A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Solid Tumors

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02403271
• Collaborator: (none)
• Enrollment: 124
• Locations: 17
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer; Breast Cancer; Pancreatic Cancer	Drug: Ibrutinib; Drug: Durvalumab	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Durvalumab (MEDI4736), in Subjects With Relapsed or Refractory Solid Tumors
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6+3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).	Drug: Ibrutinib; BTK Inhibitor; Other Names: PCI-32765 ; Drug: Durvalumab; Anti PDL-1; Other Names: MEDI4736
Experimental: Phase 2 Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.	Drug: Ibrutinib; BTK Inhibitor; Other Names: PCI-32765 ; Drug: Durvalumab; Anti PDL-1; Other Names: MEDI4736

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) and to Find the Recommended Phase II Dose. [From the date of first study treatment until DLT or disease progression per RECIST 1.1.]

2. Phase 2: Efficacy of Ibrutinib in Combination With Durvalumab (MEDI4736) in Participants With Relapsed or Refractory Solid Tumors by Assessing the ORR Per RECIST 1.1. [From the date of first study treatment until progressive disease per RECIST 1.1 or unacceptable toxicity.]

Secondary Outcome Measures

1. Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib [0hr, 1hr, 2hr, and 4hr post-dose]

   Cmax = the peak (maximum) plasma concentration of ibrutinib during the dosing interval on Cycle 3 Day 1.

2. Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib [0hr, 1hr, 2hr, and 4hr post-dose]

   AUC0-24 = the area under the plasma concentration-time curve of ibrutinib during the dosing interval on Cycle 3 Day 1

3. Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736) [60 minutes post-dose (dose administered as an infusion over a 1 hour period)]

   Cmax = the peak (maximum) plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1.

4. Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736) [Pre-dose]

   Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1

5. Phase 1b: Pharmacodynamics [From the date of first study treatment until DLT or disease progression per RECIST 1.1.]

   BTK occupancy

6. Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) [From the date of first study treatment until DLT or disease progression per RECIST 1.1.]

7. Phase 2: Pharmacodynamics [Pre-dose]

   BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Pathologically confirmed: Non-small cell lung cancer (NSCLC, adenocarcinoma or squamous-cell carcinoma), Breast Cancer (HER2 positive or triple negative), Pancreatic Cancer (adenocarcinoma)

2. Relapsed or refractory disease (Stage III or IV): NSCLC or pancreatic cancer must have failed at least 1 prior treatment. Breast cancer must have failed at least 2 prior treatments.

3. Measurable lesion by RECIST 1.1

4. Adequate hematologic function:

• ANC >1500 cells/mm3

• Platelet count >100,000 cells/mm3

• HGB >9.0 g/dL

1. Adequate hepatic and renal function:

• AST and ALT ≤2.5 x ULN for subjects without liver metastases and ≤3.5 x ULN for subjects with liver metastases

• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

• Creatinine ≤2.0 x ULN and Creatinine Clearance ≥40 mL/min (Cockcroft-Gault or 24-hour creatinine clearance collection)

1. PT/INR <1.5 x ULN and PTT/ aPTT <1.5 x ULN

Exclusion Criteria:

1. Mixed small cell and NSCLC histology

2. A history of CNS involvement except as follows: Subjects with previously treated CNS metastases that are adequately treated with whole brain radiotherapy, that are neurologically stable, and do not require corticosteroids for symptomatic management for at least 14 days prior to first dose of study drug. There must be no clear evidence of radiographically active disease for at least 90 days prior to enrollment.

3. Anti-tumor therapy within 21 days of study Day 1

4. Prior treatment with ibrutinib or other BTK inhibitor anti-CD137 or CTLA-4 antibody. The following are exceptions to this criterion: Subjects previously treated with an anti-PD1, anti-PD-L1, or anti-PD-L2 antibody.

5. History of allogeneic organ transplant

6. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35294
2		Scottsdale	Arizona	United States	85258
3		La Jolla	California	United States	92093
4		Los Angeles	California	United States	90025
5		Los Angeles	California	United States	90048
6		Palo Alto	California	United States	94305
7		San Francisco	California	United States	94115
8		Gainesville	Florida	United States	32610
9		Orlando	Florida	United States	32806
10		Chicago	Illinois	United States	60637
11		Peoria	Illinois	United States	61615
12		Hackensack	New Jersey	United States	07601
13		Durham	North Carolina	United States	27710
14		Germantown	Tennessee	United States	38120
15		Nashville	Tennessee	United States	37212
16		Houston	Texas	United States	77030
17		San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Pharmacyclics LLC.

