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Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO-1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patients

Sponsor
Clovis Oncology, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT01526928
Collaborator
(none)
612
Enrollment
49
Locations
6
Arms
77
Actual Duration (Months)
12.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.

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

Detailed Description

Lung cancer remains the most common cancer worldwide with non-small cell lung cancer accounting for 85% of cases. Cytotoxic chemotherapy has been the mainstay of patients with NSCLC; however, survival rates remain low and toxicity is significant. Molecularly targeted therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. There are currently no approved therapies for patients who progress on TKIs. Rociletinib may provide an effective therapy for a patient population with few alternative treatment options. Nonclinical data demonstrate that rociletinib inhibits T790M. It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs.

This is a two-part, open-label study of oral rociletinib administered daily in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or afatinib.

This study will include 2 parts:

Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22

Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have:

Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test

Study Design

Study Type:
Interventional
Actual Enrollment :
612 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date :
Mar 27, 2012
Actual Primary Completion Date :
Jul 3, 2018
Actual Study Completion Date :
Aug 27, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Rociletinib <900 mg BID FB formulation

Rociletinib free base (FB) dose <900 mg twice a day (BID)

Drug: Rociletinib
Phase 1: Rociletinib <900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles
Other Names:
  • CO-1686

    		•
    Experimental: Rociletinib 900 mg BID FB formulation

    Rociletinib free base (FB) dose 900 mg twice a day (BID)

    Drug: Rociletinib
    Phase 1: Rociletinib 900 mg BID FB will be administered in escalating dosages in a period of 21-day cycles
    Other Names:
  • CO-1686

    		•
    Experimental: Rociletinib 500 mg BID HBr formulation

    Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID)

    Drug: Rociletinib
    Phase 1: Rociletinib 500 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 500 mg BID HBr will be administered daily
    Other Names:
  • CO-1686

    		•
    Experimental: Rociletinib 625 mg BID HBr formulation

    Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID)

    Drug: Rociletinib
    Phase 1: Rociletinib 625 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 625 mg BID HBr will be administered daily
    Other Names:
  • CO-1686

    		•
    Experimental: Rociletinib 750 mg BID HBr formulation

    Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID)

    Drug: Rociletinib
    Phase 1: Rociletinib 750 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 750 mg BID HBr will be administered daily
    Other Names:
  • CO-1686

    		•
    Experimental: Rociletinib 1000 mg BID HBr formulation

    Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)

    Drug: Rociletinib
    Phase 1: Rociletinib 1000 mg BID HBr will be administered in escalating dosages in a period of 21-day cycles Phase 2: Rociletinib 1000 mg BID HBr will be administered daily
    Other Names:
  • CO-1686

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of T790M Positive Patients With Confirmed Response Per Investigator [Cycle 1 Day 1 to End of Treatment, up to approximately 42 months]

      Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

    2. Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment [Cycle 1 Day 1 to End of Treatment, up to approximately 36 months]

      Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

    3. Dose Limiting Toxicity (DLT) Incidence [Cycle 1 Day 1 to Cycle 1 Day 21]

      The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.

    Secondary Outcome Measures

    1. Overall Survival (OS) Determined by Investigator Assessment [Cycle 1 Day 1 to date of death, assessed up to 42 months]

      Overall survival was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.

    2. Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) [Cycle 1 Day 1 to End of Treatment, up to approximately 42 months]

      Progression-free survival was calculated as the number of days from the date of the first dose of study drug to the date of disease progression or death due to any cause + 1. Patients without a documented event of disease progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments have been performed. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

    3. PK Profile of Rociletinib - Cmax [Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days]

      Cmax = maximum concentration following administration of rociletinib

    4. PK Profile of Rociletinib - Tmax [Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days]

      Tmax = time to maximum concentration following administration of rociletinib

    5. PK Profile of Rociletinib - AUC 0-24 [Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days]

      AUC 0-24 = area under the curve from 0 to 24 hours

    6. PK Profile of Rociletinib - T 1/2 [Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days]

      T 1/2 = elimination half-life following administration of rociletinib

    7. Food Effect on PK of Rociletinib - Cmax [Day -7 prior to Cycle 1 Day 1, or approximately 7 days]

      Cmax = maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

    8. Food Effect on PK of Rociletinib - Tmax [Day -7 prior to Cycle 1 Day 1, or approximately 7 days]

      Tmax = time to maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

    9. Food Effect on PK of Rociletinib - AUC 0-24 [Day -7 prior to Cycle 1 Day 1, or approximately 7 days]

      AUC 0-24 = area under the curve from 0 to 24 hours. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

    10. Food Effect on PK of Rociletinib - C24 [Day -7 prior to Cycle 1 Day 1, or approximately 7 days]

      C24 = rociletinib plasma concentration at 24 hours post the morning dose. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

    11. Food Effect on PK of Rociletinib - T 1/2 [Day -7 prior to Cycle 1 Day 1, or approximately 7 days]

      T 1/2 = elimination half-life following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

    12. QTcF Values Post Baseline by Daily Dose [Screening to End of Treatment, up to approximately 42 months]

      Frequency of QT interval prolongation by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

    13. QTcF Value Change From Baseline [Screening to End of Treatment, up to approximately 42 months]

      QTcF value change from baseline by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

    14. Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR [Cycle 1 Day 1 to End of Treatment / End of Follow-up]

      Objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST Version 1.1 as determined by independent radiology review (IRR)

    Eligibility Criteria

    Criteria

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

    Inclusion Criteria -

    All patients must meet the following inclusion criteria:

    1. Metastatic or unresectable locally advanced NSCLC

    2. Evidence of a tumor with one or more EGFR mutations excluding exon 20 insertion

    3. Biopsy of either primary or metastatic tumor tissue within 60 days of dosing

    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

    5. Minimum age of 18 years

    6. Adequate hematological and biological function

    7. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation

    Phase 2 Cohorts must also meet the following inclusion criteria:

    • Disease progression confirmed by radiologic assessment while on treatment with EGFR- TKI Or

    • Disease progression confirmed by radiologic assessment while on treatment with the first single agent EGFR TKI and

    • Documented evidence of T790M mutation in EGFR following disease progression on the first single agent EGFR TKI.

    • Measureable disease according to RECIST Version 1.1

    Exclusion Criteria -

    Any of the following criteria will exclude patients from study participation:

    1. Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene

    2. Active second malignancy

    3. Known pre-existing interstitial lung disease

    4. Patients with Leptomeningeal carcinomatosis are excluded. Other CNS metastases are only permitted if treated, asymptomatic and stable (not requiring steroids for at least 4 weeks prior to start of study treatment).

    5. Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib

    6. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib

    7. Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR

    8. Certain cardiac abnormalities or history

    9. Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib

    10. Females who are pregnant or breastfeeding

    11. Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib

    12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study

    13. Any other reason the investigator considers the patient should not participate in the study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope National Medical Center Duarte California United States 91010
    2 Compassionate Care Research Group, Inc. Fountain Valley California United States 92708
    3 University of Southern California, Norris Comprehensive Cancer Center Los Angeles California United States 90033
    4 Samuel Oschin Cancer Center Los Angeles California United States 90048
    5 University of California, Irvine Orange California United States 92868
    6 University of California Davis Medical Center Sacramento California United States 95817
    7 UCLA Health System Santa Monica California United States 90404
    8 Stanford Cancer Institute Stanford California United States 94305
    9 East Valley Hematology and Oncology Medical Group, Inc. Whittier California United States 90603
    10 The Oncology Institute of Hope and Innovations Whittier California United States 90603
    11 University of Colorado Anschutz Medical Campus Aurora Colorado United States 80045
    12 Georgetown University Hospital Washington District of Columbia United States 20007
    13 Sylvester Comprehensive Cancer Center/UMHC Miami Florida United States 33136
    14 Florida Hospital Cancer Institute Orlando Florida United States 32804
    15 University Cancer & Blood Center Athens Georgia United States 30607
    16 University of Chicago Medical Center, The Duchossois Center for Advanced Medicine Chicago Illinois United States 60637
    17 University of Maryland Baltimore Maryland United States 21201
    18 Mass General Hospital Boston Massachusetts United States 02114
    19 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    20 Saint Joseph Mercy Hospital Ann Arbor Michigan United States 48106-0995
    21 Karmanos Cancer Care Institute Detroit Michigan United States 48201
    22 Regional Cancer Care Associates Morristown New Jersey United States 07962
    23 Regional Cancer Center New Brunswick New Jersey United States 07834
    24 Roswell Park Cancer Institute Buffalo New York United States 14263
    25 Monter Cancer Center Lake Success New York United States 11042
    26 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    27 University of Cincinnati Medical Center Cincinnati Ohio United States 45219
    28 Ohio State University, Comprehensive Cancer Center Columbus Ohio United States 43202
    29 Tulsa Cancer Institute Tulsa Oklahoma United States 74146
    30 Providence CancerCenter Oncology and Hematology Care Clinic-Eastside Portland Portland Oregon United States 97213
    31 Perelman Center for Advanced Medicine Philadelphia Pennsylvania United States 19104
    32 University of Pittsburgh Cancer Institute (UPMC), Div. of Medical Oncology Pittsburgh Pennsylvania United States 15232
    33 Vanderbilt University Nashville Tennessee United States 37235
    34 University of Texas Southwestern Medical Center Dallas Texas United States 75390-9179
    35 MD Anderson Cancer Center Houston Texas United States 77030
    36 Huntsman Cancer Institute Salt Lake City Utah United States 84112
    37 Virginia Cancer Specialists, PC Fairfax Virginia United States 22031
    38 Swedish Cancer Institute Seattle Washington United States 98104
    39 University of Washington Seattle Washington United States 98109
    40 Chris O'Brien Lifehouse Camperdown New South Wales Australia 2050
    41 Peter MacCallum Cancer Centre East Melbourne Australia
    42 Centre Antoine Lacassagne Nice Cedex 2 Provence Alpes COTE D'azur France 06189
    43 Centre Hospitalier Universitaire de Grenoble Grenoble Cedex 9 Rhone-alpes France
    44 Centre Léon Bérard Lyon Cedex 04 Rhone-alpes France
    45 Centre François Baclesse Caen Cedex 05 France
    46 Centre Hospitalier Intercommunal Créteil Creteil cedex France
    47 Centre Hospitalier Régional Universitaire de Lille Lille France
    48 Institut Gustave Roussy Villejuif France 94805
    49 Med University Gdansk Gdansk Poland

