Metastatic Renal Cell Carcinoma
Conditions
Keywords
CVX-060, PF-04856884, AG-013736, axitinib, mRCC, metastatic renal cell cancer, second line, anti-angiogenic, Ang-2
Brief summary
To evaluate the combination of PF-04856884 (CVX-060) in combination with Axitinib (AG-013736) in patients that have received one prior systemic regimen for metastatic renal cell carcinoma (mRCC) vs. axitinib alone.
Detailed description
The study was prematurely discontinued on 06Nov2012 due to tolerability findings in patients treated in Part I of the study that have prompted the Sponsor to re-evaluate the strategic development of the program. An unexpected frequency of arterial thrombotic events (ATEs) and venous thrombotic events (VTEs) were reported in patients treated in Part I.
Interventions
BIOLOGICALPF-04856884
15 mg/kg/week intravenously \[IV\] until toxicity or disease progression
5 mg PO BID
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult male or female patients with histologically or cytologically confirmed renal cell cancer (RCC) with a component of clear cell subtype and evidence of metastasis * Evidence of unidimensionally measurable disease * Prior therapy: Part I: Having received 1 to 3 prior systemic regimens for treatment of mRCC * Part II: Evidence of disease progression following 1 prior regimen administered as 1st line therapy for mRCC. The prior regimen must have contained one of the following: VEGFR2 tyrosine kinase inhibitor (TKI) or other anti VEGF \[Vascular Endothelial Growth Factor\] compounds, such as bevacizumab * adequate bone marrow, liver and renal function
Exclusion criteria
Part I: * Intolerant to prior AG 013736 therapy or prior treatment with compounds which contain the core platform antibody as PF 04856884 Part II: * Prior AG 013736 therapy, more than one systemic first-line regimen for the treatment of mRCC and prior treatment with compounds which contain the core platform antibody as PF 04856884 * major surgery \<4 weeks or radiation therapy \<2 weeks prior to start of therapy * clinically significant gastrointestinal abnormalities * current use or anticipated need for drugs that are known potent CYP3A4 inhibitors and drugs that are known CYP3A4 or CYP1A2 inducers * history of bleeding diathesis or coagulopathy * Grade 3 or greater hemorrhage from any cause \<4 weeks prior to screening; * hemoptysis \>½ teaspoon of blood per day within 2 weeks prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | 4 months | Incidence and severity of all treatment-emergent AEs (TEAEs) of both all-causality and treatment-related by preferred term (PT) categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades reported in ≥2 participants overall (CTCAE Grades 3, 4 and 5, combined) for any PT are presented. Participants who are included under all-causality TEAE PT are coded as NA if they appear for the same PT under treatment-related TEAE below. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). |
| Number of Participants With Serious Adverse Events (SAEs) in Part I | 4 months | Incidence and severity of all-causality serious adverse events (SAEs) are presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). Participants with treatment-related TEAE are coded as NA if they appear for the same preferred term under all-causality TEAE. |
| Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) in Part II | 3 years | PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. Progression free survival was to be calculated as (first event date - the date of randomization +1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax (Time When Maximum Serum PF-04856884 Concentration Was Reached) | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | Pharmacokinetic parameter, Tmax (Time when maximum serum PF-04856884 concentration was reached) was done using non-compartmental methods. |
| Cmax (Observed Peak Serum PF-04856884 Concentration) | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | Pharmacokinetic parameter Cmax (observed peak PF-04856884 serum concentration) was estimated using noncompartmental methods. |
| Cmin (Trough PF-04856884 Serum Concentration) | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | Pharmacokinetic parameter Cmin (trough PF-04856884 serum concentration) was estimated using noncompartmental methods. |
| Number of Participants With Non-serious AEs and SAEs | 3 years | Incidence and severity of all-causality AEs and SAEs to be presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). |
| Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) as Measured by an Independent Radiological Assessment | 3 years | PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. PFS was to be calculated as (first event date - the date of randomization +1). |
| Overall Survival (OS) at 2 Years | 5 years | OS is defined as the time from the first dose date to date of death. For participants not expiring, their survival times will be censored at the last date they are known to be alive, or 2 year whichever is earlier. The 2-year OS rate will be estimated from a time-to event analysis of OS. |
| Number of Anti-drug Antibodies (ADA) Samples Confirmed Positive | 0 and 360 hours post dose and end of study | Detection of neutralizing anti-PF-04856884 antibodies was based on the ability of anti-PF-04856884 neutralizing antibodies to bind to Tag-PF-04856884. |
| Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone. | 4 months | ORR is defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST), relative to all randomized participants as defined in the FA Set. Confirmed responses are those that persist on repeat imaging study ≥ 4 weeks after initial documentation of response. Participants who do not have on-study radiographic tumor evaluation or who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as non-responders (NR) in the assessment of ORR. |
| Duration of Response (DR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone | 3 years | DR is defined as the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of tumor progression or to death due to cancer. Duration of tumor response was to be calculated as (the end date for DR - first CR or PR that is subsequently confirmed +1). |
Countries
Czechia, United States
Participant flow
Recruitment details
This multicenter, open-label study consisted of a safety lead in stage (Part I) followed by a randomized Phase 2 stage (Part II). A total of 18 participants were screened and assigned to treatment in Part I, with 3 participants completing Part I of the study. At the completion of Part I, all 18 participants had discontinued combined treatment.
