (263)
    1407
    (314)
    Cycle 1 Day 1, 4 hours post-dose
    600
    (18)
    876
    (420)
    661
    (212)
    636
    (43)
    979
    (491)
    975
    (361)
    1757
    (351)
    Cycle 1 Day 1, 6 hours post-dose
    579
    (152)
    677
    (351)
    556
    (210)
    462
    (23)
    744
    (412)
    780
    (222)
    1537
    (469)
    Cycle 1 Day 1, 8 hours post-dose
    416
    (153)
    521
    (232)
    422
    (180)
    276
    (101)
    604
    (373)
    586
    (209)
    1063
    (256)
    Cycle 1 Day 3, pre-dose
    NA
    (NA)
    NA
    (NA)
    776
    (341)
    NA
    (NA)
    NA
    (NA)
    1560
    (414)
    NA
    (NA)
    Cycle 1 Day 3, 1 hour post-dose
    NA
    (NA)
    NA
    (NA)
    983
    (522)
    NA
    (NA)
    NA
    (NA)
    2090
    (403)
    NA
    (NA)
    Cycle 1 Day 3, 2 hours post-dose
    NA
    (NA)
    NA
    (NA)
    1350
    (673)
    NA
    (NA)
    NA
    (NA)
    2440
    (571)
    NA
    (NA)
    Cycle 1 Day 3, 4 hours post-dose
    NA
    (NA)
    NA
    (NA)
    1440
    (655)
    NA
    (NA)
    NA
    (NA)
    2450
    (583)
    NA
    (NA)
    Cycle 1 Day 3, 6 hours post-dose
    NA
    (NA)
    NA
    (NA)
    1210
    (633)
    NA
    (NA)
    NA
    (NA)
    2190
    (437)
    NA
    (NA)
    Cycle 1 Day 3, 8 hours post-dose
    NA
    (NA)
    NA
    (NA)
    1030
    (509)
    NA
    (NA)
    NA
    (NA)
    1980
    (455)
    NA
    (NA)
    Cycle 1 Day 5, pre-dose
    235
    (55)
    325
    (231)
    NA
    (NA)
    167
    (48)
    237
    (82)
    NA
    (NA)
    671
    (156)
    Cycle 1 Day 5, 1 hour post-dose
    461
    (108)
    961
    (492)
    NA
    (NA)
    734
    (88)
    774
    (394)
    NA
    (NA)
    1970
    (301)
    Cycle 1 Day 5, 2 hours post-dose
    782
    (83)
    1128
    (465)
    NA
    (NA)
    1135
    (266)
    1697
    (1062)
    NA
    (NA)
    3036
    (572)
    Cycle 1 Day 5, 4 hours post-dose
    952
    (66)
    1115
    (440)
    NA
    (NA)
    1114
    (238)
    1638
    (860)
    NA
    (NA)
    2597
    (211)
    Cycle 1 Day 5, 6 hours post-dose
    790
    (95)
    985
    (441)
    NA
    (NA)
    787
    (177)
    1222
    (491)
    NA
    (NA)
    2062
    (511)
    Cycle 1 Day 5, 8 hours post-dose
    597
    (79)
    892
    (367)
    NA
    (NA)
    605
    (147)
    965
    (388)
    NA
    (NA)
    1697
    (115)
    4. Secondary Outcome
    Title To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors
    Description Objective Response is defined as a Complete Response + Partial Response and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
    Time Frame 21 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily
    Measure Participants 6 4 6 3 3 6 3 3 13 20
    Complete Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial Response
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    66.7%
    1
    7.7%
    4
    20%
    5. Other Pre-specified Outcome
    Title Number of Participants With a Dose-Limiting Toxicity (DLT)
    Description DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of MK-1775 (Adavosertib (AZD1775). Examples are Grade ≥ 3 non-hematological toxicity, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding, Grade 3 fatigue of greater than 1 week duration, and failure to tolerate 100% of the dosing in the first cycle will be considered a DLT, etc.