    Sponsors and Collaborators

    • Clovis Oncology, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Clovis Oncology, Inc.
    ClinicalTrials.gov Identifier:
    NCT01526928
    Other Study ID Numbers:
    • CO-1686-008
    First Posted:
    Feb 6, 2012
    Last Update Posted:
    Aug 4, 2020
    Last Verified:
    Jul 1, 2020
    Keywords provided by Clovis Oncology, Inc.
    cancer
    metastatic
    locally advanced
    lung
    non-small cell lung cancer
    NSCLC
    epidermal growth factor receptor
    EGFR
    T790M
    CO-1686
    unresectable
    recurrent
    EGFR-directed therapy
    irreversible EGFR inhibitor
    TIGER
    Rociletinib
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung

    Study Results

    Participant Flow

    Recruitment Details There were 612 patients who received rociletinib-111 enrolled in Phase 1 and 501 enrolled in Phase 2. The Phase 1 component of the study was conducted at 8 study sites in the US, Australia, and France. Phase 2 was conducted at 49 study sites in the US, France, Poland, and Australia.
    Pre-assignment Detail
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). FB doses tested ranged from 150 mg once a day (QD) up to 900 mg twice a day (BID). This arm also includes a 400 mg three times a day (TID) dose. Rociletinib FB capsules were administered in Phase 1 only (until November 2013) and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day treatment cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved. Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib FB capsules were administered in Phase 1 only (until November 2013) and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day treatment cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved. Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved. Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved. Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved. Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID). Rociletinib hydrobromide (HBr) tablets were administered in Phase 1 (starting in August 2013) and in all Phase 2 cohorts and were provided in 50 mg or 150 mg white capsules. Patients were instructed to take each dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Patients received rociletinib in 21-day cycles and were treated until there was progression by RECIST v1.1, clinical tumor progression, or unacceptable toxicity, or other discontinuation criteria were met. Patients could opt to continue to receive treatment with rociletinib following radiographic progression as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if the patient provided consent, and the investigator and sponsor approved.
    Period Title: Overall Study
    STARTED 38 19 209 245 95 6
    Started Phase 1 38 19 18 17 13 6
    Started Phase 2 0 0 191 228 82 0
    COMPLETED 0 0 0 0 0 0
    NOT COMPLETED 38 19 209 245 95 6

    Baseline Characteristics

    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets Total
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID). Total of all reporting groups
    Overall Participants 38 19 209 245 95 6 612
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.1
    (11.54)
    58.9
    (8.37)
    63.6
    (11.45)
    62.5
    (11.14)
    61.5
    (11.82)
    65.2
    (5.53)
    62.5
    (11.29)
    Sex: Female, Male (Count of Participants)
    Female
    31
    81.6%
    15
    78.9%
    155
    74.2%
    155
    63.3%
    63
    66.3%
    5
    83.3%
    424
    69.3%
    Male
    7
    18.4%
    4
    21.1%
    54
    25.8%
    90
    36.7%
    32
    33.7%
    1
    16.7%
    188
    30.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    5.3%
    2
    10.5%
    5
    2.4%
    14
    5.7%
    2
    2.1%
    0
    0%
    25
    4.1%
    Not Hispanic or Latino
    30
    78.9%
    15
    78.9%
    170
    81.3%
    184
    75.1%
    90
    94.7%
    6
    100%
    495
    80.9%
    Unknown or Not Reported
    6
    15.8%
    2
    10.5%
    34
    16.3%
    47
    19.2%
    3
    3.2%
    0
    0%
    92
    15%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    1
    0.4%
    0
    0%
    0
    0%
    1
    0.2%
    Asian
    5
    13.2%
    4
    21.1%
    41
    19.6%
    49
    20%
    24
    25.3%
    1
    16.7%
    124
    20.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    4
    1.9%
    3
    1.2%
    0
    0%
    0
    0%
    7
    1.1%
    Black or African American
    0
    0%
    0
    0%
    7
    3.3%
    8
    3.3%
    2
    2.1%
    0
    0%
    17
    2.8%
    White
    27
    71.1%
    13
    68.4%
    122
    58.4%
    137
    55.9%
    64
    67.4%
    5
    83.3%
    368
    60.1%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    1
    0.4%
    0
    0%
    0
    0%
    1
    0.2%
    Unknown or Not Reported
    6
    15.8%
    2
    10.5%
    35
    16.7%
    46
    18.8%
    5
    5.3%
    0
    0%
    94
    15.4%
    Race/Ethnicity, Customized (Count of Participants)
    White
    27
    71.1%
    13
    68.4%
    122
    58.4%
    137
    55.9%
    64
    67.4%
    5
    83.3%
    368
    60.1%
    Black or African American
    0
    0%
    0
    0%
    7
    3.3%
    8
    3.3%
    2
    2.1%
    0
    0%
    17
    2.8%
    Asian
    5
    13.2%
    4
    21.1%
    41
    19.6%
    49
    20%
    24
    25.3%
    1
    16.7%
    124
    20.3%
    Other
    6
    15.8%
    2
    10.5%
    39
    18.7%
    51
    20.8%
    5
    5.3%
    0
    0%
    103
    16.8%
    Time Since Diagnosis of NSCLC (months) (Months) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Months]
    40.4
    (29.2)
    45.4
    (31.94)
    36.7
    (25.81)
    36.7
    (31.41)
    37.6
    (29.97)
    47.4
    (27.03)
    37.4
    (29.17)
    T790M Status ( Determined by Central Lab) (Count of Participants)
    Negative
    5
    13.2%
    4
    21.1%
    6
    2.9%
    25
    10.2%
    9
    9.5%
    0
    0%
    49
    8%
    Positive
    23
    60.5%
    9
    47.4%
    188
    90%
    176
    71.8%
    80
    84.2%
    4
    66.7%
    480
    78.4%
    Unknown
    10
    26.3%
    6
    31.6%
    4
    1.9%
    1
    0.4%
    1
    1.1%
    2
    33.3%
    24
    3.9%
    Missing
    0
    0%
    0
    0%
    11
    5.3%
    43
    17.6%
    5
    5.3%
    0
    0%
    59
    9.6%
    History of CNS Metastases (Count of Participants)
    Count of Participants [Participants]
    20
    52.6%
    7
    36.8%
    86
    41.1%
    107
    43.7%
    44
    46.3%
    3
    50%
    267
    43.6%
    Number of Previous Therapies (Therapies) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Therapies]
    3.8
    (1.65)
    3.7
    (1.66)
    2.6
    (1.74)
    2.8
    (1.91)
    2.9
    (2.11)
    3.8
    (2.04)
    2.9
    (1.88)
    Number of Previous TKI Therapies (Therapies) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Therapies]
    1.7
    (0.77)
    2.3
    (1.48)
    1.5
    (0.87)
    1.6
    (0.77)
    1.6
    (0.86)
    1.8
    (0.75)
    1.6
    (0.86)

    Outcome Measures

    1. Primary Outcome
    Title Percentage of T790M Positive Patients With Confirmed Response Per Investigator
    Description Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
    Time Frame Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat: All randomized patients who are confirmed by central lab to be T790M positive
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 23 9 188 176 80 4
    Count of Participants [Participants]
    0
    0%
    3
    15.8%
    54
    25.8%
    72
    29.4%
    23
    24.2%
    3
    50%
    2. Primary Outcome
    Title Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment
    Description Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.
    Time Frame Cycle 1 Day 1 to End of Treatment, up to approximately 36 months