Pre-assignment details
During Part I, 3 to 4 participants were initially treated with the study drug combination in 28-day cycles. If no participants experienced Cycle 1 dose limiting toxicities (DLTs), another 6 to 9 participants were treated at this dose level. Part II of the study was to be initiated if Cycle 1 DLTs were observed in \<33% in at least 12 participants.
Participants by arm
| Arm | Count |
|---|---|
| PF-04856884 + AG-013736 Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice a day. Following the decision of 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Other reasons | 3 |
| Overall Study | Participant died | 9 |
| Overall Study | Study terminated by sponsor | 2 |
| Overall Study | Subject refused further follow-up | 1 |
Baseline characteristics
| Characteristic | PF-04856884 + AG-013736 |
|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 12 / 18 |
Outcome results
Primary
Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall).
Incidence and severity of all treatment-emergent AEs (TEAEs) of both all-causality and treatment-related by preferred term (PT) categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades reported in ≥2 participants overall (CTCAE Grades 3, 4 and 5, combined) for any PT are presented. Participants who are included under all-causality TEAE PT are coded as NA if they appear for the same PT under treatment-related TEAE below. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).
Time frame: 4 months
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 5 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | 2 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 2 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 5 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 4 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 4 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | NA participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 1 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 1 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 1 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | NA participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 0 participants |
| Treatment-related CTCAE Grade 4 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 0 participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | NA participants |
| Treatment-related CTCAE Grade 5 | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 0 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 4 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 5 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | NA participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | NA participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 8 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 10 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 11 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 10 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 11 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | NA participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 4 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 12 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | 6 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | 5 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | 4 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 7 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 2 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | 7 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | 3 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 10 participants |
| All-causality Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | 4 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypoxia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dyspnoea | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cerebrovascular accident | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Anaemia | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Night sweats | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Myalgia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscular weakness | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Muscle spasms | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Back pain | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Arthralgia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Palmar-plantar erythrodysaesthesia | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypovolaemia | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Insomnia | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyponatraemia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypokalaemia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypercalcaemia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dehydration | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Decreased appetite | 11 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Weight decreased | 4 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Asthenia | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Proteinuria | 3 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Blood creatinine increased | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Urinary tract infection | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Upper respiratory tract infection | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pneumonia | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oedema peripheral | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Constipation | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Cough | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Fatigue | 8 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vomiting | 6 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Toothache | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Stomatitis | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Oral pain | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Nausea | 7 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Gastritis | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dry mouth | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Diarrhoea | 9 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Vision blurred | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hot flush | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Abdominal pain | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypothyroidism | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hyperthyroidism | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pericardial effusion | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dysphonia | 5 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Leukocytosis | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Depression | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Neuropathy peripheral | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Migraine | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypotension | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Headache | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Hypertension | 9 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pulmonary embolism | 2 participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Dizziness | NA participants |
| Treatment-related Overall | Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Pleural effusion | NA participants |
Primary
Number of Participants With Serious Adverse Events (SAEs) in Part I
Incidence and severity of all-causality serious adverse events (SAEs) are presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). Participants with treatment-related TEAE are coded as NA if they appear for the same preferred term under all-causality TEAE.
Time frame: 4 months
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Back pain | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pericardial effusion | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Abdominal pain | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Gastrointestinal disorder | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Musculoskeletal chest pain | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypertension | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pleural effusion | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pneumonia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ileus | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Meningioma | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Convulsion | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Embolism | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Migraine | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hyponatraemia | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Dyspnoea | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ascites | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Cerebrovascular accident | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypotension | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Chest discomfort | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypovolaemia | 1 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Lung infection | 0 participants |
| All-causality CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pulmonary embolism | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Meningioma | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hyponatraemia | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pericardial effusion | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Lung infection | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Abdominal pain | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Cerebrovascular accident | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Gastrointestinal disorder | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypertension | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Chest discomfort | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pulmonary embolism | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pleural effusion | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Dyspnoea | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Musculoskeletal chest pain | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Convulsion | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Back pain | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypovolaemia | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypotension | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pneumonia | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ileus | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Migraine | 1 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ascites | 0 participants |
| All-causality CTCAE Grade 4 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Embolism | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypotension | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pneumonia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pleural effusion | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Lung infection | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Musculoskeletal chest pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Convulsion | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hyponatraemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Dyspnoea | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Migraine | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Meningioma | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypovolaemia | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pericardial effusion | 1 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Gastrointestinal disorder | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Chest discomfort | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypertension | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ileus | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Abdominal pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ascites | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Back pain | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Embolism | 0 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Cerebrovascular accident | 1 participants |
| All-causality CTCAE Grade 5 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pulmonary embolism | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Abdominal pain | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Musculoskeletal chest pain | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Lung infection | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pulmonary embolism | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypovolaemia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pneumonia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Back pain | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Meningioma | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Migraine | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Gastrointestinal disorder | 1 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Cerebrovascular accident | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypotension | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Dyspnoea | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hyponatraemia | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ascites | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Hypertension | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Chest discomfort | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pleural effusion | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Embolism | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Ileus | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Pericardial effusion | 0 participants |
| Treatment-related CTCAE Grade 3 | Number of Participants With Serious Adverse Events (SAEs) in Part I | Convulsion | 0 participants |
Primary
Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) in Part II
PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. Progression free survival was to be calculated as (first event date - the date of randomization +1).