Investigators

• Study Director: Isaiah Dimery, Pharmacyclics LLC.

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 1, 2017
• Study Protocol - Dec 18, 2015

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02403271
• Other Study ID Numbers: PCYC-1135-CA
• First Posted: Mar 31, 2015
• Last Update Posted: Jan 3, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Pharmacyclics LLC.: Pharmacyclics; PCYC; Ibrutinib; Durvalumab (MEDI4736); Relapsed Refractory Solid Tumor; Non-Small Cell Lung Cancer; NSCLC; Squamous; Squamous NSCLC; Squamous Non-Small Cell Lung Cancer; Immunotherapy; IMBRUVICA®; Tumor Immunotherapy; Anti-PD-L1; Lung Cancer; Breast Cancer; Triple Negative; HER2 Positive; HER2 + Breast Cancer; Pancreatic Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Pancreatic Neoplasms; Durvalumab

Study Results

Participant Flow

Arm/Group Title	Phase 1b	Phase 2
Arm/Group Description	In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).	Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Period Title: Period 1
STARTED	7	0
COMPLETED	6	0
NOT COMPLETED	1	0
Period Title: Period 1
STARTED	0	124
COMPLETED	0	0
NOT COMPLETED	0	124

Baseline Characteristics

Arm/Group Title	Phase 1b/2
Arm/Group Description	All participants who received at least one dose of study treatment.
Overall Participants	122
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	78 63.9%
>=65 years	44 36.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (12.03)
Sex: Female, Male (Count of Participants)
Female	75 61.5%
Male	47 38.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 4.9%
Not Hispanic or Latino	116 95.1%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%
Asian	5 4.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 9%
White	104 85.2%
More than one race	0 0%
Unknown or Not Reported	1 0.8%
Region of Enrollment (Count of Participants)
United States	122 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736) and to Find the Recommended Phase II Dose.
Time Frame	From the date of first study treatment until DLT or disease progression per RECIST 1.1.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1b
Arm/Group Description	In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).
Measure Participants	6
Number [participants]	6 4.9%

2. Primary Outcome

Title	Phase 2: Efficacy of Ibrutinib in Combination With Durvalumab (MEDI4736) in Participants With Relapsed or Refractory Solid Tumors by Assessing the ORR Per RECIST 1.1.
Time Frame	From the date of first study treatment until progressive disease per RECIST 1.1 or unacceptable toxicity.

Outcome Measure Data

Analysis Population Description

The Response-evaluable population was participants who received at least 1 dose of treatment (ibrutinib and durvalumab) and provided 1 post-baseline response assessment.

Arm/Group Title	Phase 2
Arm/Group Description	Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Measure Participants	105
Count of Participants [Participants]	2 1.6%

3. Secondary Outcome

Title	Phase 1b/2: Pharmacokinetics (Cmax) of Ibrutinib
Description	Cmax = the peak (maximum) plasma concentration of ibrutinib during the dosing interval on Cycle 3 Day 1.
Time Frame	0hr, 1hr, 2hr, and 4hr post-dose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data. Data were analyzed together for Phase 1b and Phase 2 because the dose was the same.

Arm/Group Title	Phase 1b/2 (Pharmacokinetic Population)
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	34
Mean (Standard Deviation) [ng/mL]	218 (163)

4. Secondary Outcome

Title	Phase 1b/2: Pharmacokinetics (AUC0-24h) of Ibrutinib
Description	AUC0-24 = the area under the plasma concentration-time curve of ibrutinib during the dosing interval on Cycle 3 Day 1
Time Frame	0hr, 1hr, 2hr, and 4hr post-dose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data. Data were analyzed together for Phase 1b/2 because the dose was the same.

Arm/Group Title	Phase 1b/2 (Pharmacokinetic Population)
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	34
Mean (Standard Deviation) [h.ng/mL]	2126 (1315)

5. Secondary Outcome

Title	Phase 1b/2: Pharmacokinetics (Cmax) of Durvalumab (MEDI4736)
Description	Cmax = the peak (maximum) plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1.
Time Frame	60 minutes post-dose (dose administered as an infusion over a 1 hour period)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/2 (Pharmacokinetic Population)
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	386 (19.5)

6. Secondary Outcome

Title	Phase 1b/2: Pharmacokinetics (Ctrough) of Durvalumab (MEDI4736)
Description	Ctrough = the trough plasma concentration of durvalumab (MEDI4736) after administration on Cycle 6 Day 1
Time Frame	Pre-dose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/2 (Pharmacokinetic Population)
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	168 (19.6)

7. Secondary Outcome

Title	Phase 1b: Pharmacodynamics
Description	BTK occupancy
Time Frame	From the date of first study treatment until DLT or disease progression per RECIST 1.1.