    Outcome Measure Data

    Analysis Population Description
    The DOR was measured only in T790M positive patients with a Complete Response (CR) or Partial Response (PR). There were no responders in the Rociletinib <900 mg BID treatment group so DOR is not applicable and thus not reported.
    Arm/Group Title Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose 900 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
    Measure Participants 3 54 72 23 3
    Median (95% Confidence Interval) [Days]
    329.0
    275.0
    274.0
    217.0
    428
    3. Primary Outcome
    Title Dose Limiting Toxicity (DLT) Incidence
    Description The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
    Time Frame Cycle 1 Day 1 to Cycle 1 Day 21

    Outcome Measure Data

    Analysis Population Description
    The dose limiting toxicity (DLT) evaluable population includes all patients who have completed Cycle 1, and who were enrolled while the dose escalation (Phase 1) part of the study was ongoing.
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 24 6 6 8 9 6
    Count of Participants [Participants]
    1
    2.6%
    1
    5.3%
    1
    0.5%
    2
    0.8%
    1
    1.1%
    1
    16.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rociletinib <900 mg BID FB Capsules, Rociletinib 900 mg BID FB Capsules, Rociletinib 500 mg BID HBr Tablets, Rociletinib 625 mg BID HBr Tablets, Rociletinib 750 mg BID HBr Tablets, Rociletinib 1000 mg BID HBr Tablets
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Other Statistical Analysis Since an MTD was never reached for any of the rociletinib FB or HBr formulations/doses, a 750 mg BID HBr starting dose was selected based on early efficacy data from Phase 1, and enrollment into Phase 2 was initiated at this dosage. As the Phase 1 efficacy data matured, the recommended dose was adjusted to 625 mg BID based on antitumor activity and safety evaluations.
    4. Secondary Outcome
    Title Overall Survival (OS) Determined by Investigator Assessment
    Description Overall survival was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.
    Time Frame Cycle 1 Day 1 to date of death, assessed up to 42 months

    Outcome Measure Data

    Analysis Population Description
    The overall number of patients analyzed contains centrally determined T790M positive patients only. There are 2 less patients in the <900 mg BID FB group, and 1 less patient in each of the 500, 625 and 750 mg BID dose groups because they were not followed for OS.
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID) Rociletinib free base (FB) dose 900 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
    Measure Participants 21 9 187 175 79 4
    Median (95% Confidence Interval) [months]
    16.3
    23.7
    18.5
    15.0
    12.9
    7.2
    5. Secondary Outcome
    Title Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)
    Description Progression-free survival was calculated as the number of days from the date of the first dose of study drug to the date of disease progression or death due to any cause + 1. Patients without a documented event of disease progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments have been performed. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
    Time Frame Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

    Outcome Measure Data

    Analysis Population Description
    The overall number of patients analyzed contains centrally determined T790M positive patients only. There are 2 less patients in the <900 mg BID FB group, and 1 less patient in each of the 500 and 625 mg BID dose groups because they were not followed for PFS.
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID) Rociletinib free base (FB) dose 900 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID) Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
    Measure Participants 21 9 187 175 80 4
    Median (95% Confidence Interval) [months]
    2.6
    10.4
    5.7
    5.2
    4.3
    7.2
    6. Secondary Outcome
    Title PK Profile of Rociletinib - Cmax
    Description Cmax = maximum concentration following administration of rociletinib
    Time Frame Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

    Outcome Measure Data

    Analysis Population Description
    PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point.
    Arm/Group Title Rociletinib 150 mg QD FB Capsules Rociletinib 200 mg QD FB Capsules Rociletinib 300 mg QD FB Capsules Rociletinib 450 mg QD FB Capsules Rociletinib 600 mg QD FB Capsules Rociletinib 900 mg QD FB Capsules Rociletinib 100 mg BID FB Capsules Rociletinib 300 mg BID FB Capsules Rociletinib 600 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 400 mg TID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose 150 mg once a day (QD). Rociletinib free base (FB) dose 200 mg once a day (QD). Rociletinib free base (FB) dose 300 mg once a day (QD). Rociletinib free base (FB) dose 450 mg once a day (QD). Rociletinib free base (FB) dose 600 mg once a day (QD). Rociletinib free base (FB) dose 900 mg once a day (QD). Rociletinib free base (FB) dose 100 mg twice a day (BID). Rociletinib free base (FB) dose 300 mg twice a day (BID). Rociletinib free base (FB) dose 600 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib free base (FB) dose 400 mg three times a day (TID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 9 3 3 3 3 3 3 3 5 19 3 18 21 23 6
    Day 1 Cmax
    537
    (71)
    533
    (63)
    1290
    (1019)
    1800
    (1224)
    969
    (824)
    2470
    (1482)
    574
    (293)
    706
    (88)
    1680
    (1126)
    1650
    (809)
    704
    (352)
    2800
    (2128)
    2980
    (2235)
    2570
    (1850)
    4250
    (2678)
    Day 15 Cmax
    250
    (188)
    503
    (377)
    1760
    (1056)
    942
    (857)
    981
    (343)
    2200
    (1100)
    729
    (576)
    647
    (304)
    928
    (95)
    1510
    (997)
    1140
    (274)
    2330
    (1375)
    3070
    (2272)
    2100
    (1029)
    2510
    (728)
    7. Secondary Outcome
    Title PK Profile of Rociletinib - Tmax
    Description Tmax = time to maximum concentration following administration of rociletinib
    Time Frame Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

    Outcome Measure Data

    Analysis Population Description
    PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point.
    Arm/Group Title Rociletinib 150 mg QD FB Capsules Rociletinib 200 mg QD FB Capsules Rociletinib 300 mg QD FB Capsules Rociletinib 450 mg QD FB Capsules Rociletinib 600 mg QD FB Capsules Rociletinib 900 mg QD FB Capsules Rociletinib 100 mg BID FB Capsules Rociletinib 300 mg BID FB Capsules Rociletinib 600 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 400 mg TID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose 150 mg once a day (QD). Rociletinib free base (FB) dose 200 mg once a day (QD). Rociletinib free base (FB) dose 300 mg once a day (QD). Rociletinib free base (FB) dose 450 mg once a day (QD). Rociletinib free base (FB) dose 600 mg once a day (QD). Rociletinib free base (FB) dose 900 mg once a day (QD). Rociletinib free base (FB) dose 100 mg twice a day (BID). Rociletinib free base (FB) dose 300 mg twice a day (BID). Rociletinib free base (FB) dose 600 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib free base (FB) dose 400 mg three times a day (TID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 9 3 3 3 3 3 3 3 5 19 3 18 21 23 6
    Day 1 Tmax
    1.5
    2.5
    2.5
    1.5
    2.0
    2.5
    2.5
    4.0
    4.0
    4.0
    2.5
    1.5
    2.5
    2.5
    3.25
    Day 15 Tmax
    2.0
    1.5
    2.5
    1.5
    2.5
    4.0
    2.5
    1.5
    2.5
    4
    10
    2.5
    2.5
    2.5
    1.5
    8. Secondary Outcome
    Title PK Profile of Rociletinib - AUC 0-24
    Description AUC 0-24 = area under the curve from 0 to 24 hours
    Time Frame Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

    Outcome Measure Data

    Analysis Population Description
    PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point. AUC was not calculated for patients in the 400 mg TID treatment group.
    Arm/Group Title Rociletinib 150 mg QD FB Capsules Rociletinib 200 mg QD FB Capsules Rociletinib 300 mg QD FB Capsules Rociletinib 450 mg QD FB Capsules Rociletinib 600 mg QD FB Capsules Rociletinib 900 mg QD FB Capsules Rociletinib 100 mg BID FB Capsules Rociletinib 300 mg BID FB Capsules Rociletinib 600 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose 150 mg once a day (QD). Rociletinib free base (FB) dose 200 mg once a day (QD). Rociletinib free base (FB) dose 300 mg once a day (QD). Rociletinib free base (FB) dose 450 mg once a day (QD). Rociletinib free base (FB) dose 600 mg once a day (QD). Rociletinib free base (FB) dose 900 mg once a day (QD). Rociletinib free base (FB) dose 100 mg twice a day (BID). Rociletinib free base (FB) dose 300 mg twice a day (BID). Rociletinib free base (FB) dose 600 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 9 3 3 3 3 3 3 3 5 19 18 21 23 6
    Day 1 AUC 0-24
    2900
    (290)
    5330
    (5880)
    8370
    (6612)
    8850
    (6461)
    5840
    (3387)
    13300
    (6650)
    5740
    (2927)
    8470
    (1008)
    20400
    (12444)
    16000
    (8960)
    26800
    (13668)
    33100
    (26149)
    30300
    (16968)
    50100
    (35070)
    Day 15 AUC 0-24
    1540
    (970)
    3510
    (2620)
    12100
    (11616)
    4490
    (3817)
    4800
    (2256)
    11500
    (6555)
    7100
    (4189)
    6080
    (4560)
    12100
    (1404)
    17500
    (10675)
    23700
    (13035)
    31700
    (18386)
    25800
    (14190)
    28200
    (16638)
    9. Secondary Outcome
    Title PK Profile of Rociletinib - T 1/2
    Description T 1/2 = elimination half-life following administration of rociletinib
    Time Frame Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