    Time Frame First cycle (21 days) of treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily
    Measure Participants 6 4 6 3 3 6 3 3
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    66.7%
    0
    0%

    Adverse Events

    Time Frame Date treatment consent signed to date off study, approximately 19 mo. & 8 days for Arm 1, 3 mo. & 28 days for Arm 2, 10 mo. & 28 days for Arm 3, 2 mo. & 14 days for Arm 4, 20 mo. & 24 days for Arm 5, 10 mo. & 23 days for Arm 6, 4 mo. & 23 days for Arm 7, 14 mo. & 11 days for Arm 8, 15 mo. & 24 days for Arm 9, and 77 mo. & 6 days for Arm 10.
    Adverse Event Reporting Description
    Arm/Group Title ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    Arm/Group Description Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily
    All Cause Mortality
    ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/13 (0%) 3/20 (15%)
    Serious Adverse Events
    ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/6 (33.3%) 2/4 (50%) 3/6 (50%) 2/3 (66.7%) 0/3 (0%) 3/6 (50%) 2/3 (66.7%) 3/3 (100%) 5/13 (38.5%) 16/20 (80%)
    Blood and lymphatic system disorders
    Anemia 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 2 0/13 (0%) 0 1/20 (5%) 1
    Febrile neutropenia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/13 (0%) 0 0/20 (0%) 0
    Cardiac disorders
    Sinus tachycardia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Supraventricular tachycardia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 1/20 (5%) 1
    Ascites 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 0/20 (0%) 0
    Colonic fistula 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Constipation 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Diarrhea 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 2/20 (10%) 2
    Gastrointestinal disorders - Other, Gastrointestinal DIS;Hernia Wrapped around bowel 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Nausea 1/6 (16.7%) 1 0/4 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 2/20 (10%) 2
    Pancreatitis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Rectal hemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Rectal obstruction 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Small intestinal obstruction 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Vomiting 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 2/20 (10%) 2
    General disorders
    Death NOS 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Disease progression 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Fatigue 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Fever 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Infections and infestations
    Bronchial infection 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Lung infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Periorbital infection 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Sepsis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 2 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Upper respiratory infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Urinary tract infection 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Injury, poisoning and procedural complications
    Acute kidney injury 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Fall 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Fracture 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Spinal fracture 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Investigations
    Creatinine increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Ejection fraction decreased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Lymphocyte count decreased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Neutrophil count decreased 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/13 (7.7%) 1 2/20 (10%) 3
    Platelet count decreased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/13 (0%) 0 1/20 (5%) 1
    White blood cell decreased 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 1/20 (5%) 2
    Metabolism and nutrition disorders
    Anorexia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Dehydration 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 2 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hyperglycemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Hypocalcemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Hypokalemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hypomagnesemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 0/20 (0%) 0
    Hyponatremia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 2/20 (10%) 2
    Hypophosphatemia 1/6 (16.7%) 2 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 1/20 (5%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Tumor pain 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Nervous system disorders
    Dizziness 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Headache 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Paresthesia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Stroke 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Psychiatric disorders