Time frame: 3 years
Population: The primary efficacy endpoint of estimating median PFS in Part II was not assessed due to early termination of the study.
Secondary
Cmax (Observed Peak Serum PF-04856884 Concentration)
Pharmacokinetic parameter Cmax (observed peak PF-04856884 serum concentration) was estimated using noncompartmental methods.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All-causality CTCAE Grade 3 | Cmax (Observed Peak Serum PF-04856884 Concentration) | CYCLE1/DAY1 | 337100 ng/mL | Standard Deviation 76245 |
| All-causality CTCAE Grade 3 | Cmax (Observed Peak Serum PF-04856884 Concentration) | CYCLE1/DAY22 | 531400 ng/mL | Standard Deviation 154780 |
Secondary
Cmin (Trough PF-04856884 Serum Concentration)
Pharmacokinetic parameter Cmin (trough PF-04856884 serum concentration) was estimated using noncompartmental methods.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All-causality CTCAE Grade 3 | Cmin (Trough PF-04856884 Serum Concentration) | CYCLE1/DAY1 | 932.7 ng/mL | Standard Deviation 3499.1 |
| All-causality CTCAE Grade 3 | Cmin (Trough PF-04856884 Serum Concentration) | CYCLE1/DAY22 | 168900 ng/mL | Standard Deviation 84507 |
Secondary
Duration of Response (DR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone
DR is defined as the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of tumor progression or to death due to cancer. Duration of tumor response was to be calculated as (the end date for DR - first CR or PR that is subsequently confirmed +1).
Time frame: 3 years
Population: This endpoint was not assessed due to the early termination of the study.
Secondary
Number of Anti-drug Antibodies (ADA) Samples Confirmed Positive
Detection of neutralizing anti-PF-04856884 antibodies was based on the ability of anti-PF-04856884 neutralizing antibodies to bind to Tag-PF-04856884.
Time frame: 0 and 360 hours post dose and end of study
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All-causality CTCAE Grade 3 | Number of Anti-drug Antibodies (ADA) Samples Confirmed Positive | 8 ADA samples |
Secondary
Number of Participants With Non-serious AEs and SAEs
Incidence and severity of all-causality AEs and SAEs to be presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week).
Time frame: 3 years
Population: This endpoint was not assessed due to the early termination of the study.
Secondary
Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone.
ORR is defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST), relative to all randomized participants as defined in the FA Set. Confirmed responses are those that persist on repeat imaging study ≥ 4 weeks after initial documentation of response. Participants who do not have on-study radiographic tumor evaluation or who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as non-responders (NR) in the assessment of ORR.
Time frame: 4 months
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All-causality CTCAE Grade 3 | Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone. | Partial response (PR) | 11.1 Percentage of participants |
| All-causality CTCAE Grade 3 | Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone. | ORR (CR + PR) | 11.1 Percentage of participants |
| All-causality CTCAE Grade 3 | Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone. | Complete response (CR) | 0 Percentage of participants |
Secondary
Overall Survival (OS) at 2 Years
OS is defined as the time from the first dose date to date of death. For participants not expiring, their survival times will be censored at the last date they are known to be alive, or 2 year whichever is earlier. The 2-year OS rate will be estimated from a time-to event analysis of OS.
Time frame: 5 years
Population: This endpoint was not assessed due to the early termination of the study.
Secondary
Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) as Measured by an Independent Radiological Assessment
PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. PFS was to be calculated as (first event date - the date of randomization +1).
Time frame: 3 years
Population: This endpoint of estimating median PFS was not assessed due to early termination of the study.
Secondary
Tmax (Time When Maximum Serum PF-04856884 Concentration Was Reached)
Pharmacokinetic parameter, Tmax (Time when maximum serum PF-04856884 concentration was reached) was done using non-compartmental methods.
Time frame: Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment
Population: The FA set was the primary population for evaluating all safety and efficacy endpoints per the treatment randomization as well as participant characteristics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All-causality CTCAE Grade 3 | Tmax (Time When Maximum Serum PF-04856884 Concentration Was Reached) | CYCLE1/DAY1 | 2.000 hr | Standard Deviation 1.645 |
| All-causality CTCAE Grade 3 | Tmax (Time When Maximum Serum PF-04856884 Concentration Was Reached) | CYCLE1/DAY22 | 3.000 hr | Standard Deviation 2.1122 |