    Outcome Measure Data

    Analysis Population Description
    PK parameters were assessed in a subset of patients treated with rociletinib. For some parameters, the number analyzed at Day 1 and Day 15 differs from the overall number analyzed based on the number of evaluable samples collected at each time point. Elimination half-life was not calculated for patients in the 400 mg TID treatment group.
    Arm/Group Title Rociletinib 150 mg QD FB Capsules Rociletinib 200 mg QD FB Capsules Rociletinib 300 mg QD FB Capsules Rociletinib 450 mg QD FB Capsules Rociletinib 600 mg QD FB Capsules Rociletinib 900 mg QD FB Capsules Rociletinib 100 mg BID FB Capsules Rociletinib 300 mg BID FB Capsules Rociletinib 600 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose 150 mg once a day (QD). Rociletinib free base (FB) dose 200 mg once a day (QD). Rociletinib free base (FB) dose 300 mg once a day (QD). Rociletinib free base (FB) dose 450 mg once a day (QD). Rociletinib free base (FB) dose 600 mg once a day (QD). Rociletinib free base (FB) dose 900 mg once a day (QD). Rociletinib free base (FB) dose 100 mg twice a day (BID). Rociletinib free base (FB) dose 300 mg twice a day (BID). Rociletinib free base (FB) dose 600 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 9 3 3 3 3 3 3 3 5 19 18 21 23 6
    Day 1 T 1/2
    4.8
    (3.6)
    3.9
    (2.3)
    4.6
    (1.7)
    3.7
    (1.1)
    4.4
    (0.9)
    3.5
    (2.8)
    3.0
    (0.8)
    3.5
    (1.0)
    3.6
    (0.9)
    2.8
    (0.7)
    2.7
    (0.7)
    3.5
    (1.5)
    3.1
    (1.5)
    3.4
    (0.9)
    Day 15 T 1/2
    5.5
    (3.1)
    3.5
    (1.3)
    4.3
    (1.2)
    3.9
    (2.5)
    4.1
    (2.2)
    3.5
    (.56)
    3.1
    (0.9)
    2.9
    (0.7)
    4.7
    (3.4)
    2.7
    (1.9)
    3.0
    (1.6)
    3.2
    (0.8)
    3.6
    (3.1)
    3.9
    (1.9)
    10. Secondary Outcome
    Title Food Effect on PK of Rociletinib - Cmax
    Description Cmax = maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
    Time Frame Day -7 prior to Cycle 1 Day 1, or approximately 7 days

    Outcome Measure Data

    Analysis Population Description
    A subset of 3 patients treated with rociletinib 150 mg FB capsules
    Arm/Group Title Cmax Fasting Cmax Fed
    Arm/Group Description Rociletinib 150 mg FB single dose given while fasting Rociletinib 150 mg FB single dose given with a high-fat breakfast
    Measure Participants 3 3
    Mean (Standard Deviation) [ng/mL]
    727
    (354)
    1873
    (2570)
    11. Secondary Outcome
    Title Food Effect on PK of Rociletinib - Tmax
    Description Tmax = time to maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
    Time Frame Day -7 prior to Cycle 1 Day 1, or approximately 7 days

    Outcome Measure Data

    Analysis Population Description
    A subset of 3 patients treated with rociletinib 150 mg FB capsules
    Arm/Group Title Tmax Fasting Tmax Fed
    Arm/Group Description Rociletinib 150 mg FB single dose given while fasting Rociletinib 150 mg FB single dose given with a high-fat breakfast
    Measure Participants 3 3
    Median (Full Range) [Hours]
    1.5
    4.8
    12. Secondary Outcome
    Title Food Effect on PK of Rociletinib - AUC 0-24
    Description AUC 0-24 = area under the curve from 0 to 24 hours. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
    Time Frame Day -7 prior to Cycle 1 Day 1, or approximately 7 days

    Outcome Measure Data

    Analysis Population Description
    A subset of 3 patients treated with rociletinib 150 mg FB capsules. AUC could not be determined for 1 patient in the Fed arm.
    Arm/Group Title AUC 0-24 Fasting AUC 0-24 Fed
    Arm/Group Description Rociletinib 150 mg FB single dose given while fasting Rociletinib 150 mg FB single dose given with a high-fat breakfast
    Measure Participants 3 2
    Mean (Standard Deviation) [ng*hr/mL]
    4780
    (3625)
    4455
    (2256)
    13. Secondary Outcome
    Title Food Effect on PK of Rociletinib - C24
    Description C24 = rociletinib plasma concentration at 24 hours post the morning dose. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
    Time Frame Day -7 prior to Cycle 1 Day 1, or approximately 7 days

    Outcome Measure Data

    Analysis Population Description
    A subset of 3 patients treated with rociletinib 150 mg FB capsules
    Arm/Group Title C24 Fasting C24 Fed
    Arm/Group Description Rociletinib 150 mg FB single dose given while fasting Rociletinib 150 mg FB single dose given with a high-fat breakfast
    Measure Participants 3 3
    Mean (Standard Deviation) [ng/mL]
    21.3
    (22)
    46.5
    (51)
    14. Secondary Outcome
    Title Food Effect on PK of Rociletinib - T 1/2
    Description T 1/2 = elimination half-life following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.
    Time Frame Day -7 prior to Cycle 1 Day 1, or approximately 7 days

    Outcome Measure Data

    Analysis Population Description
    A subset of 3 patients treated with rociletinib 150 mg FB capsules. Data did not allow the calculation of half-life with high fat mean in 2 patients.
    Arm/Group Title T 1/2 Fasting T 1/2 Fed
    Arm/Group Description Rociletinib 150 mg FB single dose given while fasting Rociletinib 150 mg FB single dose given with a high-fat breakfast
    Measure Participants 3 1
    Mean (Standard Deviation) [Hours]
    4.3
    (1)
    3.1
    (NA)
    15. Secondary Outcome
    Title QTcF Values Post Baseline by Daily Dose
    Description Frequency of QT interval prolongation by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.
    Time Frame Screening to End of Treatment, up to approximately 42 months

    Outcome Measure Data

    Analysis Population Description
    Safety population by daily dose
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 38 19 209 245 95 6
    QTcF Post-Baseline <450 msec
    34
    89.5%
    10
    52.6%
    93
    44.5%
    99
    40.4%
    35
    36.8%
    2
    33.3%
    QTcF Post-Baseline 450-480 msec
    4
    10.5%
    7
    36.8%
    71
    34%
    93
    38%
    30
    31.6%
    2
    33.3%
    QTcF Post-Baseline 481-500 msec
    0
    0%
    1
    5.3%
    23
    11%
    24
    9.8%
    11
    11.6%
    2
    33.3%
    QTcF Post-Baseline >=501 msec
    0
    0%
    1
    5.3%
    22
    10.5%
    29
    11.8%
    19
    20%
    0
    0%
    16. Secondary Outcome
    Title QTcF Value Change From Baseline
    Description QTcF value change from baseline by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.
    Time Frame Screening to End of Treatment, up to approximately 42 months

    Outcome Measure Data

    Analysis Population Description
    Safety population by daily dose
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    Measure Participants 38 19 209 245 95 6
    QTcF Change from Baseline <=30 msec
    29
    76.3%
    11
    57.9%
    47
    22.5%
    55
    22.4%
    12
    12.6%
    1
    16.7%
    QTcF Change from Baseline 30-60 msec
    9
    23.7%
    8
    42.1%
    104
    49.8%
    101
    41.2%
    39
    41.1%
    3
    50%
    QTcF Change from Baseline >60 msec
    0
    0%
    0
    0%
    58
    27.8%
    89
    36.3%
    44
    46.3%
    2
    33.3%
    17. Secondary Outcome
    Title Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR
    Description Objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST Version 1.1 as determined by independent radiology review (IRR)
    Time Frame Cycle 1 Day 1 to End of Treatment / End of Follow-up

    Outcome Measure Data

    Analysis Population Description
    Tumor scans were collected for independent evaluation, however ORR, DOR and PFS analyses were not performed by the central reader since the sponsor deemed not necessary following early study termination. Therefore, all IRR outcome measures were not collected and can not be reported.
    Arm/Group Title Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets
    Arm/Group Description Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID).
    Measure Participants 0 0