    Confusion 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Renal and urinary disorders
    Hematuria 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Bronchial stricture 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Cough 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Dyspnea 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 2 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Hypoxia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Pleural effusion 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Pneumothorax 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Productive cough 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, Respiratory - Pneumonia 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Wheezing 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Surgical and medical procedures
    Surgical and medical procedures - Other, Surgical and medical procedures - Pleurodesis, pleurx 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Surgical and medical procedures - Other, Surgical and medical procedures - Thoracentesis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 2 0/20 (0%) 0
    Vascular disorders
    Hypertension 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 4/20 (20%) 4
    Hypotension 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Thromboembolic event 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Other (Not Including Serious) Adverse Events
    ARM 1 AZD1775 200 mg Once Daily ARM 2 AZD1775 225 mg Once Daily ARM 3 AZD1775 225 mg Twice Daily ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) ARM 5 AZD1775 250 mg Once Daily ARM 6 AZD1775 300 mg Once Daily ARM 7 AZD1775 300 mg Twice Daily ARM 8 AZD1775 400 mg Once Daily ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 4/4 (100%) 6/6 (100%) 3/3 (100%) 3/3 (100%) 6/6 (100%) 3/3 (100%) 3/3 (100%) 13/13 (100%) 20/20 (100%)
    Blood and lymphatic system disorders
    Anemia 4/6 (66.7%) 7 3/4 (75%) 5 3/6 (50%) 5 3/3 (100%) 7 1/3 (33.3%) 1 4/6 (66.7%) 14 3/3 (100%) 5 3/3 (100%) 24 9/13 (69.2%) 23 17/20 (85%) 47
    Cardiac disorders
    Electrocardiogram QT corrected interval prolonged 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 3/13 (23.1%) 3 0/20 (0%) 0
    Palpitations 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 2 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Sinus bradycardia 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 1/20 (5%) 2
    Sinus tachycardia 0/6 (0%) 0 0/4 (0%) 0 3/6 (50%) 3 1/3 (33.3%) 3 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 4/20 (20%) 4
    Ear and labyrinth disorders
    Ear pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 1/20 (5%) 1
    Hearing impaired 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Otitis externa 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Tinnitus 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 0/20 (0%) 0
    Vertigo 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Eye disorders
    Blurred vision 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Dry eye 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Eye pain 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Flashing lights 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Floaters 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Periorbital edema 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Watering eyes 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 0 1/4 (25%) 1 2/6 (33.3%) 4 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 1 5/13 (38.5%) 9 4/20 (20%) 6
    Anal fissure 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Bloating 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 1 3/13 (23.1%) 8 0/20 (0%) 0
    Constipation 0/6 (0%) 0 1/4 (25%) 1 3/6 (50%) 6 1/3 (33.3%) 2 2/3 (66.7%) 3 0/6 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 3 3/13 (23.1%) 4 7/20 (35%) 13
    Dental caries 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Diarrhea 4/6 (66.7%) 13 2/4 (50%) 6 4/6 (66.7%) 21 2/3 (66.7%) 2 3/3 (100%) 11 4/6 (66.7%) 6 2/3 (66.7%) 2 3/3 (100%) 7 12/13 (92.3%) 47 14/20 (70%) 24
    Dyspepsia 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 3 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 2/20 (10%) 2
    Flatulence 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/13 (23.1%) 4 1/20 (5%) 1
    Gastric hemorrhage 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Gastritis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Gastroesophageal reflux disease 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Gastrointestinal disorders - Other, specify 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Mucositis oral 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/13 (7.7%) 1 1/20 (5%) 1
    Nausea 6/6 (100%) 12 4/4 (100%) 8 4/6 (66.7%) 17 2/3 (66.7%) 5 3/3 (100%) 11 2/6 (33.3%) 3 1/3 (33.3%) 1 3/3 (100%) 4 11/13 (84.6%) 49 16/20 (80%) 26