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Phase 1b
Arm/Group Description	In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6 + 3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma).
Measure Participants	0

8. Secondary Outcome

Title	Phase 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Durvalumab (MEDI4736)
Time Frame	From the date of first study treatment until DLT or disease progression per RECIST 1.1.

Outcome Measure Data

Analysis Population Description

Participants who enrolled and received at least 1 dose of study treatment.

Arm/Group Title	Phase 2
Arm/Group Description	Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Measure Participants	122
Count of Participants [Participants]	122 100%

9. Secondary Outcome

Title	Phase 2: Pharmacodynamics
Description	BTK binding site occupancy of ibrutinib was measured from peripheral blood samples collected from participants during Cycle 3 Day 1.
Time Frame	Pre-dose

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of ibrutinib and who had at least one evaluable BTK occupancy assay result at Cycle 3 Day 1.

Arm/Group Title	Phase 2
Arm/Group Description	Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), breast cancer (triple-negative and HER2-positive cancer), and pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Measure Participants	30
Mean (Standard Error) [percentage of BTK binding site occupancy]	87.8 (4.2)

Adverse Events

Time Frame	2 years, 5 months
Adverse Event Reporting Description	Adverse events were not collected by phase (Arm) because the treatments between Phase 1b and Phase 2 were not appreciably different.
Arm/Group Title	Phase 1b/2
Arm/Group Description	All subjects who received at least one dose of study treatment.
All Cause Mortality
	Phase 1b/2
	Affected / at Risk (%)	# Events
Total	96/122 (78.7%)
Serious Adverse Events
	Phase 1b/2
	Affected / at Risk (%)	# Events
Total	77/122 (63.1%)
Blood and lymphatic system disorders
Anaemia	1/122 (0.8%)
Thrombocytopenia	1/122 (0.8%)
Cardiac disorders
Pericardial effusion	3/122 (2.5%)
Supraventricular tachycardia	2/122 (1.6%)
Acute myocardial infarction	1/122 (0.8%)
Atrial fibrillation	1/122 (0.8%)
Sinus tachycardia	1/122 (0.8%)
Ventricular tachycardia	1/122 (0.8%)
Endocrine disorders
Hypothyroidism	1/122 (0.8%)
Gastrointestinal disorders
Abdominal pain	4/122 (3.3%)
Diarrhoea	3/122 (2.5%)
Vomiting	3/122 (2.5%)
Constipation	2/122 (1.6%)
Nausea	2/122 (1.6%)
Ascites	1/122 (0.8%)
Gastrointestinal haemorrhage	1/122 (0.8%)
Intestinal obstruction	1/122 (0.8%)
Obstruction gastric	1/122 (0.8%)
Small intestinal obstruction	1/122 (0.8%)
Intestinal perforation	1/122 (0.8%)
General disorders
Pyrexia	6/122 (4.9%)
Death	3/122 (2.5%)
Multiple organ dysfunction syndrome	2/122 (1.6%)
Asthenia	1/122 (0.8%)
Malaise	1/122 (0.8%)
Oedema peripheral	1/122 (0.8%)
Hepatobiliary disorders
Cholangitis	1/122 (0.8%)
Hepatic failure	1/122 (0.8%)
Hepatic function abnormal	1/122 (0.8%)
Pneumonia	8/122 (6.6%)
Infections and infestations
Sepsis	4/122 (3.3%)
Cellulitis	2/122 (1.6%)
Pneumonia bacterial	2/122 (1.6%)
Urinary tract infection	2/122 (1.6%)
Diverticulitis	1/122 (0.8%)
Escherichia sepsis	1/122 (0.8%)
Gastroenteritis	1/122 (0.8%)
Pyelonephritis	1/122 (0.8%)
Serratia bacteraemia	1/122 (0.8%)
Staphylococcal bacteraemia	1/122 (0.8%)
Staphylococcal sepsis	1/122 (0.8%)
Pneumonia	8/122 (6.6%)
Stenotrophomonas sepsis	1/122 (0.8%)
Injury, poisoning and procedural complications
Compression fracture	1/122 (0.8%)
Metabolism and nutrition disorders