    Adverse Events

    Time Frame Adverse events were reported from the date of first dose of study drug and within 28 days after last dose of study drug, or up to approximately 42 months. In addition, study procedure-related AEs that occur after signing of the informed consent form and before first dose of study drug were expected to be reported. Any Serious Adverse Events or Adverse Events of Special Interest were followed until resolution or stabilization, or until patient is lost to follow-up.
    Adverse Event Reporting Description If a subject experiences the same preferred term (system organ class) multiple times, then the subject will be counted only once for that preferred term (system organ class).
    Arm/Group Title Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    Arm/Group Description Rociletinib free base (FB) dose <900 mg twice a day (BID). Rociletinib free base (FB) dose 900 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID). Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID).
    All Cause Mortality
    Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    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 4/38 (10.5%) 4/19 (21.1%) 31/209 (14.8%) 40/245 (16.3%) 19/95 (20%) 3/6 (50%)
    Serious Adverse Events
    Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    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 14/38 (36.8%) 8/19 (42.1%) 106/209 (50.7%) 138/245 (56.3%) 54/95 (56.8%) 5/6 (83.3%)
    Blood and lymphatic system disorders
    Anaemia 0/38 (0%) 0/19 (0%) 4/209 (1.9%) 2/245 (0.8%) 2/95 (2.1%) 0/6 (0%)
    Lymphadenopathy 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cardiac disorders
    Acute myocardial infarction 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Atrial fibrillation 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 2/95 (2.1%) 0/6 (0%)
    Atrial tachycardia 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Atrioventricular block complete 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Bradycardia 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Cardiac arrest 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Cardiac failure congestive 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Palpitations 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Pericardial effusion 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Pericarditis 1/38 (2.6%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Sinus tachycardia 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Supraventricular tachycardia 0/38 (0%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Torsade de pointes 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Ventricular tachyarrhythmia 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Ear and labyrinth disorders
    Vertigo 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Endocrine disorders
    Adrenal insufficiency 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Inappropriate antidiuretic hormone secretion 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Eye disorders
    Cataract 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 4/245 (1.6%) 3/95 (3.2%) 1/6 (16.7%)
    Gastrointestinal disorders
    Abdominal pain 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 7/245 (2.9%) 1/95 (1.1%) 0/6 (0%)
    Abdominal pain upper 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Ascites 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Colitis 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Constipation 0/38 (0%) 0/19 (0%) 0/209 (0%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Diarrhoea 1/38 (2.6%) 1/19 (5.3%) 2/209 (1%) 5/245 (2%) 1/95 (1.1%) 0/6 (0%)
    Gastrointestinal haemorrhage 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 2/95 (2.1%) 0/6 (0%)
    Gastrooesophageal reflux disease 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Ileus 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Intestinal dilatation 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Intestinal Obstruction 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Large intestinal obstruction 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Mallory-Weiss syndrome 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Melaena 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Nausea 1/38 (2.6%) 0/19 (0%) 5/209 (2.4%) 6/245 (2.4%) 1/95 (1.1%) 0/6 (0%)
    Oesophagitis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Pancreatitis 0/38 (0%) 0/19 (0%) 5/209 (2.4%) 4/245 (1.6%) 1/95 (1.1%) 1/6 (16.7%)
    Pancreatitis acute 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Rectal haemorrhage 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Small intestinal obstruction 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Small intestinal perforation 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Subileus 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Upper gastrointestinal haemorrhage 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Vomiting 1/38 (2.6%) 0/19 (0%) 7/209 (3.3%) 7/245 (2.9%) 1/95 (1.1%) 0/6 (0%)
    General disorders
    Asthenia 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 2/245 (0.8%) 2/95 (2.1%) 0/6 (0%)
    Fatigue 0/38 (0%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 1/6 (16.7%)
    General physical health deterioration 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Non-cardiac chest pain 0/38 (0%) 0/19 (0%) 2/209 (1%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Oedema peripheral 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pain 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Pyrexia 0/38 (0%) 0/19 (0%) 4/209 (1.9%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Sudden death 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Hepatobiliary disorders
    Bile duct obstruction 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Bile duct stone 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cholecystitis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Cholecystitis acute 0/38 (0%) 0/19 (0%) 2/209 (1%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Cholelithiasis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Hepatic pain 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Liver injury 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Immune system disorders
    Drug hypersensitivity 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hypersensitivity 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Infections and infestations
    Arthritis bacterial 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Bacteraemia 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Bronchitis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Cellulitis 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Clostridium difficile colitis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Clostridium difficile infection 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 1/6 (16.7%)
    Device related infection 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Endocarditis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Gastroenteritis 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Hepatic infection 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Influenza 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Liver abscess 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Lung infection 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Pneumonia 2/38 (5.3%) 0/19 (0%) 7/209 (3.3%) 10/245 (4.1%) 7/95 (7.4%) 2/6 (33.3%)
    Pneumonia bacterial 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pneumonia influenzal 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Postoperative wound infection 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Pyelonephritis 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Sepsis 1/38 (2.6%) 0/19 (0%) 4/209 (1.9%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Septic shock 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Serratia bacteraemia 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Staphylococcal bacteraemia 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Urinary tract infection 0/38 (0%) 0/19 (0%) 3/209 (1.4%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Urosepsis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Injury, poisoning and procedural complications
