Combination Immunotherapy of GM.CD40L Vaccine With CCL21 in Lung Cancer

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01433172
• Collaborator: Bankhead-Coley Florida Biomedical Research Program (Other), James and Esther King Biomedical Research Program (Other)
• Enrollment: 73
• Location: 1
• Arms: 3
• Actual Duration (Months): 82.2
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects (good and bad) a tumor vaccine used in combination with GM.CD40L and CCL21 have on the patient and their cancer. We also want to find out if the vaccine and the drugs can boost the immune system of these patients and how their immune system reacts, both before and after the vaccine treatment.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer; Adenocarcinoma	Biological: Phase I - GM.CD40L.CCL21 Vaccinations; Biological: Phase II - GM.CD40L cells Vaccinations; Biological: Phase II - GM.CD40L.CCL21 Vaccinations	Phase 1/Phase 2

Detailed Description

The vaccine will be made by mixing two kinds of cells: 1) some lung cancer cells, which have been grown in the lab, and 2) experimental "bystander (present but not taking part in the immune response)" cells. All the cells in the vaccine will be treated with high-dose X-rays to make sure that none of them grow and cause more cancer. The bystander cells are human cells that have been genetically changed to express GM-CSF and CD40L. These are called "GM.CD40L". (That is the original cells, called K562, with the genes for human GM-CSF and CD40L inserted into them). These changes are designed to help boost the participants' immune system to better fight the cancer in their body. GM-CSF is a hormone that is known to stimulate bone marrow to make more white blood cells.

CCL21 is a chemokine (protein) that helps to recruit T cells (a type of white blood cell that helps to protect the body from infections) and leads to hyper-responsive T cells. This leads to heightened immune responses when T cells are exposed to both CCL21 and antigen (a substance that when introduced into the body lead to production of an antibody)-presenting cells (A cell that can "present" antigen in a form that T cells can recognize it ). The induction of a strong cell-mediated immune response is the type of immunity expected to be most involved in controlling cancer cell growth. A randomized trial of a vaccine consisting of the GM.CD40L bystander cells and an equivalent number of allogeneic (taken from different individuals) tumor cells plus or minus CCL21 is proposed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase I/II Trial Using a GM-CSF-Producing and CD40L-Expressing Bystander Cell Line (GM.CD40L) Vaccine in Combination With CCL21 for Patients With Stage IV Adenocarcinoma of the Lung
• Actual Study Start Date: Mar 26, 2012
• Actual Primary Completion Date: Jan 31, 2016
• Actual Study Completion Date: Feb 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Vaccinations Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. Note for the phase I portion: the use of steroid medication is to be avoided for 4 weeks prior to the initiation of vaccine therapy and during the vaccine treatment period.	Biological: Phase I - GM.CD40L.CCL21 Vaccinations; This is a dual-agent, Phase I study with an expansion of each group at the recommended Phase II dose. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. Phase I: Participants receive the GM.CD40L.CCL21 vaccine in a standard 3+3 design.; Other Names: chemokine
Active Comparator: Phase II Arm A Vaccinations Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals. Note on either Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.	Biological: Phase II - GM.CD40L cells Vaccinations; Patients randomized to Arm A will receive vaccinations on 3 occasions, at 2 week intervals. 7.5 X 10^6 irradiated H1944 tumor cells, 7.5 X 10^6 irradiated H2122 cells, and containing 15 X 10^6 GM.CD40L cells (1.1 mL) will be injected intradermally into 4 separate sites (0.25 ml injected at each site), in bilateral proximal upper and lower extremities (in the regions of the axillary and inguinal nodal basins). Patients will be restaged approximately 2 weeks after vaccine 3. If patients show no sign of disease progression, patients will then be vaccinated at 4-week intervals.; Other Names: MHC-negative cell line
Active Comparator: Phase II Arm B Vaccinations Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. Note on either Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.	Biological: Phase II - GM.CD40L.CCL21 Vaccinations; This is a dual-agent, Phase I study with an expansion of each group at the recommended Phase II dose. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. Phase II: Participants are randomized to one of the 2 arms (ratio 1:1): GM.CD40L versus GM.CD40L.CCL21. Patients in Arm B will receive vaccines at the same dose and schedule as described for patients in Arm A. In addition, their vaccine will include H1944 cells expressing CCL21. Note for patients on Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.; Other Names: chemokine

Outcome Measures

Primary Outcome Measures

1. Phase I: Recommend Phase II Dose (RPDII) [Up to 6 Months]

   Highest dose level of GMCD40L vaccine in combination with CCL21 that induced dose limiting toxicity (DLT) in fewer than 33% of patients. DLT: Intervention-specific acute toxicity; i.e., occurrence within 28 days of drug administration, according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), V 4: 1.) that precludes further dose escalation. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. If 2 or more patients experience toxicity in dose level 1 (30X10^6 cells per injection), dose de-escalation will occur. Dose level -1 will be defined by 10 % reduction of cells administered from dose level 1 and follow the same rules. It is not feasible to escalate the dose of the vaccine beyond 30X10^6 cells per injection; therefore the Maximum Tolerated Dose (MTD) may not be reached in this study. In that case, the highest dose level will be used in the phase II component.

2. Phase II: Progression Free Survival (PFS) [Up to 6 Months]

   PFS is measured as the time from start of treatment to progression or death. 6 month progression free survival will be estimated from available clinical and radiographic assessments and RECIST 1.1 will be used to make tumor measurements. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.

Secondary Outcome Measures

1. Response Rate [Up to 12 Months]

   Response according to Response Evaluation in Solid Tumors (RECIST) 1.1. Complete Response (CR): Complete disappearance of all measurable and non-measurable disease; No new lesions. Partial Response (PR): Applies only to patients with at least one measurable lesion; Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. Progressive Disease (PD): 20% or greater increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Stable Disease (SD): Does not qualify for CR, PR, Progression or Symptomatic Deterioration; All target measurable lesions must be assessed using the same techniques as baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed metastatic adenocarcinoma of the lung

• Patients must have received and completed first line therapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1

• No external beam radiation therapy within 2 weeks of first vaccine administration

• No stereotactic radiation therapy within 3 days of first vaccine

• No targeted therapy within 2 weeks of first vaccine administration

• No immunomodulatory therapy within 2 weeks of first vaccine administration

• No chemotherapy within 4 weeks of first vaccine administration

• During Screening period, no steroid therapy within 4 weeks of first vaccine administration

• Patient's written informed consent

• Adequate organ function (measured within a week of beginning treatment):

• White blood count (WBC) > 3,000/mm³ and absolute neutrophil count (ANC) >/= 1500/mm³

• Platelets > 100,000/mm³

• Hematocrit > 25%

• Bilirubin < 2.0 mg/dL

• Creatinine < 2.0 mg/dL, or creatinine clearance > 60 mL/min

• Patients will be tested for HLA-A0201 as determined by flow cytometry followed by molecular analysis of a peripheral blood specimen; however this result will not be an inclusion criterion.

• Measurable metastatic tumor as defined by standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Lesions must be accurately measured in at least one dimension with the longest diameter ≥20 mm. With spiral computed tomography (CT) scan, lesion must be ≥10 mm in at least one dimension.

Exclusion Criteria:

• Symptomatic brain metastasis or Uncontrolled central nervous system (CNS) metastasis will not be permitted.

• Any acute medical problems requiring active intervention

• Current corticosteroid (other than replacement doses in patients who are hypo-adrenal) or other immunosuppressive therapy

• Any other pre-existing immunodeficiency condition (including known human immunodeficiency virus [HIV] infection)

• Any known pre-existing autoimmune disorder

• History of a second malignancy within the previous 2 years (except non-melanoma skin cancer and cervical in-situ)

• Patients who have had major surgery without full recovery or major surgery within three weeks of the start of vaccine treatment

• Pregnant or lactating women: Patients in reproductive age must agree to use contraceptive methods for the duration of the study (*A pregnancy test will be obtained before treatment).

• Eastern Cooperative Oncology Group (ECOG) performance status of 2, 3, or 4

• Patients with other significant diseases or disorders that, in the Investigator's opinion, would exclude them from the study.

• Patients who at the discretion of the investigator are deemed to have rapidly progressive disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Bankhead-Coley Florida Biomedical Research Program
• James and Esther King Biomedical Research Program

Investigators

• Principal Investigator: Jhanelle Gray, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT01433172
• Other Study ID Numbers: MCC-16439
• First Posted: Sep 13, 2011
• Last Update Posted: Aug 6, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: stage IV; adenocarcinoma; vaccine therapy; immunology; tumor vaccine; colony stimulating factor(CSF); granulocyte-macrophage colony-stimulating factor (GM-CSF); CC chemokine ligand 21 (CCL21); Chemokine [C-C motif] ligand 21 (CCL21); human leukocyte antigen serotype (HLA)
• Additional relevant MeSH terms: Lung Neoplasms; Adenocarcinoma

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center between April 2012 and June 2015.
Pre-assignment Detail	Three participants were enrolled in the Phase I portion of the study, followed by seventy participants enrolled in the Randomized Phase II portion of the study.

Arm/Group Title	Phase I GM.CD40L.CCL21 Vaccinations	Phase II Arm A GM.CD40L Cells Vaccinations	Phase II Arm B GM.CD40L.CCL21 Vaccinations
Arm/Group Description	Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. Note for the phase I portion: the use of steroid medication is to be avoided for 4 weeks prior to the initiation of vaccine therapy and during the vaccine treatment period.	Phase II Arm A: Participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals. Note on either Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.	Phase II Arm B: Participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. Note on either Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.
Period Title: Overall Study
STARTED	3	37	33
COMPLETED	3	34	32
NOT COMPLETED	0	3	1

Baseline Characteristics

Arm/Group Title	Phase I Vaccinations	Phase II Arm A Vaccinations	Phase II Arm B Vaccinations	Total
Arm/Group Description	Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.	Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals.	Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.	Total of all reporting groups
Overall Participants	3	37	33	73
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 33.3%	16 43.2%	10 30.3%	27 37%
>=65 years	2 66.7%	21 56.8%	23 69.7%	46 63%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68	62	65	62
Sex: Female, Male (Count of Participants)
Female	0 0%	19 51.4%	19 57.6%	38 52.1%
Male	3 100%	18 48.6%	14 42.4%	35 47.9%
Region of Enrollment (Count of Participants)
United States	3 100%	37 100%	33 100%	73 100%

Outcome Measures

1. Primary Outcome

Title	Phase I: Recommend Phase II Dose (RPDII)
Description	Highest dose level of GMCD40L vaccine in combination with CCL21 that induced dose limiting toxicity (DLT) in fewer than 33% of patients. DLT: Intervention-specific acute toxicity; i.e., occurrence within 28 days of drug administration, according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), V 4: 1.) that precludes further dose escalation. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. If 2 or more patients experience toxicity in dose level 1 (30X10^6 cells per injection), dose de-escalation will occur. Dose level -1 will be defined by 10 % reduction of cells administered from dose level 1 and follow the same rules. It is not feasible to escalate the dose of the vaccine beyond 30X10^6 cells per injection; therefore the Maximum Tolerated Dose (MTD) may not be reached in this study. In that case, the highest dose level will be used in the phase II component.
Time Frame	Up to 6 Months

Outcome Measure Data

Analysis Population Description

All Phase I Participants

Arm/Group Title	Phase I GM.CD40L.CCL21 Vaccinations
Arm/Group Description	Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.
Measure Participants	3
Number [Recommend Phase II Dose Level]	1

2. Primary Outcome

Title	Phase II: Progression Free Survival (PFS)
Description	PFS is measured as the time from start of treatment to progression or death. 6 month progression free survival will be estimated from available clinical and radiographic assessments and RECIST 1.1 will be used to make tumor measurements. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.
Time Frame	Up to 6 Months

Outcome Measure Data

Analysis Population Description

A Phase II participants evaluable at time of analysis.

Arm/Group Title	Phase II Arm A GM.CD40L Cells Vaccinations	Phase II Arm B GM.CD40L.CCL21 Vaccinations
Arm/Group Description	Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals.	Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.
Measure Participants	33	32
Median (95% Confidence Interval) [months]	2.4	3.1

3. Secondary Outcome

Title	Response Rate
Description	Response according to Response Evaluation in Solid Tumors (RECIST) 1.1. Complete Response (CR): Complete disappearance of all measurable and non-measurable disease; No new lesions. Partial Response (PR): Applies only to patients with at least one measurable lesion; Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. Progressive Disease (PD): 20% or greater increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Stable Disease (SD): Does not qualify for CR, PR, Progression or Symptomatic Deterioration; All target measurable lesions must be assessed using the same techniques as baseline.
Time Frame	Up to 12 Months

Outcome Measure Data

Analysis Population Description

All Phase II participants

Arm/Group Title	Phase II Arm A GM.CD40L Cells Vaccinations	Phase II Arm B GM.CD40L.CCL21 Vaccinations
Arm/Group Description	Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals.	Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.
Measure Participants	37	33
Complete Response	0 0%	0 0%
Partial Response	0 0%	0 0%
Progressive Disease	19 633.3%	20 54.1%
Stable Disease	18 600%	12 32.4%

Adverse Events

Time Frame	3 years, 8 months
Adverse Event Reporting Description	All Serious Adverse Events and Other (not including Serious) Adverse Events are listed, regardless of causality. All SAEs were either not related or unlikely to be related to study vaccines.
Arm/Group Title	Phase I GM.CD40L.CCL21 Vaccinations		Phase II Arm A GM.CD40L Vaccinations		Phase II Arm B GM.CD40L.CCL21 Vaccinations
Arm/Group Description	Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.		Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals.		Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals.
All Cause Mortality
	Phase I GM.CD40L.CCL21 Vaccinations		Phase II Arm A GM.CD40L Vaccinations		Phase II Arm B GM.CD40L.CCL21 Vaccinations
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I GM.CD40L.CCL21 Vaccinations		Phase II Arm A GM.CD40L Vaccinations		Phase II Arm B GM.CD40L.CCL21 Vaccinations
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		14/37 (37.8%)		7/33 (21.2%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Leukocytosis	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Cardiac disorders
Supraventricular tachycardia	1/3 (33.3%)	1	0/37 (0%)	0	1/33 (3%)	2
Endocrine disorders
Adrenal insufficiency	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Gastrointestinal disorders
Diarrhea	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Nausea	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Vomiting	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
General disorders
Death NOS	0/3 (0%)	0	0/37 (0%)	0	5/33 (15.2%)	5
Fatigue	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Fever	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Pain	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Infections and infestations
Gallbladder infection	0/3 (0%)	0	1/37 (2.7%)	2	0/33 (0%)	0
Lung infection	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Upper respiratory infection	1/3 (33.3%)	1	0/37 (0%)	0	0/33 (0%)	0
Investigations
Blood bilirubin increased	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
Chest wall pain	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Generalized muscle weakness	0/3 (0%)	0	1/37 (2.7%)	1	2/33 (6.1%)	2
Pain in extremity	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/3 (33.3%)	1	0/37 (0%)	0	0/33 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Dyspnea	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Hypoxia	1/3 (33.3%)	1	0/37 (0%)	0	1/33 (3%)	1
Pleural effusion	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Pneumothorax	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Respiratory failure	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Vascular disorders
Hypotension	1/3 (33.3%)	1	1/37 (2.7%)	1	1/33 (3%)	1
Thromboembolic event	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase I GM.CD40L.CCL21 Vaccinations		Phase II Arm A GM.CD40L Vaccinations		Phase II Arm B GM.CD40L.CCL21 Vaccinations
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		35/37 (94.6%)		33/33 (100%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	9/37 (24.3%)	12	7/33 (21.2%)	10
Blood and lymphatic system disorders - Other	0/3 (0%)	0	2/37 (5.4%)	2	1/33 (3%)	1
Leukocytosis	1/3 (33.3%)	1	0/37 (0%)	0	1/33 (3%)	1
Spleen disorder	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Thrombotic thrombocytopenic purpura	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Cardiac disorders
Palpitations	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Supraventricular tachycardia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Sinus tachycardia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Ventricular tachycardia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Ear pain	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Eye disorders
Blurred vision	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Gastrointestinal disorders
Constipation	0/3 (0%)	0	9/37 (24.3%)	10	7/33 (21.2%)	7
Nausea	0/3 (0%)	0	5/37 (13.5%)	8	6/33 (18.2%)	6
Diarrhea	0/3 (0%)	0	4/37 (10.8%)	4	8/33 (24.2%)	9
Vomiting	0/3 (0%)	0	4/37 (10.8%)	5	5/33 (15.2%)	5
Dry mouth	0/3 (0%)	0	3/37 (8.1%)	3	3/33 (9.1%)	3
Gastrointestinal disorders - Other	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	2
Stomach pain	1/3 (33.3%)	1	2/37 (5.4%)	2	1/33 (3%)	1
Abdominal pain	0/3 (0%)	0	0/37 (0%)	0	3/33 (9.1%)	7
Abdominal distension	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Ascites	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Bloating	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Dyspepsia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Gastroesophageal reflux disease	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Oral pain	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Pancreatitis	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Tooth development disorder	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
General disorders
Injection site reaction	1/3 (33.3%)	2	19/37 (51.4%)	39	21/33 (63.6%)	45
Fatigue	2/3 (66.7%)	3	19/37 (51.4%)	21	15/33 (45.5%)	18
Edema limbs	0/3 (0%)	0	5/37 (13.5%)	5	4/33 (12.1%)	4
Pain	0/3 (0%)	0	2/37 (5.4%)	2	7/33 (21.2%)	8
Fever	1/3 (33.3%)	1	3/37 (8.1%)	3	1/33 (3%)	1
Flu like symptoms	0/3 (0%)	0	2/37 (5.4%)	3	2/33 (6.1%)	2
Non-cardiac chest pain	0/3 (0%)	0	3/37 (8.1%)	3	1/33 (3%)	1
Chills	1/3 (33.3%)	1	1/37 (2.7%)	1	0/33 (0%)	0
General disorders and administration site conditions - Other	0/3 (0%)	0	2/37 (5.4%)	4	0/33 (0%)	0
Gait disturbance	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Localized edema	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Immune system disorders
Allergic reaction	0/3 (0%)	0	0/37 (0%)	0	2/33 (6.1%)	3
Infections and infestations
Infections and infestations - Other	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	3
Lung infection	0/3 (0%)	0	0/37 (0%)	0	2/33 (6.1%)	2
Urinary tract infection	0/3 (0%)	0	1/37 (2.7%)	1	2/33 (6.1%)	2
Bronchial infection	0/3 (0%)	0	0/37 (0%)	0	2/33 (6.1%)	2
Skin infection	0/3 (0%)	0	0/37 (0%)	0	2/33 (6.1%)	2
Papulopustular rash	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Wound infection	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Injury, poisoning and procedural complications
Bruising	0/3 (0%)	0	1/37 (2.7%)	1	2/33 (6.1%)	2
Fall	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Injury, poisoning and procedural complications - Other	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Investigations
Alkaline phosphatase increased	0/3 (0%)	0	6/37 (16.2%)	10	6/33 (18.2%)	8
Investigations - Other	0/3 (0%)	0	3/37 (8.1%)	4	9/33 (27.3%)	13
Alanine aminotransferase increased	0/3 (0%)	0	2/37 (5.4%)	6	3/33 (9.1%)	6
Aspartate aminotransferase increased	0/3 (0%)	0	1/37 (2.7%)	2	3/33 (9.1%)	4
Weight loss	1/3 (33.3%)	1	2/37 (5.4%)	2	1/33 (3%)	1
Lymphocyte count decreased	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Platelet count decreased	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
White blood cell decreased	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Blood bilirubin increased	0/3 (0%)	0	1/37 (2.7%)	3	0/33 (0%)	0
Creatinine increased	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
INR increased	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Metabolism and nutrition disorders
Anorexia	2/3 (66.7%)	3	6/37 (16.2%)	8	11/33 (33.3%)	11
Hyperkalemia	0/3 (0%)	0	7/37 (18.9%)	8	4/33 (12.1%)	6
Hyponatremia	0/3 (0%)	0	3/37 (8.1%)	3	4/33 (12.1%)	6
Dehydration	0/3 (0%)	0	4/37 (10.8%)	5	1/33 (3%)	2
Hypermagnesemia	0/3 (0%)	0	2/37 (5.4%)	2	4/33 (12.1%)	4
Hypoalbuminemia	1/3 (33.3%)	1	1/37 (2.7%)	2	2/33 (6.1%)	2
Metabolism and nutrition disorders - Other	0/3 (0%)	0	3/37 (8.1%)	4	1/33 (3%)	1
Hypomagnesemia	2/3 (66.7%)	2	1/37 (2.7%)	1	0/33 (0%)	0
Hypophosphatemia	0/3 (0%)	0	3/37 (8.1%)	6	0/33 (0%)	0
Hypernatremia	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Hypocalcemia	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Hypercalcemia	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Hyperglycemia	1/3 (33.3%)	1	0/37 (0%)	0	0/33 (0%)	0
Hypoglycemia	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Hypokalemia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	3/37 (8.1%)	4	7/33 (21.2%)	7
Bone pain	0/3 (0%)	0	1/37 (2.7%)	1	5/33 (15.2%)	6
Generalized muscle weakness	0/3 (0%)	0	3/37 (8.1%)	4	2/33 (6.1%)	2
Pain in extremity	0/3 (0%)	0	1/37 (2.7%)	1	5/33 (15.2%)	6
Chest wall pain	0/3 (0%)	0	1/37 (2.7%)	1	3/33 (9.1%)	3
Musculoskeletal and connective tissue disorder - Other	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Muscle weakness lower limb	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Neck pain	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	0/3 (0%)	0	4/37 (10.8%)	5	4/33 (12.1%)	4
Nervous system disorders
Headache	0/3 (0%)	0	5/37 (13.5%)	5	4/33 (12.1%)	5
Peripheral sensory neuropathy	0/3 (0%)	0	2/37 (5.4%)	2	4/33 (12.1%)	4
Dizziness	0/3 (0%)	0	4/37 (10.8%)	4	0/33 (0%)	0
Nervous system disorders - Other	0/3 (0%)	0	1/37 (2.7%)	2	1/33 (3%)	1
Amnesia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Ataxia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Peripheral motor neuropathy	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Psychiatric disorders
Anxiety	1/3 (33.3%)	1	2/37 (5.4%)	2	2/33 (6.1%)	2
Insomnia	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	2
Confusion	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Renal and urinary disorders
Proteinuria	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Hematuria	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Urine discoloration	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Reproductive system and breast disorders
Premature menopause	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/3 (0%)	0	11/37 (29.7%)	14	13/33 (39.4%)	15
Cough	1/3 (33.3%)	2	10/37 (27%)	10	13/33 (39.4%)	14
Nasal congestion	0/3 (0%)	0	1/37 (2.7%)	1	3/33 (9.1%)	3
Productive cough	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	2
Sore throat	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	2
Pneumonitis	1/3 (33.3%)	1	0/37 (0%)	0	2/33 (6.1%)	2
Respiratory, thoracic and mediastinal disorders - Other	0/3 (0%)	0	0/37 (0%)	0	2/33 (6.1%)	2
Epistaxis	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Hoarseness	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Hypoxia	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Laryngeal mucositis	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Pleural effusion	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Postnasal drip	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Wheezing	0/3 (0%)	0	1/37 (2.7%)	1	1/33 (3%)	1
Allergic rhinitis	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Atelectasis	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Laryngeal hemorrhage	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Pleuritic pain	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Skin and subcutaneous tissue disorders
Dry skin	0/3 (0%)	0	2/37 (5.4%)	2	3/33 (9.1%)	4
Pruritus	0/3 (0%)	0	2/37 (5.4%)	2	2/33 (6.1%)	3
Alopecia	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Rash maculo-papular	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Skin and subcutaneous tissue disorders - Other	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Vascular disorders
Hypotension	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Hypertension	0/3 (0%)	0	2/37 (5.4%)	2	0/33 (0%)	0
Flushing	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Hematoma	0/3 (0%)	0	0/37 (0%)	0	1/33 (3%)	1
Hot flashes	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0
Vascular disorders - Other	0/3 (0%)	0	1/37 (2.7%)	1	0/33 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

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