Dehydration	6/122 (4.9%)
Hyponatraemia	4/122 (3.3%)
Electrolyte imbalance	1/122 (0.8%)
Failure to thrive	1/122 (0.8%)
Hypercalcaemia	1/122 (0.8%)
Hyperkalaemia	1/122 (0.8%)
Hypoglycaemia	1/122 (0.8%)
Hypokalaemia	1/122 (0.8%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/122 (0.8%)
Myalgia	1/122 (0.8%)
Rhabdomyolysis	1/122 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma	14/122 (11.5%)
Breast cancer	6/122 (4.9%)
Metastases to central nervous system	2/122 (1.6%)
Pancreatic carcinoma metastatic	2/122 (1.6%)
Breast cancer metastatic	1/122 (0.8%)
Cancer pain	1/122 (0.8%)
Lung neoplasm malignant	1/122 (0.8%)
Metastases to meninges	1/122 (0.8%)
Non-small cell lung cancer	1/122 (0.8%)
Tumour pain	1/122 (0.8%)
Nervous system disorders
Cerebrovascular accident	3/122 (2.5%)
Embolic stroke	1/122 (0.8%)
Metabolic encephalopathy	1/122 (0.8%)
Seizure	1/122 (0.8%)
Psychiatric disorders
Mental status changes	4/122 (3.3%)
Renal and urinary disorders
Acute kidney injury	3/122 (2.5%)
Urinary retention	2/122 (1.6%)
Haematuria	1/122 (0.8%)
Obstructive uropathy	1/122 (0.8%)
Renal failure	1/122 (0.8%)
Reproductive system and breast disorders
Breast mass	1/122 (0.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/122 (4.1%)
Pleural effusion	5/122 (4.1%)
Acute respiratory failure	3/122 (2.5%)
Pulmonary embolism	3/122 (2.5%)
Chronic obstructive pulmonary disease	2/122 (1.6%)
Pneumothorax	2/122 (1.6%)
Acute respiratory distress syndrome	1/122 (0.8%)
Alveolitis allergic	1/122 (0.8%)
Dyspnoea exertional	1/122 (0.8%)
Hypoxia	1/122 (0.8%)
Pneumonitis	1/122 (0.8%)
Respiratory failure	3/122 (2.5%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/122 (1.6%)
Purpura	1/122 (0.8%)
Rash	1/122 (0.8%)
Urticaria	1/122 (0.8%)
Vascular disorders
Hypotension	3/122 (2.5%)
Deep vein thrombosis	2/122 (1.6%)
Other (Not Including Serious) Adverse Events
	Phase 1b/2
	Affected / at Risk (%)	# Events
Total	122/122 (100%)
Blood and lymphatic system disorders
Anaemia	26/122 (21.3%)
Gastrointestinal disorders
Nausea	33/122 (27%)
Diarrhoea	22/122 (18%)
Abdominal pain	19/122 (15.6%)
Constipation	21/122 (17.2%)
Vomiting	19/122 (15.6%)
Stomatitis	16/122 (13.1%)
Dyspepsia	8/122 (6.6%)
Gastrooesophageal reflux disease	7/122 (5.7%)
General disorders
Fatigue	53/122 (43.4%)
Oedema peripheral	26/122 (21.3%)
Pyrexia	19/122 (15.6%)
Infections and infestations
Urinary tract infection	8/122 (6.6%)
Investigations
Aspartate aminotransferase increase	15/122 (12.3%)
Weight decreased	12/122 (9.8%)
Alanine aminotransferase increased	11/122 (9%)
Blood alkaline phosphatase increased	8/122 (6.6%)
Metabolism and nutrition disorders
Decreased appetite	32/122 (26.2%)
Hypomagnesaemia	28/122 (23%)
Hyponatraemia	15/122 (12.3%)
Hypokalaemia	13/122 (10.7%)
Dehydration	9/122 (7.4%)
Hypoalbuminaemia	8/122 (6.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/122 (9.8%)
Back pain	12/122 (9.8%)
Myalgia	12/122 (9.8%)
Muscle spasms	11/122 (9%)
Muscular weakness	8/122 (6.6%)
Pain in extremity	8/122 (6.6%)
Nervous system disorders
Dizziness	13/122 (10.7%)
Headache	12/122 (9.8%)
Psychiatric disorders
Insomnia	8/122 (6.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	21/122 (17.2%)
Cough	17/122 (13.9%)
Epistaxis	12/122 (9.8%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	19/122 (15.6%)
Pruritus	14/122 (11.5%)
Rash erythematous	11/122 (9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Institution/Investigator will not publish without Sponsor prior review and approval Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination