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Vevorisertib (ARQ 751) as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (MK-4440-001)

Sponsor
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
Overall Status
Terminated
CT.gov ID
NCT02761694
Collaborator
(none)
78
Enrollment
6
Locations
12
Arms
56.4
Actual Duration (Months)
13
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of this study are: Part 1 - Vevorisertib as single agent: To assess the safety and tolerability of vevorisertib in participants with advanced solid tumors with v-Akt murine thymoma viral oncogene homolog (AKT) 1, 2, 3 genetic alterations, activating phosphatidylinositol-3-kinase (PI3K) mutations, phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null, or other known actionable PTEN mutations; Part 2 - Vevorisertib in combination with other anti-cancer agents: To assess the safety and tolerability of vevorisertib in combination with paclitaxel or fulvestrant in participants with advanced, inoperable, metastatic and/or recurrent solid tumors with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) / PTEN actionable mutations and/or AKT genetic alterations.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This study was terminated due to business reasons, and pharmacokinetic (PK) testing was prioritized.

Study Design

Study Type:
Interventional
Actual Enrollment :
78 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1b Study of ARQ 751 as a Single Agent or in Combination With Other Anti-cancer Agents in Adult Subjects With Advanced Solid Tumors With PIK3CA / AKT / PTEN Mutations
Actual Study Start Date :
Jun 26, 2016
Actual Primary Completion Date :
Mar 10, 2021
Actual Study Completion Date :
Mar 10, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1: Vevorisertib 5 mg QD

Participants will receive vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity.

Drug: Vevorisertib
Administered as an oral dose every day or every other day.
Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 10 mg QD

    Participants will receive vevorisertib 10 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 20 mg QD

    Participants will receive vevorisertib 20 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 25 mg QD

    Participants will receive vevorisertib 25 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 25 mg QOD

    Participants will receive vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 50 mg QD

    Participants will receive vevorisertib 50 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 75 mg QD

    Participants will receive vevorisertib 75 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 1: Vevorisertib 100 mg QD

    Participants will receive vevorisertib 100 mg orally QD until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    		•
    Experimental: Part 2: Vevorisertib 50 mg QD plus Paclitaxel

    Participants will receive vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    • Drug: Paclitaxel
    Administered as an intravenous (IV) infusion.
    Other Names:
  • Taxol

    		•
    Experimental: Part 2: Vevorisertib 75 mg QD plus Paclitaxel

    Participants will receive vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    • Drug: Paclitaxel
    Administered as an intravenous (IV) infusion.
    Other Names:
  • Taxol

    		•
    Experimental: Part 2: Vevorisertib 50 mg QD plus Fulvestrant

    Participants will receive vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    • Drug: Fulvestrant
    Administered as an intramuscular (IM) injection.
    Other Names:
  • Faslodex

    		•
    Experimental: Part 2: Vevorisertib 75 mg QD plus Fulvestrant

    Participants will receive vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.

    Drug: Vevorisertib
    Administered as an oral dose every day or every other day.
    Other Names:
  • ARQ 751
  • MK-4440

    • Drug: Fulvestrant
    Administered as an intramuscular (IM) injection.
    Other Names:
  • Faslodex

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Who Experience One or More Adverse Events (AEs) [Up to approximately 120 weeks]

      An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.

    2. Number of Participants Who Discontinue Study Treatment Due to an AE [Up to approximately 116 weeks]

      An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.

    Secondary Outcome Measures

    1. Maximum Plasma Concentration (Cmax) of Vevorisertib [Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.]

      Cmax was defined as the maximum plasma drug concentration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. Cmax is reported as geometric mean with a percent coefficient of variation.

    2. Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib [Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.]

      AUC0-24hrs was defined as area under the concentration-time curve from time 0 to 24 hours after dose administration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. AUC0-24 is reported as geometric mean with a percent coefficient of variation.

    3. Elimination Half-life (t½) of Vevorisertib [Cycle 1 Day 1: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.]

      t1/2 was defined as the terminal elimination half-life of drug. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. t1/2 is reported as geometric mean with a percent coefficient of variation.

    4. Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [Cycle 1 (Up to approximately 28 days)]

      DLTs consisted of hematologic or non-hematologic toxicities. Hematologic DLT was any grade (Gr) 4 anemia, Gr 4 neutropenia, Gr 4 thrombocytopenia, Gr 3 lasting >7 days, Gr 3 thrombocytopenia in the presence of bleeding, or ≥ Gr 3 hyperglycemia. Non-hematologic DLT was any Gr 3, 4 or 5 non-hematologic toxicity with the exception of: (1) Gr 3 nausea, vomiting, diarrhea or responding to optimal medical management within 48 hours; (2) alopecia. Per protocol DLTs were analyzed in the first 28-day treatment cycle. The number of participants experiencing DLTs is reported here for all participants who got ≥1 dose of study drug.

    5. Objective Response Rate (ORR) [Up to approximately 116 weeks]

      ORR was defined as the percentage of participants who have best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

    6. Best Overall Response (BOR) [Up to approximately 116 weeks]

      BOR was assessed using RECIST 1.1. Response categories included: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; and Inevaluable: participants who have SD as their best overall response but fail to achieve the protocol-defined duration for SD. Percentage of participants with CR, PR, SD, PD, or inevaluable as a best overall response have been reported.

    7. Disease Control Rate (DCR) [Up to approximately 116 weeks]

      DCR was defined, per RECIST 1.1, as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD].

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    1. Signed written informed consent granted prior to initiation of any study-specific procedures

    2. 18 years of age and older

    3. Histologically and/or cytologically documented diagnosis of a selected tumor type that is locally advanced, inoperable, metastatic or recurrent (including but not restricted to breast cancer, TNBC [triple negative]; HR-positive [HR+]/HER2-negative [HER2-] or endometrial cancer)

    4. Documented AKT genetic alterations or known actionable PIK3CA/PTEN mutations by genetic testing

    • Participants with tumors with PTEN null/PTEN loss-of-function mutations are not eligible

    1. For combination arms; participants should be eligible for paclitaxel or fulvestrant therapy as per Investigator assessment

    2. Failure to respond to standard systemic therapy, or for whom standard or curative systemic therapy does not exist or is not tolerable

    • Participants in single agent arm (with AKT genetic alterations) and participants in dose escalation cohorts of combination therapy arms should have at least one line of standard systemic therapy

    • Participants in single agent arm (with PIK3CA/PTEN actionable mutations) and participants in the expansion cohorts of combination therapy arms should have no more than 3 prior systemic regimens for the advanced disease

    • Neoadjuvant and adjuvant chemotherapy are considered one regimen if they are a continuation of the same regimen with interval debulking surgery

    • If the participant is refractory or has disease progression within 6 months after completion of the adjuvant treatment, then the adjuvant treatment should be considered as the line of treatment rather than an adjuvant therapy.

    • Endocrine (hormonal) therapy does not count toward total lines of therapy

    • Maintenance therapy is considered part of the preceding regimen if one or more of the same drugs are continued

    1. Has at least one measurable target lesion according to RECIST v. 1.1

    2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1

    3. Adequate organ function as indicated by the following laboratory values. (All laboratory tests must be obtained within 14 days prior to the first dose of study treatment):

    4. Hematological

    • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L

    • Platelet count (Plt) ≥ 100 x 10⁹/L

    • Hemoglobin (Hb) ≥ 9 g/dL

    • International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for participants receiving anticoagulant therapy such as Coumadin or heparin

    1. Renal
    • Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels > 1.5 x institutional ULN
    1. Hepatic

    • Total bilirubin ≤ 1.5 x ULN

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN or ≤ 5 x ULN for participants with known liver metastases

    1. Metabolic
    • Glycated hemoglobin (HbA1c) ≤ 8% (≤ 64 mmol/mol)
    1. If a participant is currently receiving bisphosphonates or any other drug for treatment of osteoporosis, treatment-induced bone loss and metastases to bone, the participant must have received the bisphosphonates for at least four weeks prior to the first dose of study treatment

    • Initiation of bisphosphonates or similar agents during the study may be allowed provided the participant completes the first cycle of treatment without any dose limiting toxicity (DLT) and the Investigator rules out tumor progression

    1. Male or female participants of child-producing potential must agree to use adequate contraception, including double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of study treatment

    2. Women of childbearing potential must have a negative serum pregnancy test. "Women of childbearing potential" is defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months prior to the first dose of study treatment

    Exclusion Criteria

    1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted therapy, or investigational agents within five half-lives or four weeks, whichever is shorter, prior to administration of the first dose of study treatment

    • To be eligible for study treatment, toxicity from prior treatment(s) must recover to Grade ≤ 1, except for alopecia

    • Concurrent systemic high-dose corticosteroids (in dosing exceeding 10 mg QD of prednisone equivalent) when used intermittently in an antiemetic regimen, for central nervous system (CNS) metastases management, or as a part of the premedication regimen are allowed

    1. Radiation therapy within four weeks, or palliative radiation therapy within two weeks, prior to administration of the first dose of study treatment

    • To be eligible for study treatment, radiation therapy-related toxicity must recover to Grade ≤ 1 prior to administration of the first dose of study treatment

    • Concurrent palliative radiotherapy for local pain-control or prevention of fracture (for known bone metastases) may be allowed provided the participant completes the first cycle of treatment, does not meet criteria of progressive disease, and treated lesions will not be included in the target/non-target lesion assessment

    1. Major surgical procedure within four weeks prior to administration of the first dose of study treatment

    • To be eligible for the study treatment, all surgical wounds must be fully healed, and any surgery-related adverse events must recover to Grade ≤ 1.

    1. Unable or unwilling to swallow the complete daily dose of vevorisertib

    2. Previous treatment with

    • AKT inhibitors (e.g., ARQ 092, MK-2206, GSK2141795, AZD5363; prior treatment with PI3K or mammalian target of rapamycin (mTOR) inhibitor are allowed)

    • Prior taxane therapy for the advanced, metastatic disease (for participants considered for vevorisertib +paclitaxel combination arm only)

    1. Known prior allergic reaction to or severe intolerance of paclitaxel or fulvestrant. Intolerance is defined as a serious adverse event (AE), a grade 3 or 4 AE per Common Terminology Criteria for Adverse Events (CTCAE) v.4.03, or permanent treatment discontinuation

    2. History of Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring regular medication (other than oral hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at Screening visit

    3. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of vevorisertib (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, extensive gastric resection)

    4. Known untreated or active CNS metastases and/or carcinomatous meningitis

    • To be eligible for the study treatment, participants must have stable disease ≥ 1 month, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications

    1. History of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV congestive heart failure within 6 months of the administration of the first dose of study treatment (MI occurring > 6 months of the first dose of study treatment will be permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch block)

    2. A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula QTcF

    3. Left ventricular ejection fraction (LVEF) <50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO) in participants who received prior treatment with anthracyclines

    4. Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements, including but not limited to:

    • Psychiatric illness, substance abuse

    • Ongoing or active known infection, including human immunodeficiency virus (HIV) infection, hepatitis B or C virus

    • Significant pulmonary dysfunction, including pneumonitis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, severe chronic obstructive pulmonary disease (COPD)

    • Peripheral neuropathy grade ≥2 (vevorisertib+paclitaxel combination arm)

    • Bleeding diathesis, thrombocytopenia or coagulation disorders (vevorisertib+fulvestrant combination arm)

    • Thrombotic/coagulation disorders within 6 months prior to the first dose of study treatment unless stable on anticoagulation for > 3 months

    1. Active or history of other malignancy other than the current cancer within 2 years of the first dose of study treatment, with the exception of carcinoma in-situ of the cervix, basal cell carcinoma, and superficial bladder tumors curatively treated

    2. Blood transfusion or administration of growth factors within 5 days prior to a blood draw being used to confirm eligibility

    3. Pregnant or breastfeeding

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Comprehensive Cancer Centers of Nevada Las Vegas Nevada United States 89169
    2 Stephenson Cancer Center Oklahoma City Oklahoma United States 73104
    3 Charleston Hematology Oncology Charleston South Carolina United States 29414
    4 The Sarah Cannon Research Institute Nashville Tennessee United States 37203
    5 Mary Crowley Cancer Research Dallas Texas United States 75230
    6 MD Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
    ClinicalTrials.gov Identifier:
    NCT02761694
    Other Study ID Numbers:
    • 4440-001
    • ARQ 751-101
    • MK-4440-001
    First Posted:
    May 4, 2016
    Last Update Posted:
    Jun 15, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
    AKT1
    AKT2
    AKT3
    PI3K
    solid tumors
    cancer
    ARQ 751
    PTEN
    Additional relevant MeSH terms:
    Neoplasms
    Paclitaxel
    Fulvestrant

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Period Title: Overall Study
    STARTED 4 4 1 3 3 3 33 8 5 5 3 6
    Treated 4 4 1 3 3 3 32 8 5 5 3 6
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 4 4 1 3 3 3 33 8 5 5 3 6

    Baseline Characteristics

    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant Total
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Total of all reporting groups
    Overall Participants 4 4 1 3 3 3 33 8 5 5 3 6 78
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    60.5
    (11.5)
    57.0
    (14.4)
    65.0
    (NA)
    62.0
    (3.6)
    58.3
    (11.6)
    53.0
    (20.2)
    58.6
    (11.9)
    59.0
    (8.4)
    57.2
    (19.7)
    59.8
    (11.3)
    52.3
    (7.6)
    65.8
    (5.6)
    59.0
    (11.4)
    Sex: Female, Male (Count of Participants)
    Female
    3
    75%
    2
    50%
    0
    0%
    3
    100%
    3
    100%
    3
    100%
    19
    57.6%
    7
    87.5%
    5
    100%
    2
    40%
    3
    100%
    6
    100%
    56
    71.8%
    Male
    1
    25%
    2
    50%
    1
    100%
    0
    0%
    0
    0%
    0
    0%
    14
    42.4%
    1
    12.5%
    0
    0%
    3
    60%
    0
    0%
    0
    0%
    22
    28.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3%
    1
    12.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    3.8%
    Not Hispanic or Latino
    3
    75%
    4
    100%
    1
    100%
    3
    100%
    3
    100%
    3
    100%
    31
    93.9%
    7
    87.5%
    5
    100%
    5
    100%
    3
    100%
    6
    100%
    74
    94.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.3%
    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%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    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%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    6.1%
    2
    25%
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    6
    7.7%
    White
    4
    100%
    3
    75%
    1
    100%
    3
    100%
    3
    100%
    3
    100%
    30
    90.9%
    6
    75%
    5
    100%
    4
    80%
    3
    100%
    6
    100%
    71
    91%
    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%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.3%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Who Experience One or More Adverse Events (AEs)
    Description An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.
    Time Frame Up to approximately 120 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 4 4 1 3 3 3 32 8 5 5 3 6
    Count of Participants [Participants]
    4
    100%
    4
    100%
    1
    100%
    3
    100%
    3
    100%
    3
    100%
    32
    97%
    8
    100%
    5
    100%
    5
    100%
    3
    100%
    6
    100%
    2. Primary Outcome
    Title Number of Participants Who Discontinue Study Treatment Due to an AE
    Description An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.
    Time Frame Up to approximately 116 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 4 4 1 3 3 3 32 8 5 5 3 6
    Count of Participants [Participants]
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    9.1%
    0
    0%
    1
    20%
    1
    20%
    0
    0%
    1
    16.7%
    3. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of Vevorisertib
    Description Cmax was defined as the maximum plasma drug concentration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. Cmax is reported as geometric mean with a percent coefficient of variation.
    Time Frame Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess Cmax at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 2 3 1 3 3 3 28 8 4 4 3 6
    Cycle 1 Day 1
    NA
    (NA)
    4.820
    (80.1)
    15.3
    (NA)
    51.39
    (68.1)
    22.73
    (5.9)
    59.79
    (7.6)
    98.75
    (88.2)
    122.6
    (107.1)
    29.13
    (245.6)
    49.11
    (67.0)
    91.7
    (NA)
    166.7
    (101.7)
    Cycle 1 Day 22
    4.154
    (45.3)
    12.82
    (71.1)
    7.79
    (NA)
    65.40
    (61.5)
    19.49
    (96.5)
    55.15
    (76.7)
    225.1
    (80.0)
    207.7
    (80.6)
    Cycle 2 Day 1
    186.8
    (47.3)
    78.36
    (216.8)
    79.52
    (69.6)
    62.59
    (140.1)
    138.2
    (48.4)
    4. Secondary Outcome
    Title Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib
    Description AUC0-24hrs was defined as area under the concentration-time curve from time 0 to 24 hours after dose administration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. AUC0-24 is reported as geometric mean with a percent coefficient of variation.
    Time Frame Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess AUC0-24 at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 2 2 1 3 3 3 28 8 4 3 3 6
    Cycle 1 Day1
    NA
    (NA)
    12.27
    (NA)
    42.2
    (NA)
    244.1
    (113.3)
    128.6
    (52.4)
    287.5
    (4.5)
    667.6
    (84.6)
    786.1
    (117.7)
    391.1
    (NA)
    649.6
    (41.7)
    449
    (NA)
    1115
    (73.5)
    Cycle 1 Day 22
    67.89
    (197.1)
    78.5
    (NA)
    501.8
    (35.5)
    181.2
    (59.0)
    543.8
    (78.2)
    1832
    (68.5)
    1786
    (82.4)
    Cycle 2 Day 1
    2013
    (66.4)
    837.2
    (200.6)
    1280
    (39.1)
    750.7
    (67.0)
    1948
    (49.7)
    5. Secondary Outcome
    Title Elimination Half-life (t½) of Vevorisertib
    Description t1/2 was defined as the terminal elimination half-life of drug. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. t1/2 is reported as geometric mean with a percent coefficient of variation.
    Time Frame Cycle 1 Day 1: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess t1/2 at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 2 2 1 3 2 3 25 7 3 3 2 6
    Cycle 1 Day 1
    NA
    (NA)
    3.68
    (NA)
    15.43
    (104.2)
    8.257
    (102.7)
    15.94
    (19.3)
    12.39
    (37.7)
    7.437
    (69.0)
    8.920
    (NA)
    8.909
    (16.3)
    9.48
    (NA)
    9.176
    (46.7)
    Cycle 1 Day 22
    10.12
    (87.0)
    39.33
    (48.6)
    21.25
    (13.8)
    20.03
    (1.6)
    12.94
    (71.8)
    24.59
    (6.9)
    Cycle 2 Day 1
    22.93
    (36.8)
    20.89
    (70.9)
    28.78
    (16.3)
    11.46
    (NA)
    6. Secondary Outcome
    Title Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
    Description DLTs consisted of hematologic or non-hematologic toxicities. Hematologic DLT was any grade (Gr) 4 anemia, Gr 4 neutropenia, Gr 4 thrombocytopenia, Gr 3 lasting >7 days, Gr 3 thrombocytopenia in the presence of bleeding, or ≥ Gr 3 hyperglycemia. Non-hematologic DLT was any Gr 3, 4 or 5 non-hematologic toxicity with the exception of: (1) Gr 3 nausea, vomiting, diarrhea or responding to optimal medical management within 48 hours; (2) alopecia. Per protocol DLTs were analyzed in the first 28-day treatment cycle. The number of participants experiencing DLTs is reported here for all participants who got ≥1 dose of study drug.
    Time Frame Cycle 1 (Up to approximately 28 days)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 4 4 1 3 3 3 32 8 5 5 3 6
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3%
    1
    12.5%
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    7. Secondary Outcome
    Title Objective Response Rate (ORR)
    Description ORR was defined as the percentage of participants who have best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
    Time Frame Up to approximately 116 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment and had ORR data available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 3 3 1 3 3 2 24 7 4 3 2 4
    Number (95% Confidence Interval) [Percentage of Participants]
    0
    0%
    0
    0%
    0
    0%
    33.3
    1110%
    0
    0%
    0
    0%
    4.2
    12.7%
    14.3
    178.8%
    50.0
    1000%
    0
    0%
    0
    0%
    0
    0%
    8. Secondary Outcome
    Title Best Overall Response (BOR)
    Description BOR was assessed using RECIST 1.1. Response categories included: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; and Inevaluable: participants who have SD as their best overall response but fail to achieve the protocol-defined duration for SD. Percentage of participants with CR, PR, SD, PD, or inevaluable as a best overall response have been reported.
    Time Frame Up to approximately 116 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment and had BOR data available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 3 3 1 3 3 2 24 7 4 3 2 4
    Complete Response (CR)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial Response (PR)
    0
    0%
    0
    0%
    0
    0%
    33.3
    1110%
    0
    0%
    0
    0%
    4.2
    12.7%
    14.3
    178.8%
    50.0
    1000%
    0
    0%
    0
    0%
    0
    0%
    Stable Disease (SD)
    0
    0%
    0
    0%
    100.0
    10000%
    66.7
    2223.3%
    33.3
    1110%
    50.0
    1666.7%
    41.7
    126.4%
    42.9
    536.3%
    25.0
    500%
    33.3
    666%
    0
    0%
    50.0
    833.3%
    Progressive Disease (PD)
    100.0
    2500%
    100.0
    2500%
    0
    0%
    0
    0%
    66.7
    2223.3%
    50.0
    1666.7%
    54.2
    164.2%
    28.6
    357.5%
    0
    0%
    66.7
    1334%
    100.0
    3333.3%
    50.0
    833.3%
    Inevaluable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    14.3
    178.8%
    25.0
    500%
    0
    0%
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Disease Control Rate (DCR)
    Description DCR was defined, per RECIST 1.1, as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD].
    Time Frame Up to approximately 116 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study treatment and had DCR data available.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    Measure Participants 3 3 1 3 3 2 24 7 4 3 2 4
    Number (95% Confidence Interval) [Percentage of Participants]
    0
    0%
    0
    0%
    100.0
    10000%
    100.0
    3333.3%
    33.3
    1110%
    50.0
    1666.7%
    45.8
    138.8%
    57.1
    713.8%
    75.0
    1500%
    33.3
    666%
    0
    0%
    50.0
    833.3%

    Adverse Events

    Time Frame Up to approximately 120 weeks
    Adverse Event Reporting Description The analysis population for All-Cause Mortality included all randomized participants.The analysis population for AEs included all randomized participants who received at least 1 dose of study treatment.
    Arm/Group Title Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    Arm/Group Description Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity.
    All Cause Mortality
    Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 2/4 (50%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 7/33 (21.2%) 2/8 (25%) 2/5 (40%) 2/5 (40%) 1/3 (33.3%) 0/6 (0%)
    Serious Adverse Events
    Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 3/4 (75%) 0/1 (0%) 2/3 (66.7%) 1/3 (33.3%) 2/3 (66.7%) 12/32 (37.5%) 5/8 (62.5%) 3/5 (60%) 2/5 (40%) 0/3 (0%) 3/6 (50%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Cardiac disorders
    Pericardial effusion 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Eye disorders
    Eyelid ptosis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Ascites 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Colitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Diarrhoea 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Nausea 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Proctalgia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rectal haemorrhage 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Small intestinal obstruction 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 4 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Umbilical hernia, obstructive 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Vomiting 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    General disorders
    Disease progression 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pyrexia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/32 (3.1%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Infections and infestations
    Bacteraemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Herpes zoster 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pneumonia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Sepsis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Urinary tract infection 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Metabolism and nutrition disorders
    Hypercalcaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Hyperglycaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hyponatraemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Muscular weakness 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pain in extremity 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rotator cuff syndrome 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Endometrial cancer 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Gastric cancer 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Ovarian cancer 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Prostate cancer 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Small intestine carcinoma 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Squamous cell carcinoma 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Uterine cancer 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Nervous system disorders
    Cerebrovascular accident 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hemiparesis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hepatic encephalopathy 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pneumonitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Surgical and medical procedures
    Spinal operation 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Vascular disorders
    Embolism 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypertension 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Other (Not Including Serious) Adverse Events
    Part 1: Vevorisertib 5 mg QD Part 1: Vevorisertib 10 mg QD Part 1: Vevorisertib 20 mg QD Part 1: Vevorisertib 25 mg QD Part 1: Vevorisertib 25 mg QOD Part 1: Vevorisertib 50 mg QD Part 1: Vevorisertib 75 mg QD Part 1: Vevorisertib 100 mg QD Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Part 2: Vevorisertib 75 mg QD Plus Fulvestrant
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 4/4 (100%) 1/1 (100%) 3/3 (100%) 3/3 (100%) 3/3 (100%) 32/32 (100%) 8/8 (100%) 5/5 (100%) 5/5 (100%) 3/3 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0 2/4 (50%) 2 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 5 1/8 (12.5%) 2 1/5 (20%) 3 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2
    Lymphopenia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Neutropenia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Thrombocytopenia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Cardiac disorders
    Palpitations 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Pericardial effusion 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Ventricular arrhythmia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Ear and labyrinth disorders
    Deafness bilateral 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Ear pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Vertigo 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Eye disorders
    Dry eye 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Ocular hypertension 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Refraction disorder 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Vision blurred 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Visual impairment 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Abdominal distension 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0
    Abdominal pain 0/4 (0%) 0 2/4 (50%) 2 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 5/32 (15.6%) 7 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 2 0/3 (0%) 0 1/6 (16.7%) 1
    Abdominal pain lower 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Abdominal pain upper 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 2 1/32 (3.1%) 1 2/8 (25%) 3 1/5 (20%) 1 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Ascites 0/4 (0%) 0 0/4 (0%) 0 1/1 (100%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Cheilitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 3 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Constipation 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 2/3 (66.7%) 3 0/3 (0%) 0 1/3 (33.3%) 1 5/32 (15.6%) 5 0/8 (0%) 0 1/5 (20%) 1 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Diarrhoea 1/4 (25%) 2 2/4 (50%) 2 0/1 (0%) 0 2/3 (66.7%) 6 1/3 (33.3%) 2 2/3 (66.7%) 3 19/32 (59.4%) 44 6/8 (75%) 12 1/5 (20%) 6 2/5 (40%) 3 3/3 (100%) 5 2/6 (33.3%) 6
    Dry mouth 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 5/32 (15.6%) 5 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dyspepsia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 4 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Dysphagia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Flatulence 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Gastrooesophageal reflux disease 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Haemorrhoids 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hyperaesthesia teeth 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Nausea 2/4 (50%) 2 4/4 (100%) 6 1/1 (100%) 1 2/3 (66.7%) 5 1/3 (33.3%) 1 1/3 (33.3%) 1 8/32 (25%) 13 1/8 (12.5%) 1 0/5 (0%) 0 2/5 (40%) 2 2/3 (66.7%) 2 3/6 (50%) 4
    Rectal discharge 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Rectal haemorrhage 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rectal tenesmus 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Stomatitis 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 5/32 (15.6%) 8 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 2
    Vomiting 0/4 (0%) 0 3/4 (75%) 4 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 2 9/32 (28.1%) 12 3/8 (37.5%) 3 1/5 (20%) 1 1/5 (20%) 1 1/3 (33.3%) 1 3/6 (50%) 4
    General disorders
    Asthenia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 1/5 (20%) 1 2/5 (40%) 4 0/3 (0%) 0 1/6 (16.7%) 1
    Chills 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Fatigue 2/4 (50%) 3 3/4 (75%) 3 0/1 (0%) 0 2/3 (66.7%) 4 1/3 (33.3%) 1 1/3 (33.3%) 1 8/32 (25%) 8 2/8 (25%) 3 1/5 (20%) 2 2/5 (40%) 7 0/3 (0%) 0 1/6 (16.7%) 1
    Gait disturbance 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Influenza like illness 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Mucosal inflammation 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/3 (0%) 0 3/32 (9.4%) 5 2/8 (25%) 2 1/5 (20%) 2 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Non-cardiac chest pain 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Oedema peripheral 1/4 (25%) 2 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 3/8 (37.5%) 3 0/5 (0%) 0 1/5 (20%) 2 0/3 (0%) 0 0/6 (0%) 0
    Peripheral swelling 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pyrexia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 5/32 (15.6%) 7 1/8 (12.5%) 1 1/5 (20%) 1 1/5 (20%) 3 0/3 (0%) 0 3/6 (50%) 3
    Infections and infestations
    Bronchitis viral 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Conjunctivitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Labyrinthitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rash pustular 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/3 (0%) 0 0/6 (0%) 0
    Upper respiratory tract infection 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Urinary tract infection 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 2/32 (6.3%) 3 3/8 (37.5%) 3 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Wound infection 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Injury, poisoning and procedural complications
    Fall 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Procedural pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Sunburn 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/32 (3.1%) 2 2/8 (25%) 2 1/5 (20%) 2 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Aspartate aminotransferase increased 1/4 (25%) 1 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/32 (3.1%) 3 2/8 (25%) 2 1/5 (20%) 3 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Blood alkaline phosphatase increased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 4 1/8 (12.5%) 1 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Blood bilirubin increased 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 1/8 (12.5%) 1 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Blood creatinine increased 1/4 (25%) 2 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 2
    Blood lactate dehydrogenase increased 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Electrocardiogram QT prolonged 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 5 1/8 (12.5%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Lymphocyte count decreased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Neutrophil count decreased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 2/5 (40%) 2 1/5 (20%) 5 0/3 (0%) 0 0/6 (0%) 0
    Weight decreased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 1/5 (20%) 1 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Weight increased 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    White blood cell count decreased 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 3 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 4 0/3 (0%) 0 0/6 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 1/4 (25%) 1 2/4 (50%) 3 1/1 (100%) 1 2/3 (66.7%) 2 0/3 (0%) 0 2/3 (66.7%) 2 10/32 (31.3%) 11 3/8 (37.5%) 4 2/5 (40%) 3 1/5 (20%) 1 1/3 (33.3%) 1 3/6 (50%) 3
    Dehydration 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/3 (0%) 0 4/32 (12.5%) 5 2/8 (25%) 2 1/5 (20%) 1 1/5 (20%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1
    Early satiety 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypercalcaemia 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Hyperglycaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 4/32 (12.5%) 7 1/8 (12.5%) 1 0/5 (0%) 0 2/5 (40%) 3 0/3 (0%) 0 0/6 (0%) 0
    Hyperkalaemia 2/4 (50%) 2 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 3 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypertriglyceridaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hyperuricaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 2/8 (25%) 3 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypoalbuminaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Hypocalcaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 2/3 (66.7%) 3 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypokalaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 6/32 (18.8%) 8 2/8 (25%) 2 2/5 (40%) 3 2/5 (40%) 3 1/3 (33.3%) 1 2/6 (33.3%) 3
    Hypomagnesaemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 7 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hyponatraemia 0/4 (0%) 0 2/4 (50%) 2 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypophosphataemia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Malnutrition 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 4 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 0/8 (0%) 0 1/5 (20%) 1 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Back pain 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 1/3 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Flank pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Joint swelling 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Muscular weakness 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 3 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Musculoskeletal chest pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Myalgia 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Pain in extremity 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Rotator cuff syndrome 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Trismus 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Tumour pain 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Nervous system disorders
    Balance disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Coordination abnormal 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Cranial nerve disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dizziness 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dysarthria 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Facial paralysis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Headache 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 2 0/3 (0%) 0 3/32 (9.4%) 3 3/8 (37.5%) 3 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Hemiparesis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hyperaesthesia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypoaesthesia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Memory impairment 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Muscle tone disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Neuropathy peripheral 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Poor quality sleep 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Post herpetic neuralgia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Reflexes abnormal 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Sensory loss 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Taste disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 2/8 (25%) 2 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    Adjustment disorder with depressed mood 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Agitation 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Anxiety 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Confusional state 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Depression 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Emotional distress 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hallucination 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Insomnia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Mental status changes 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Sleep disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Chromaturia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dysuria 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Haematuria 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hydronephrosis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 2/8 (25%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pollakiuria 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 2/32 (6.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Renal failure 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Reproductive system and breast disorders
    Vaginal haemorrhage 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 3 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 2/3 (66.7%) 2 4/32 (12.5%) 4 1/8 (12.5%) 2 2/5 (40%) 3 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dysphonia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dyspnoea 2/4 (50%) 2 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 5/32 (15.6%) 6 1/8 (12.5%) 1 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Dyspnoea exertional 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 1 2/32 (6.3%) 2 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Epistaxis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Oropharyngeal pain 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Orthopnoea 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pleural effusion 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Pneumonitis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 2 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Productive cough 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Respiratory tract congestion 1/4 (25%) 1 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rhinitis allergic 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rhinorrhoea 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Dermatitis acneiform 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/32 (6.3%) 2 1/8 (12.5%) 2 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Erythema 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Night sweats 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/32 (9.4%) 3 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1
    Pruritus 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 5/32 (15.6%) 6 1/8 (12.5%) 1 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Rash 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 8/32 (25%) 17 1/8 (12.5%) 2 0/5 (0%) 0 3/5 (60%) 3 0/3 (0%) 0 1/6 (16.7%) 2
    Rash erythematous 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 3 0/3 (0%) 0 1/3 (33.3%) 1 1/32 (3.1%) 1 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Rash macular 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 1 1/8 (12.5%) 2 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0
    Rash maculo-papular 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 4/32 (12.5%) 13 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Rash pruritic 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/32 (3.1%) 2 3/8 (37.5%) 5 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Skin disorder 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Skin mass 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Flushing 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hot flush 0/4 (0%) 0 1/4 (25%) 1 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0
    Hypertension 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 1/6 (16.7%) 1
    Hypotension 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/32 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 2/5 (40%) 2 0/3 (0%) 0 0/6 (0%) 0
    Lymphoedema 0/4 (0%) 0 0/4 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/32 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The Investigator agrees not to independently publish the findings except as part of an overall multi-center publication, unless specifically approved in writing by the Sponsor or unless more than 12 months have elapsed since the last participant in the study has completed study treatment.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme LLC
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
    ClinicalTrials.gov Identifier:
    NCT02761694
    Other Study ID Numbers:
    • 4440-001
    • ARQ 751-101
    • MK-4440-001
    First Posted:
    May 4, 2016
    Last Update Posted:
    Jun 15, 2022
    Last Verified:
    Jun 1, 2022