    Oral pain 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Rectal hemorrhage 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Stomach pain 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 2 1/20 (5%) 1
    Vomiting 4/6 (66.7%) 13 3/4 (75%) 6 5/6 (83.3%) 11 1/3 (33.3%) 3 2/3 (66.7%) 4 3/6 (50%) 3 1/3 (33.3%) 1 3/3 (100%) 3 9/13 (69.2%) 31 15/20 (75%) 25
    General disorders
    Chills 1/6 (16.7%) 1 1/4 (25%) 1 1/6 (16.7%) 2 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/13 (15.4%) 3 2/20 (10%) 2
    Edema face 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Edema limbs 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 2/3 (66.7%) 2 1/13 (7.7%) 3 2/20 (10%) 2
    Fatigue 4/6 (66.7%) 8 2/4 (50%) 2 3/6 (50%) 3 2/3 (66.7%) 2 2/3 (66.7%) 3 1/6 (16.7%) 1 1/3 (33.3%) 1 2/3 (66.7%) 2 2/13 (15.4%) 3 13/20 (65%) 19
    Fever 0/6 (0%) 0 2/4 (50%) 2 2/6 (33.3%) 2 2/3 (66.7%) 2 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 2/13 (15.4%) 2 1/20 (5%) 1
    Flu like symptoms 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 3 3/3 (100%) 6 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 4/13 (30.8%) 5 1/20 (5%) 1
    Gait disturbance 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Irritability 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Malaise 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Pain 0/6 (0%) 0 0/4 (0%) 0 3/6 (50%) 6 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, Hepatobiliary disorders - fatty liver 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Immune system disorders
    Allergic reaction 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Infections and infestations
    Bronchial infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Gum infection 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Infections and infestations - Other, Infections and infestations - MRSA at hospital 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 0/20 (0%) 0
    Lip infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Lung infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Nail infection 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Periorbital infection 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Pharyngitis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/13 (0%) 0 0/20 (0%) 0
    Sinusitis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Upper respiratory infection 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Urinary tract infection 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 2/13 (15.4%) 2 3/20 (15%) 3
    Injury, poisoning and procedural complications
    Bruising 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Fall 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Investigations
    Activated partial thromboplastin time prolonged 3/6 (50%) 5 4/4 (100%) 5 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 3 1/6 (16.7%) 3 0/3 (0%) 0 2/3 (66.7%) 3 0/13 (0%) 0 3/20 (15%) 3
    Alanine aminotransferase increased 2/6 (33.3%) 2 0/4 (0%) 0 4/6 (66.7%) 7 0/3 (0%) 0 2/3 (66.7%) 6 3/6 (50%) 3 1/3 (33.3%) 1 1/3 (33.3%) 1 4/13 (30.8%) 6 3/20 (15%) 6
    Alkaline phosphatase increased 4/6 (66.7%) 8 3/4 (75%) 3 3/6 (50%) 5 1/3 (33.3%) 1 0/3 (0%) 0 3/6 (50%) 5 1/3 (33.3%) 1 2/3 (66.7%) 4 4/13 (30.8%) 5 8/20 (40%) 13
    Aspartate aminotransferase increased 1/6 (16.7%) 6 1/4 (25%) 1 4/6 (66.7%) 5 0/3 (0%) 0 1/3 (33.3%) 6 2/6 (33.3%) 3 1/3 (33.3%) 1 1/3 (33.3%) 2 3/13 (23.1%) 5 7/20 (35%) 9
    Blood bilirubin increased 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 4/20 (20%) 5
    Blood lactate dehydrogenase increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Cardiac troponin I increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Cholesterol high 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Creatinine increased 2/6 (33.3%) 3 1/4 (25%) 2 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 3 2/6 (33.3%) 6 2/3 (66.7%) 3 2/3 (66.7%) 2 2/13 (15.4%) 3 4/20 (20%) 8
    GGT increased 1/6 (16.7%) 1 1/4 (25%) 1 4/6 (66.7%) 5 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Investigations - Other, Gamma Glutamyl Transferase increased )GGT) 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Investigations - Other, Protein total decreased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Lipase increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 4 0/20 (0%) 0
    Lymphocyte count decreased 5/6 (83.3%) 12 3/4 (75%) 12 4/6 (66.7%) 9 3/3 (100%) 5 2/3 (66.7%) 10 4/6 (66.7%) 12 2/3 (66.7%) 3 2/3 (66.7%) 28 7/13 (53.8%) 11 18/20 (90%) 47
    Lymphocyte count increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Neutrophil count decreased 0/6 (0%) 0 1/4 (25%) 2 1/6 (16.7%) 2 0/3 (0%) 0 1/3 (33.3%) 7 1/6 (16.7%) 1 2/3 (66.7%) 3 3/3 (100%) 17 4/13 (30.8%) 11 7/20 (35%) 20
    Platelet count decreased 2/6 (33.3%) 4 1/4 (25%) 1 3/6 (50%) 4 2/3 (66.7%) 4 1/3 (33.3%) 1 2/6 (33.3%) 10 2/3 (66.7%) 4 3/3 (100%) 23 6/13 (46.2%) 20 10/20 (50%) 31
    Serum amylase increased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 2 0/20 (0%) 0
    Urine output decreased 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Weight gain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Weight loss 0/6 (0%) 0 0/4 (0%) 0 3/6 (50%) 3 0/3 (0%) 0 1/3 (33.3%) 2 1/6 (16.7%) 1 2/3 (66.7%) 2 0/3 (0%) 0 3/13 (23.1%) 3 2/20 (10%) 3
    White blood cell decreased 1/6 (16.7%) 1 1/4 (25%) 2 3/6 (50%) 6 3/3 (100%) 6 1/3 (33.3%) 7 2/6 (33.3%) 3 3/3 (100%) 3 2/3 (66.7%) 23 7/13 (53.8%) 14 14/20 (70%) 37
    Metabolism and nutrition disorders
    Anorexia 4/6 (66.7%) 4 1/4 (25%) 1 3/6 (50%) 5 2/3 (66.7%) 2 2/3 (66.7%) 2 0/6 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 6/13 (46.2%) 14 11/20 (55%) 16
    Dehydration 1/6 (16.7%) 2 3/4 (75%) 5 1/6 (16.7%) 2 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 3 1/3 (33.3%) 1 1/13 (7.7%) 1 3/20 (15%) 3
    Hypercalcemia 3/6 (50%) 5 1/4 (25%) 2 2/6 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 3 1/3 (33.3%) 2 1/3 (33.3%) 1 2/13 (15.4%) 3 2/20 (10%) 3
    Hyperglycemia 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 5 0/3 (0%) 0 2/3 (66.7%) 2 0/13 (0%) 0 9/20 (45%) 21
    Hyperkalemia 1/6 (16.7%) 1 2/4 (50%) 4 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/13 (7.7%) 1 2/20 (10%) 2
    Hypermagnesemia 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Hypernatremia 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 2/20 (10%) 4
    Hyperphosphatemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Hypertriglyceridemia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 1/20 (5%) 1
    Hyperuricemia 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hypoalbuminemia 3/6 (50%) 14 2/4 (50%) 4 4/6 (66.7%) 6 2/3 (66.7%) 4 2/3 (66.7%) 4 4/6 (66.7%) 9 1/3 (33.3%) 1 3/3 (100%) 11 9/13 (69.2%) 14 15/20 (75%) 32
    Hypocalcemia 0/6 (0%) 0 1/4 (25%) 2 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 1 2/6 (33.3%) 3 1/3 (33.3%) 1 2/3 (66.7%) 2 0/13 (0%) 0 3/20 (15%) 4
    Hypokalemia 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 8 0/3 (0%) 0 1/6 (16.7%) 5 1/3 (33.3%) 1 3/3 (100%) 9 4/13 (30.8%) 4 4/20 (20%) 5
    Hypomagnesemia 2/6 (33.3%) 4 0/4 (0%) 0 1/6 (16.7%) 4 0/3 (0%) 0 0/3 (0%) 0 3/6 (50%) 6 0/3 (0%) 0 2/3 (66.7%) 8 4/13 (30.8%) 8 5/20 (25%) 12
    Hyponatremia 2/6 (33.3%) 5 2/4 (50%) 5 0/6 (0%) 0 1/3 (33.3%) 3 1/3 (33.3%) 2 3/6 (50%) 7 2/3 (66.7%) 2 2/3 (66.7%) 2 2/13 (15.4%) 3 8/20 (40%) 13
    Hypophosphatemia 4/6 (66.7%) 8 1/4 (25%) 1 1/6 (16.7%) 2 0/3 (0%) 0 1/3 (33.3%) 1 2/6 (33.3%) 6 0/3 (0%) 0 3/3 (100%) 3 4/13 (30.8%) 6 6/20 (30%) 7
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Arthritis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Back pain 1/6 (16.7%) 1 0/4 (0%) 0 2/6 (33.3%) 2 2/3 (66.7%) 2 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 1/13 (7.7%) 2 2/20 (10%) 2
    Flank pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Generalized muscle weakness 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Musculoskeletal and connective tissue disorder - Other, Cramping of feet 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Myalgia 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 3 1/3 (33.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 2 1/20 (5%) 1
    Neck pain 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/13 (15.4%) 3 1/20 (5%) 1
    Non-cardiac chest pain 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 2 1/20 (5%) 1
    Pain in extremity 1/6 (16.7%) 1 1/4 (25%) 1 2/6 (33.3%) 2 0/3 (0%) 0 2/3 (66.7%) 6 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 0/20 (0%) 0
    Trismus 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Metastatic brain Lesion 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Tumor pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 2 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Nervous system disorders
    Akathisia 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Cognitive disturbance 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Dizziness 0/6 (0%) 0 2/4 (50%) 2 2/6 (33.3%) 2 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 2 0/3 (0%) 0 1/3 (33.3%) 2 1/13 (7.7%) 1 6/20 (30%) 7
    Dysgeusia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/13 (23.1%) 5 1/20 (5%) 1
    Dysphasia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Headache 0/6 (0%) 0 1/4 (25%) 2 3/6 (50%) 4 0/3 (0%) 0 2/3 (66.7%) 11 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 2 3/13 (23.1%) 4 2/20 (10%) 2
    Memory impairment 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Nervous system disorders - Other, Burnt Smell/Smell sensitivity 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Nervous system disorders - Other, Nervous system disorder - "hangover" 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Nervous system disorders - Other, Nervous system disorders - "foggy and dazed" 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Paresthesia 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 2 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Peripheral sensory neuropathy 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 3/20 (15%) 4
    Somnolence 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Stroke 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Tremor 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Psychiatric disorders
    Anxiety 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 2
    Confusion 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Insomnia 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 2/3 (66.7%) 2 0/3 (0%) 0 2/13 (15.4%) 2 1/20 (5%) 1
    Renal and urinary disorders
    Dysuria 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 2
    Hematuria 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Hemoglobinuria 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Proteinuria 1/6 (16.7%) 1 1/4 (25%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 1/20 (5%) 1
    Renal and urinary disorders - Other, Renal and urinary disorders - prostatitis 0/6 (0%) 0 1/4 (25%) 2 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Urinary frequency 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Urinary incontinence 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 5/20 (25%) 5
    Urinary retention 1/6 (16.7%) 1 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Urinary tract pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/13 (15.4%) 2 0/20 (0%) 0
    Urine discoloration 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Reproductive system and breast disorders
    Breast pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Vaginal hemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Aspiration 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Atelectasis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Bronchopulmonary hemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Cough 1/6 (16.7%) 1 0/4 (0%) 0 1/6 (16.7%) 1 2/3 (66.7%) 2 1/3 (33.3%) 1 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 4/20 (20%) 4
    Dyspnea 2/6 (33.3%) 2 2/4 (50%) 2 1/6 (16.7%) 1 2/3 (66.7%) 2 1/3 (33.3%) 1 1/6 (16.7%) 2 0/3 (0%) 0 2/3 (66.7%) 3 1/13 (7.7%) 1 5/20 (25%) 6
    Epistaxis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hypoxia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Nasal congestion 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Pleural effusion 0/6 (0%) 0 1/4 (25%) 1 0/6 (0%) 0 2/3 (66.7%) 5 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 2/20 (10%) 2
    Pleuritic pain 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Pneumothorax 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Postnasal drip 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Productive cough 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Rhinorrhea 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Sore throat 0/6 (0%) 0 0/4 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 1 0/20 (0%) 0
    Voice alteration 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Wheezing 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders
    Alopecia 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Dry skin 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hyperhidrosis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Nail loss 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Pain of skin 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 3 0/20 (0%) 0
    Photosensitivity 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Pruritus 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/3 (33.3%) 2 0/13 (0%) 0 0/20 (0%) 0
    Rash acneiform 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Rash maculo-papular 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/13 (0%) 0 0/20 (0%) 0
    Skin and subcutaneous tissue disorders - Other, Cellulitis (R leg) 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders - Other, specify 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/13 (7.7%) 1 0/20 (0%) 0
    Skin ulceration 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1
    Surgical and medical procedures
    Surgical and medical procedures - Other, Surgical and medical procedure - tooth extraction 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Vascular disorders
    Flushing 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/13 (0%) 0 0/20 (0%) 0
    Hot flashes 1/6 (16.7%) 1 0/4 (0%) 0 2/6 (33.3%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/13 (7.7%) 2 0/20 (0%) 0
    Hypertension 0/6 (0%) 0 2/4 (50%) 3 6/6 (100%) 13 3/3 (100%) 6 2/3 (66.7%) 5 0/6 (0%) 0 2/3 (66.7%) 7 3/3 (100%) 4 5/13 (38.5%) 14 12/20 (60%) 36
    Hypotension 0/6 (0%) 0 0/4 (0%) 0 1/6 (16.7%) 1 2/3 (66.7%) 5 0/3 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 2 1/3 (33.3%) 1 1/13 (7.7%) 1 4/20 (20%) 4
    Vascular disorders - Other, Atherosclerosis 0/6 (0%) 0 0/4 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/13 (0%) 0 1/20 (5%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Naoko Takebe
    Organization National Cancer Institute
    Phone 240-781-3320
    Email takeben@nih.gov
    Responsible Party:
    Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01748825
    Other Study ID Numbers:
    • 130032
    • 13-C-0032
    First Posted:
    Dec 13, 2012
    Last Update Posted:
    Jul 26, 2021
    Last Verified:
    Jun 1, 2021