    Fall 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Femoral neck fracture 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Hip fracture 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Jaw fracture 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Radiation necrosis 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Radiation pneumonitis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Rib fracture 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Subcutaneous haematoma 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Subdural haemorrhage 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Investigations
    Blood bilirubin increased 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Blood creatinine increased 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Electrocardiogram QT prolonged 0/38 (0%) 0/19 (0%) 2/209 (1%) 2/245 (0.8%) 1/95 (1.1%) 0/6 (0%)
    Electrocardiogram T wave inversion 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    General physical condition abnormal 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Lipase increased 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Transaminases increased 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 1/6 (16.7%)
    Troponin increased 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Dehydration 0/38 (0%) 0/19 (0%) 2/209 (1%) 7/245 (2.9%) 1/95 (1.1%) 0/6 (0%)
    Diabetic ketoacidosis 0/38 (0%) 0/19 (0%) 4/209 (1.9%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Failure to thrive 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Fluid overload 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Glucose tolerance impaired 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hypercalcaemia 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hyperglycaemia 1/38 (2.6%) 0/19 (0%) 21/209 (10%) 19/245 (7.8%) 7/95 (7.4%) 2/6 (33.3%)
    Hypoglycaemia 1/38 (2.6%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hypokalaemia 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 2/95 (2.1%) 0/6 (0%)
    Hyponatraemia 0/38 (0%) 0/19 (0%) 5/209 (2.4%) 4/245 (1.6%) 1/95 (1.1%) 0/6 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Back pain 1/38 (2.6%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Bursitis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Chondrocalcinosis pyrophosphate 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Muscular weakness 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Musculoskeletal chest pain 0/38 (0%) 0/19 (0%) 0/209 (0%) 3/245 (1.2%) 1/95 (1.1%) 0/6 (0%)
    Pain in extremity 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pathological fracture 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Spinal pain 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cancer pain 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Malignant neoplasm progression 8/38 (21.1%) 5/19 (26.3%) 25/209 (12%) 37/245 (15.1%) 21/95 (22.1%) 1/6 (16.7%)
    Malignant pleural infusion 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Metastases to central nervous system 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Metastases to skin 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Neoplasm malignant 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Transitional cell carcinoma 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Nervous system disorders
    Basilar artery thrombosis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Brain oedema 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cerebrovascular accident 0/38 (0%) 0/19 (0%) 3/209 (1.4%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Coma 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Disturbance in attention 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Dizziness 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Haemorrhage intracranial 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Headache 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 2/245 (0.8%) 3/95 (3.2%) 0/6 (0%)
    Presyncope 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Seizure 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 3/95 (3.2%) 0/6 (0%)
    Spinal cord oedema 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Status epilepticus 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Syncope 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Transient ischaemic attack 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Psychiatric disorders
    Anxiety 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Confusional state 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hallucination 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Mental status changes 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 2/95 (2.1%) 0/6 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/38 (0%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Haematuria 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Nephrolithiasis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Renal failure 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Reproductive system and breast disorders
    Pelvic pain 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Vaginal haemorrhage 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Aspiration 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cough 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Dyspnoea 0/38 (0%) 0/19 (0%) 8/209 (3.8%) 10/245 (4.1%) 0/95 (0%) 0/6 (0%)
    Dyspnoea exertional 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Epistaxis 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Haemoptysis 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Hypoxia 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 1/95 (1.1%) 0/6 (0%)
    Interstitial lung disease 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Lung disorder 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pleural effusion 0/38 (0%) 0/19 (0%) 2/209 (1%) 5/245 (2%) 2/95 (2.1%) 0/6 (0%)
    Pleuritic pain 1/38 (2.6%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pneumonia aspiration 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Pneumonitis 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 2/95 (2.1%) 0/6 (0%)
    Pneumothorax 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 4/245 (1.6%) 1/95 (1.1%) 0/6 (0%)
    Pulmonary embolism 0/38 (0%) 0/19 (0%) 3/209 (1.4%) 5/245 (2%) 1/95 (1.1%) 0/6 (0%)
    Pulmonary fibrosis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Pulmonary haemorrhage 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Pulmonary hypertension 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Respiratory distress 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Respiratory failure 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Vascular disorders
    Deep vein thrombosis 0/38 (0%) 0/19 (0%) 0/209 (0%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Hypotension 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Subgaleal haematoma 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Venous thrombosis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Other (Not Including Serious) Adverse Events
    Rociletinib <900 mg BID FB Capsules Rociletinib 900 mg BID FB Capsules Rociletinib 500 mg BID HBr Tablets Rociletinib 625 mg BID HBr Tablets Rociletinib 750 mg BID HBr Tablets Rociletinib 1000 mg BID HBr Tablets
    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 37/38 (97.4%) 19/19 (100%) 208/209 (99.5%) 244/245 (99.6%) 95/95 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Anaemia 5/38 (13.2%) 3/19 (15.8%) 47/209 (22.5%) 74/245 (30.2%) 19/95 (20%) 1/6 (16.7%)
    Increased tendency to bruise 0/38 (0%) 2/19 (10.5%) 1/209 (0.5%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Leukocytosis 2/38 (5.3%) 0/19 (0%) 3/209 (1.4%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Leukopenia 1/38 (2.6%) 0/19 (0%) 8/209 (3.8%) 8/245 (3.3%) 6/95 (6.3%) 0/6 (0%)
    Lymphopenia 0/38 (0%) 1/19 (5.3%) 9/209 (4.3%) 9/245 (3.7%) 0/95 (0%) 0/6 (0%)
    Neutropenia 1/38 (2.6%) 0/19 (0%) 10/209 (4.8%) 11/245 (4.5%) 7/95 (7.4%) 0/6 (0%)
    Thrombocytopenia 3/38 (7.9%) 3/19 (15.8%) 21/209 (10%) 19/245 (7.8%) 17/95 (17.9%) 0/6 (0%)
    Cardiac disorders
    Sinus tachycardia 1/38 (2.6%) 1/19 (5.3%) 10/209 (4.8%) 1/245 (0.4%) 2/95 (2.1%) 0/6 (0%)
    Ear and labyrinth disorders
    Deafness unilateral 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Dysacusis 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Eye disorders
    Cataract 0/38 (0%) 0/19 (0%) 16/209 (7.7%) 29/245 (11.8%) 17/95 (17.9%) 2/6 (33.3%)
    Diplopia 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Dry eye 1/38 (2.6%) 1/19 (5.3%) 4/209 (1.9%) 9/245 (3.7%) 0/95 (0%) 0/6 (0%)
    Lacrimation increased 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Vision blurred 1/38 (2.6%) 1/19 (5.3%) 13/209 (6.2%) 18/245 (7.3%) 13/95 (13.7%) 0/6 (0%)
    Visual acuity reduced 1/38 (2.6%) 1/19 (5.3%) 4/209 (1.9%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Visual impairment 0/38 (0%) 0/19 (0%) 5/209 (2.4%) 5/245 (2%) 3/95 (3.2%) 1/6 (16.7%)
    Vitreous floaters 0/38 (0%) 1/19 (5.3%) 3/209 (1.4%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Abdominal distension 0/38 (0%) 1/19 (5.3%) 8/209 (3.8%) 8/245 (3.3%) 3/95 (3.2%) 0/6 (0%)
    Abdominal pain 3/38 (7.9%) 4/19 (21.1%) 25/209 (12%) 39/245 (15.9%) 17/95 (17.9%) 0/6 (0%)
    Abdominal pain upper 2/38 (5.3%) 0/19 (0%) 15/209 (7.2%) 18/245 (7.3%) 11/95 (11.6%) 2/6 (33.3%)
    Constipation 9/38 (23.7%) 2/19 (10.5%) 42/209 (20.1%) 94/245 (38.4%) 26/95 (27.4%) 2/6 (33.3%)
    Diarrhoea 8/38 (21.1%) 11/19 (57.9%) 121/209 (57.9%) 146/245 (59.6%) 54/95 (56.8%) 3/6 (50%)
    Dry mouth 2/38 (5.3%) 0/19 (0%) 26/209 (12.4%) 22/245 (9%) 16/95 (16.8%) 0/6 (0%)
    Dyspepsia 2/38 (5.3%) 2/19 (10.5%) 7/209 (3.3%) 6/245 (2.4%) 5/95 (5.3%) 1/6 (16.7%)
    Flatulence 0/38 (0%) 1/19 (5.3%) 3/209 (1.4%) 3/245 (1.2%) 2/95 (2.1%) 0/6 (0%)
    Gastrooesophageal reflux disease 0/38 (0%) 2/19 (10.5%) 22/209 (10.5%) 26/245 (10.6%) 12/95 (12.6%) 0/6 (0%)
    Gingival bleeding 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Ileus 0/38 (0%) 2/19 (10.5%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Mouth ulceration 3/38 (7.9%) 0/19 (0%) 1/209 (0.5%) 3/245 (1.2%) 0/95 (0%) 0/6 (0%)
    Nausea 14/38 (36.8%) 11/19 (57.9%) 95/209 (45.5%) 138/245 (56.3%) 51/95 (53.7%) 3/6 (50%)
    Pancreatitis 0/38 (0%) 0/19 (0%) 5/209 (2.4%) 5/245 (2%) 1/95 (1.1%) 1/6 (16.7%)
    Retching 0/38 (0%) 1/19 (5.3%) 3/209 (1.4%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Toothache 2/38 (5.3%) 0/19 (0%) 1/209 (0.5%) 2/245 (0.8%) 2/95 (2.1%) 0/6 (0%)
    Vomiting 9/38 (23.7%) 6/19 (31.6%) 65/209 (31.1%) 82/245 (33.5%) 32/95 (33.7%) 2/6 (33.3%)
    General disorders
    Asthenia 6/38 (15.8%) 1/19 (5.3%) 28/209 (13.4%) 34/245 (13.9%) 17/95 (17.9%) 1/6 (16.7%)
    Catheter site pain 0/38 (0%) 0/19 (0%) 2/209 (1%) 3/245 (1.2%) 0/95 (0%) 1/6 (16.7%)
    Chills 1/38 (2.6%) 1/19 (5.3%) 6/209 (2.9%) 9/245 (3.7%) 1/95 (1.1%) 0/6 (0%)
    Face oedema 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Fatigue 9/38 (23.7%) 8/19 (42.1%) 109/209 (52.2%) 124/245 (50.6%) 47/95 (49.5%) 3/6 (50%)
    Feeling abnormal 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Feeling cold 1/38 (2.6%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 1/95 (1.1%) 1/6 (16.7%)
    Gait disturbance 0/38 (0%) 3/19 (15.8%) 8/209 (3.8%) 10/245 (4.1%) 1/95 (1.1%) 0/6 (0%)
    Influenza like illness 1/38 (2.6%) 1/19 (5.3%) 5/209 (2.4%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Malaise 0/38 (0%) 1/19 (5.3%) 5/209 (2.4%) 3/245 (1.2%) 2/95 (2.1%) 0/6 (0%)
    Non-cardiac chest pain 3/38 (7.9%) 1/19 (5.3%) 9/209 (4.3%) 18/245 (7.3%) 4/95 (4.2%) 0/6 (0%)
    Oedema peripheral 4/38 (10.5%) 1/19 (5.3%) 40/209 (19.1%) 31/245 (12.7%) 14/95 (14.7%) 0/6 (0%)
    Pain 1/38 (2.6%) 1/19 (5.3%) 7/209 (3.3%) 8/245 (3.3%) 6/95 (6.3%) 0/6 (0%)
    Pyrexia 4/38 (10.5%) 2/19 (10.5%) 19/209 (9.1%) 27/245 (11%) 7/95 (7.4%) 0/6 (0%)
    Temperature intolerance 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 2/38 (5.3%) 1/19 (5.3%) 6/209 (2.9%) 6/245 (2.4%) 5/95 (5.3%) 0/6 (0%)
    Jaundice 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Immune system disorders
    Seasonal allergy 2/38 (5.3%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 3/95 (3.2%) 0/6 (0%)
    Infections and infestations
    Bacterial disease carrier 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Candida infection 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 5/245 (2%) 1/95 (1.1%) 0/6 (0%)
    Clostridium difficile infection 0/38 (0%) 0/19 (0%) 0/209 (0%) 4/245 (1.6%) 0/95 (0%) 1/6 (16.7%)
    Cystitis 0/38 (0%) 1/19 (5.3%) 3/209 (1.4%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Eye infection 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 1/6 (16.7%)
    Folliculitis 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Nasopharyngitis 1/38 (2.6%) 1/19 (5.3%) 6/209 (2.9%) 9/245 (3.7%) 0/95 (0%) 0/6 (0%)
    Pneumonia 2/38 (5.3%) 1/19 (5.3%) 12/209 (5.7%) 15/245 (6.1%) 11/95 (11.6%) 2/6 (33.3%)
    Rhinitis 0/38 (0%) 2/19 (10.5%) 1/209 (0.5%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Sinusitis 0/38 (0%) 1/19 (5.3%) 6/209 (2.9%) 9/245 (3.7%) 1/95 (1.1%) 0/6 (0%)
    Tooth infection 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 6/245 (2.4%) 1/95 (1.1%) 0/6 (0%)
    Upper respiratory tract infection 3/38 (7.9%) 2/19 (10.5%) 23/209 (11%) 16/245 (6.5%) 14/95 (14.7%) 1/6 (16.7%)
    Urinary tract infection 1/38 (2.6%) 1/19 (5.3%) 27/209 (12.9%) 25/245 (10.2%) 18/95 (18.9%) 0/6 (0%)
    Viral upper respiratory tract infection 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 1/245 (0.4%) 2/95 (2.1%) 0/6 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/38 (0%) 3/19 (15.8%) 14/209 (6.7%) 14/245 (5.7%) 4/95 (4.2%) 0/6 (0%)
    Fall 0/38 (0%) 2/19 (10.5%) 9/209 (4.3%) 8/245 (3.3%) 4/95 (4.2%) 0/6 (0%)
    Femoral neck fracture 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Hip fracture 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Investigations
    Alanine aminotransferase increased 3/38 (7.9%) 3/19 (15.8%) 19/209 (9.1%) 26/245 (10.6%) 8/95 (8.4%) 0/6 (0%)
    Amylase increased 0/38 (0%) 0/19 (0%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 1/6 (16.7%)
    Aspartate aminotransferase increased 4/38 (10.5%) 4/19 (21.1%) 21/209 (10%) 26/245 (10.6%) 10/95 (10.5%) 0/6 (0%)
    Blood alkaline phosphatase increased 4/38 (10.5%) 1/19 (5.3%) 13/209 (6.2%) 16/245 (6.5%) 7/95 (7.4%) 1/6 (16.7%)
    Blood bilirubin increased 0/38 (0%) 4/19 (21.1%) 16/209 (7.7%) 15/245 (6.1%) 13/95 (13.7%) 1/6 (16.7%)
    Blood creatinine increased 0/38 (0%) 2/19 (10.5%) 13/209 (6.2%) 20/245 (8.2%) 7/95 (7.4%) 1/6 (16.7%)
    Blood glucose increased 1/38 (2.6%) 1/19 (5.3%) 4/209 (1.9%) 9/245 (3.7%) 7/95 (7.4%) 2/6 (33.3%)
    Blood phosphorus decreased 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Blood urine present 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Electrocardiogram QT prolonged 0/38 (0%) 3/19 (15.8%) 61/209 (29.2%) 77/245 (31.4%) 33/95 (34.7%) 3/6 (50%)
    Electrocardiogram T wave abnormal 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Glycosylated haemoglobin increased 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 12/245 (4.9%) 2/95 (2.1%) 1/6 (16.7%)
    Insulin C-peptide increased 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 11/245 (4.5%) 5/95 (5.3%) 0/6 (0%)
    Lipase increased 0/38 (0%) 0/19 (0%) 3/209 (1.4%) 2/245 (0.8%) 1/95 (1.1%) 1/6 (16.7%)
    Lymphocyte count decreased 0/38 (0%) 0/19 (0%) 12/209 (5.7%) 8/245 (3.3%) 2/95 (2.1%) 0/6 (0%)
    Neutrophil count increased 0/38 (0%) 1/19 (5.3%) 2/209 (1%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Platelet count decreased 0/38 (0%) 0/19 (0%) 20/209 (9.6%) 17/245 (6.9%) 3/95 (3.2%) 0/6 (0%)
    QRS axis abnormal 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Transaminases increased 0/38 (0%) 2/19 (10.5%) 5/209 (2.4%) 4/245 (1.6%) 1/95 (1.1%) 1/6 (16.7%)
    Weight decreased 4/38 (10.5%) 4/19 (21.1%) 59/209 (28.2%) 63/245 (25.7%) 39/95 (41.1%) 2/6 (33.3%)
    White blood cell count decreased 1/38 (2.6%) 0/19 (0%) 19/209 (9.1%) 20/245 (8.2%) 2/95 (2.1%) 0/6 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 9/38 (23.7%) 10/19 (52.6%) 80/209 (38.3%) 92/245 (37.6%) 43/95 (45.3%) 4/6 (66.7%)
    Dehydration 3/38 (7.9%) 4/19 (21.1%) 21/209 (10%) 30/245 (12.2%) 12/95 (12.6%) 0/6 (0%)
    Glucose tolerance impaired 0/38 (0%) 1/19 (5.3%) 6/209 (2.9%) 9/245 (3.7%) 11/95 (11.6%) 0/6 (0%)
    Gout 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Hyperglycaemia 4/38 (10.5%) 10/19 (52.6%) 113/209 (54.1%) 147/245 (60%) 56/95 (58.9%) 3/6 (50%)
    Hyperkalaemia 1/38 (2.6%) 1/19 (5.3%) 7/209 (3.3%) 6/245 (2.4%) 2/95 (2.1%) 0/6 (0%)
    Hypoalbuminaemia 2/38 (5.3%) 2/19 (10.5%) 18/209 (8.6%) 22/245 (9%) 3/95 (3.2%) 0/6 (0%)
    Hypocalcaemia 0/38 (0%) 1/19 (5.3%) 6/209 (2.9%) 11/245 (4.5%) 2/95 (2.1%) 0/6 (0%)
    Hypoglycaemia 2/38 (5.3%) 0/19 (0%) 2/209 (1%) 8/245 (3.3%) 6/95 (6.3%) 0/6 (0%)
    Hypokalaemia 0/38 (0%) 1/19 (5.3%) 27/209 (12.9%) 44/245 (18%) 14/95 (14.7%) 1/6 (16.7%)
    Hypomagnesaemia 0/38 (0%) 0/19 (0%) 25/209 (12%) 30/245 (12.2%) 10/95 (10.5%) 2/6 (33.3%)
    Hyponatraemia 0/38 (0%) 2/19 (10.5%) 25/209 (12%) 24/245 (9.8%) 8/95 (8.4%) 1/6 (16.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 5/38 (13.2%) 3/19 (15.8%) 23/209 (11%) 31/245 (12.7%) 13/95 (13.7%) 0/6 (0%)
    Back pain 6/38 (15.8%) 3/19 (15.8%) 26/209 (12.4%) 43/245 (17.6%) 15/95 (15.8%) 0/6 (0%)
    Bone pain 0/38 (0%) 2/19 (10.5%) 4/209 (1.9%) 4/245 (1.6%) 0/95 (0%) 0/6 (0%)
    Flank pain 0/38 (0%) 1/19 (5.3%) 5/209 (2.4%) 4/245 (1.6%) 3/95 (3.2%) 0/6 (0%)
    Joint swelling 0/38 (0%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 3/95 (3.2%) 1/6 (16.7%)
    Muscle spasms 4/38 (10.5%) 6/19 (31.6%) 57/209 (27.3%) 71/245 (29%) 27/95 (28.4%) 2/6 (33.3%)
    Muscular weakness 0/38 (0%) 1/19 (5.3%) 9/209 (4.3%) 12/245 (4.9%) 5/95 (5.3%) 0/6 (0%)
    Musculoskeletal chest pain 3/38 (7.9%) 2/19 (10.5%) 12/209 (5.7%) 21/245 (8.6%) 13/95 (13.7%) 1/6 (16.7%)
    Musculoskeletal discomfort 2/38 (5.3%) 0/19 (0%) 2/209 (1%) 1/245 (0.4%) 0/95 (0%) 0/6 (0%)
    Musculoskeletal pain 8/38 (21.1%) 1/19 (5.3%) 20/209 (9.6%) 22/245 (9%) 10/95 (10.5%) 0/6 (0%)
    Myalgia 5/38 (13.2%) 4/19 (21.1%) 23/209 (11%) 16/245 (6.5%) 10/95 (10.5%) 1/6 (16.7%)
    Pain in extremity 3/38 (7.9%) 0/19 (0%) 14/209 (6.7%) 23/245 (9.4%) 5/95 (5.3%) 0/6 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 11/38 (28.9%) 5/19 (26.3%) 28/209 (13.4%) 38/245 (15.5%) 26/95 (27.4%) 1/6 (16.7%)
    Nervous system disorders
    Ageusia 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Amnesia 1/38 (2.6%) 1/19 (5.3%) 4/209 (1.9%) 2/245 (0.8%) 1/95 (1.1%) 0/6 (0%)
    Ataxia 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 3/245 (1.2%) 2/95 (2.1%) 0/6 (0%)
    Balance disorder 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 3/245 (1.2%) 0/95 (0%) 1/6 (16.7%)
    Disturbance in attention 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Dizziness 4/38 (10.5%) 4/19 (21.1%) 25/209 (12%) 41/245 (16.7%) 14/95 (14.7%) 1/6 (16.7%)
    Dysarthria 0/38 (0%) 2/19 (10.5%) 0/209 (0%) 0/245 (0%) 2/95 (2.1%) 0/6 (0%)
    Dysgeusia 1/38 (2.6%) 2/19 (10.5%) 17/209 (8.1%) 16/245 (6.5%) 5/95 (5.3%) 0/6 (0%)
    Headache 6/38 (15.8%) 5/19 (26.3%) 57/209 (27.3%) 57/245 (23.3%) 20/95 (21.1%) 1/6 (16.7%)
    Hemiparesis 0/38 (0%) 1/19 (5.3%) 3/209 (1.4%) 1/245 (0.4%) 1/95 (1.1%) 0/6 (0%)
    Hypoaesthesia 1/38 (2.6%) 3/19 (15.8%) 5/209 (2.4%) 6/245 (2.4%) 2/95 (2.1%) 0/6 (0%)
    Neuropathy peripheral 1/38 (2.6%) 1/19 (5.3%) 5/209 (2.4%) 9/245 (3.7%) 4/95 (4.2%) 0/6 (0%)
    Paraesthesia 2/38 (5.3%) 0/19 (0%) 10/209 (4.8%) 17/245 (6.9%) 4/95 (4.2%) 0/6 (0%)
    Restless legs syndrome 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 1/95 (1.1%) 0/6 (0%)
    Seizure 0/38 (0%) 0/19 (0%) 1/209 (0.5%) 6/245 (2.4%) 5/95 (5.3%) 0/6 (0%)
    Tension headache 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Tremor 1/38 (2.6%) 3/19 (15.8%) 7/209 (3.3%) 7/245 (2.9%) 4/95 (4.2%) 1/6 (16.7%)
    Vocal cord paralysis 0/38 (0%) 0/19 (0%) 0/209 (0%) 1/245 (0.4%) 0/95 (0%) 1/6 (16.7%)
    Psychiatric disorders
    Anxiety 0/38 (0%) 2/19 (10.5%) 19/209 (9.1%) 20/245 (8.2%) 8/95 (8.4%) 1/6 (16.7%)
    Confusional state 0/38 (0%) 0/19 (0%) 8/209 (3.8%) 13/245 (5.3%) 3/95 (3.2%) 0/6 (0%)
    Depression 3/38 (7.9%) 3/19 (15.8%) 8/209 (3.8%) 12/245 (4.9%) 4/95 (4.2%) 1/6 (16.7%)
    Insomnia 4/38 (10.5%) 2/19 (10.5%) 19/209 (9.1%) 31/245 (12.7%) 8/95 (8.4%) 0/6 (0%)
    Renal and urinary disorders
    Micturition urgency 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 2/245 (0.8%) 0/95 (0%) 0/6 (0%)
    Pollakiuria 1/38 (2.6%) 1/19 (5.3%) 8/209 (3.8%) 12/245 (4.9%) 1/95 (1.1%) 0/6 (0%)
    Renal impairment 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Urge incontinence 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Urinary tract disorder 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Respiratory, thoracic and mediastinal disorders
    Apnoea 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Cough 9/38 (23.7%) 3/19 (15.8%) 62/209 (29.7%) 59/245 (24.1%) 15/95 (15.8%) 1/6 (16.7%)
    Dysphonia 2/38 (5.3%) 1/19 (5.3%) 4/209 (1.9%) 6/245 (2.4%) 2/95 (2.1%) 0/6 (0%)
    Dypnoea 10/38 (26.3%) 2/19 (10.5%) 51/209 (24.4%) 65/245 (26.5%) 20/95 (21.1%) 2/6 (33.3%)
    Dyspnoea exertional 3/38 (7.9%) 0/19 (0%) 12/209 (5.7%) 9/245 (3.7%) 7/95 (7.4%) 0/6 (0%)
    Epistaxis 2/38 (5.3%) 2/19 (10.5%) 7/209 (3.3%) 12/245 (4.9%) 2/95 (2.1%) 0/6 (0%)
    Haemoptysis 1/38 (2.6%) 1/19 (5.3%) 3/209 (1.4%) 12/245 (4.9%) 1/95 (1.1%) 1/6 (16.7%)
    Hypoxia 0/38 (0%) 2/19 (10.5%) 6/209 (2.9%) 7/245 (2.9%) 2/95 (2.1%) 0/6 (0%)
    Nasal congestion 1/38 (2.6%) 1/19 (5.3%) 6/209 (2.9%) 7/245 (2.9%) 2/95 (2.1%) 0/6 (0%)
    Oropharyngeal pain 2/38 (5.3%) 0/19 (0%) 8/209 (3.8%) 7/245 (2.9%) 1/95 (1.1%) 0/6 (0%)
    Paranasal sinus hypersecretion 2/38 (5.3%) 0/19 (0%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Pleural effusion 2/38 (5.3%) 2/19 (10.5%) 6/209 (2.9%) 13/245 (5.3%) 5/95 (5.3%) 1/6 (16.7%)
    Pleuritic pain 3/38 (7.9%) 2/19 (10.5%) 1/209 (0.5%) 4/245 (1.6%) 1/95 (1.1%) 0/6 (0%)
    Pneumonitis 1/38 (2.6%) 1/19 (5.3%) 1/209 (0.5%) 7/245 (2.9%) 3/95 (3.2%) 0/6 (0%)
    Pulmonary embolism 0/38 (0%) 1/19 (5.3%) 5/209 (2.4%) 6/245 (2.4%) 2/95 (2.1%) 1/6 (16.7%)
    Pulmonary hypertension 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Respiratory distress 0/38 (0%) 0/19 (0%) 2/209 (1%) 0/245 (0%) 1/95 (1.1%) 1/6 (16.7%)
    Respiratory failure 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Throat tightness 0/38 (0%) 1/19 (5.3%) 1/209 (0.5%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Wheezing 1/38 (2.6%) 1/19 (5.3%) 4/209 (1.9%) 3/245 (1.2%) 2/95 (2.1%) 0/6 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 2/38 (5.3%) 0/19 (0%) 13/209 (6.2%) 9/245 (3.7%) 11/95 (11.6%) 0/6 (0%)
    Dry skin 1/38 (2.6%) 3/19 (15.8%) 14/209 (6.7%) 18/245 (7.3%) 5/95 (5.3%) 1/6 (16.7%)
    Photosensitivity reaction 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Pruritis 1/38 (2.6%) 1/19 (5.3%) 5/209 (2.4%) 12/245 (4.9%) 4/95 (4.2%) 0/6 (0%)
    Rash 3/38 (7.9%) 2/19 (10.5%) 17/209 (8.1%) 13/245 (5.3%) 12/95 (12.6%) 0/6 (0%)
    Rash morbilliform 0/38 (0%) 1/19 (5.3%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Skin erosion 0/38 (0%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 1/6 (16.7%)
    Vascular disorders
    Flushing 2/38 (5.3%) 0/19 (0%) 0/209 (0%) 0/245 (0%) 0/95 (0%) 0/6 (0%)
    Hypertension 5/38 (13.2%) 0/19 (0%) 16/209 (7.7%) 11/245 (4.5%) 7/95 (7.4%) 0/6 (0%)
    Hypotension 0/38 (0%) 1/19 (5.3%) 4/209 (1.9%) 9/245 (3.7%) 2/95 (2.1%) 0/6 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    All parties agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This will enable all parties to protect proprietary information and to provide comments based on information that may not yet be available to other parties. The sponsor may request a delay in publication if there are important intellectual property concerns relating to publication, but does not have the right to suppress publication of the study results indefinitely.

    Results Point of Contact

    Name/Title Medical Information Department
    Organization Clovis Oncology
    Phone +1 415 409 7220
    Email medinfo@clovisoncology.com
    Responsible Party:
    Clovis Oncology, Inc.
    ClinicalTrials.gov Identifier:
    NCT01526928
    Other Study ID Numbers:
    • CO-1686-008
    First Posted:
    Feb 6, 2012
    Last Update Posted:
    Aug 4, 2020
    Last Verified:
    Jul 1, 2020