TOP 1501: Neoadjuvant Pembrolizumab

• Sponsor: Neal Ready (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02818920
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 35
• Locations: 3
• Arm: 1
• Anticipated Duration (Months): 109.9
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This multi-institutional, phase 2 clinical trial is studying two doses of pembrolizumab administered prior to surgery (neoadjuvant therapy) and 4 doses administered after surgery (adjuvant therapy) for stage IB, II or IIIA non-small cell lung cancer. Pembrolizumab is a type of immunotherapy that may enhance the ability of the immune system to fight off cancer. The study will investigate the effects of pembrolizumab on the immune system and how certain immune cells, called TILs (tumor infiltrating lymphocytes), respond to pembrolizumab. Previous studies suggest that pembrolizumab could alter the immune cells in a way that the the immune cells identify cancer cells. Pembrolizumab has been approved for the treatment of advanced lung cancer, but is investigational in this setting.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Carcinoma	Drug: Pembrolizumab	Phase 2

Detailed Description

The presumed mechanism of action for pembrolizumab is the removal of T lymphocyte inhibition by masking the PD-1 receptor. Our hypothesis is that the masking of the PD-1 receptor by pembrolizumab results in the activation and proliferation of T lymphocytes with specificities against tumor associated antigens (TILs). In untreated lung cancer tumors, we would expect few tumors to have TIL cells with specificities against tumor associated antigens. Based on the response rate to pembrolizumab in advanced lung cancer, we hypothesize that at least 20% of lung cancers would have TIL cells with specificities against tumor associated antigens after pembrolizumab therapy.

Studying neoadjuvant pembrolizumab therapy is an attractive strategy for studying the immunologic changes caused by PD-1 (programmed death receptor 1) checkpoint masking. Most of the immunologic activity associated with pembrolizumab occurs in the tumor and surrounding microenvironment. Evaluation of post-pembrolizumab tumor will be important to understanding factors associated with pembrolizumab activity, immune tolerance, and discovery of other targets for immune therapy. Pembrolizumab has known benefit in non-small cell lung cancer. The addition of pembrolizumab for two doses prior to surgery and four doses after surgery has the potential to confer clinical benefit. Large randomized phase 3 trials are now testing whether PD-1 checkpoint antibodies improve survival as adjuvant therapy after resection of early stage lung cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pembrolizumab Prior to Surgery for Stage 1B, 2 or 3A Non-small Cell Lung Cancer (NSCLC): A Phase II Study
• Actual Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Mar 19, 2019
• Anticipated Study Completion Date: Mar 1, 2026

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Pembrolizumab prior to and after surgery

Drug: Pembrolizumab; Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications; Other Names: Keytruda

Outcome Measures

Primary Outcome Measures

1. Surgical Feasibility Rate as Measured by the Number of Subjects Who Undergo Surgery Following Neoadjuvant Pembrozulimab [29-56 days after initiation of pembrolizumab]

   A patient who meets the eligibility criteria, has received at least 1 dose of pembrolizumab, and undergone surgery in the window of 29-56 days after initiation of pembrolizumab is considered surgically feasible. All other situations are considered infeasible.

Other Outcome Measures

1. Objective Response Rate [At the end of 2 cycles of neoadjuvant pembrolizumab (29-55 days after initiation)]

   The percentage of patients having a complete response or a partial response to protocol treatment. Objective response will be measured by RECIST 1.1.

2. Disease-free Survival (DFS) [Until disease recurrence or death (up to 5 years)]

   DFS is defined as the time from surgical resection to disease recurrence (first disease recurrence or death, whichever comes first) after surgery.The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval.

3. Change in Blood-based Biomarker Values [Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient)]

   Changes in levels of blood-based biomarkers before and after protocol treatment and correlated with clinical outcomes, such as objective response, overall survival, and disease-free survival.

4. Detectability of Tumor Infiltrating Lymphocytes (TILs) [End of protocol treatment (Estimated at 10.5 months from start depending on treatment components received by patient)]

   Percentage of patients with detectable TILs, defined as greater than or equal to 0.05% (with each value also being at least twice that of the background unstimulated control value TIL)

5. Adverse Events [End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)]

   Safety will be evaluated for all treated patients using CTCAE V 4.0.

6. Detectability of Circulating T Cells Specific Against TAA [End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)]

   Proportion of patients with detectable circulating T cells specific against TAA after protocol treatment.

7. Pathologic Response Rate [At surgery (day 29-56)]

   Pathologic response rate for neoadjuvant pembrolizumab

8. Change in Immunomodulatory Effects [Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient)]

   Determine if the immunomodulatory effects of neoadjuvant pembrolizumab have an impact on the suppressive mechanisms, restoring functional reactivity to important anti-tumor effects cell populations. Functional TAA-specific T cell reactivities will measured at 4 time points.

9. Detectability of Circulating T Cells Meeting New Definition of Detectability [End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)]

   Percentage of patients with circulating T cells meeting the new definition of detectable.

10. Gene Expression of the PD-1/PD-L1 Axis [End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)]

    Elucidate genes associated with function and modulation of the PD-1/PD-L1 axis.

11. Correlation of Pathologic Response to the Presence of TILs [At surgery (day 29-56)]

    A Fisher exact test will be used to evaluate the association of the presence of TILs with pathologic tumor response to neoadjuvant therapy.

12. Correlation of Pathologic Response to the Quality of TILs [At surgery (day 29-56)]

    A Fisher exact test will be used to evaluate the association of the quality of TILs with pathologic tumor response to neoadjuvant therapy.

13. Correlation of Pathologic Response to the Quantity of TILs [At surgery (days 29-56)]

    A Wilcoxon rank sum test will be used to test the association of the quantity of TILs and pathologic response to neoadjuvant therapy.

14. Patterns of Metastases as Measured by Frequency at Site. [Until disease recurrence or death (up to 5 years)]]

    The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval. The frequencies of metastases by site will be tabulated

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed NSCLC.

• Clinical stage IB (>/= 3 cm per CT), Stage IIA/IIB, or Stage IIIA (N0-2) amenable to surgical resection.

• Primary tumor >/= 3 cm (for all stages entered) to make it likely that excess tumor will be available after resection.

• Patient must be deemed a surgical candidate.

• ECOG performance status of 0 or 1 (Appendix C).

• No prior chemotherapy, radiation therapy or biologic/targeted therapy for current diagnosis of lung cancer.

• Adequate Organ Function

• Age ≥18 years.

• Non-pregnant. Females of child-bearing potential (not surgically sterilized or postmenopausal [a woman who is > 45 years of age and has not had menses for greater than 1 year]) must test negative for pregnancy within 48 hours prior to any initial study procedure based on a serum pregnancy test.

• No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. Cancers that are in-situ are not considered invasive.

• Signed written informed consent including HIPAA according to institutional guidelines.

• Patients must agree to research blood sampling to participate in study.

• Have measurable disease based on RECIST 1.1.

• Post-op predicted FEV1 and DLCO > 40% predicted (or per institutional standard).

Exclusion Criteria:

• Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry or used an investigational device within 4 weeks of the first dose of treatment.

• Has a known history of active TB (Bacillus Tuberculosis).

• Hypersensitivity to pembrolizumab or any of its excipients.

• Concurrent administration of any other anti-tumor therapy.

• Has received prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agent.

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Inability to comply with protocol or study procedures.

• Active infection requiring antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.

• Has known history of, or any evidence of active, non-infectious pneumonitis.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment. Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

• Has a known additional invasive malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

• Has had major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant disorders that in the opinion of the investigator would compromise the safety of the patient or compromise the patient's ability to complete the study.

• Has received any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 30 days before or after any dose of pembrolizumab). Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.

• Has history of myocardial infarction having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications. Patients with CAD recently treated with surgery and/or stent, if stable without symptomatic angina pectoris, active ischemia are eligible.

• Has a history of interstitial lung disease

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Prisoners or subjects who are compulsorily detained involuntarily incarcerated) for treatment of either psychiatric or physical (e.g., infectious) illness.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905
2	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
3	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Neal Ready
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Neal Ready, MD, Duke University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 11, 2018

More Information

Publications

None provided.

• Responsible Party: Neal Ready, Associate Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT02818920
• Other Study ID Numbers: Pro00071629
• First Posted: Jun 30, 2016
• Last Update Posted: Feb 21, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Neal Ready, Associate Professor of Medicine, Duke University: Pembrolizumab; Neoadjuvant; Tumor Infiltrating Lymphocytes (TILs)
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	Thirty-five subjects consented to the study. Two subjects withdrew consent before receiving protocol treatment and three were deemed ineligible.

Arm/Group Title	Pembrolizumab Prior to and After Surgery
Arm/Group Description	Pembrolizumab: Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications
Period Title: Overall Study
STARTED	30
Completed Surgery	25
Received Adjuvant Therapy	17
COMPLETED	12
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Pembrolizumab Prior to and After Surgery
Arm/Group Description	Pembrolizumab: Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications
Overall Participants	25
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	71
Sex: Female, Male (Count of Participants)
Female	9 36%
Male	16 64%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	25 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4%
White	22 88%
More than one race	0 0%
Unknown or Not Reported	2 8%
Region of Enrollment (Count of Participants)
United States	25 100%
Histological Diagnosis (Count of Participants)
Adenocarcinoma	8 32%
Squamous cell carcinoma	15 60%
Non-small cell lung cancer NOS	2 8%
Clinical Stage (Count of Participants)
Stage IB	7 28%
Stage IIA	6 24%
Stage IIB	5 20%
Stage IIIA	7 28%
History of Smoking (Count of Participants)
Never	3 12%
Current user	4 16%
Quit < or = 1 month	4 16%
Quit > 1 month to 1 year	2 8%
Quit > 1 year	12 48%
ECOG (Eastern Cooperative Oncology Group) Score (Count of Participants)
0	14 56%
1	11 44%
2	0 0%
3	0 0%
4	0 0%
5	0 0%

Outcome Measures

1. Primary Outcome

Title	Surgical Feasibility Rate as Measured by the Number of Subjects Who Undergo Surgery Following Neoadjuvant Pembrozulimab
Description	A patient who meets the eligibility criteria, has received at least 1 dose of pembrolizumab, and undergone surgery in the window of 29-56 days after initiation of pembrolizumab is considered surgically feasible. All other situations are considered infeasible.
Time Frame	29-56 days after initiation of pembrolizumab

Outcome Measure Data

Analysis Population Description

Subjects who completed surgery.

Arm/Group Title	Pembrolizumab Prior to and After Surgery
Arm/Group Description	Pembrolizumab: Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications
Measure Participants	25
Count of Participants [Participants]	24 96%

2. Other Pre-specified Outcome

Title	Objective Response Rate
Description	The percentage of patients having a complete response or a partial response to protocol treatment. Objective response will be measured by RECIST 1.1.
Time Frame	At the end of 2 cycles of neoadjuvant pembrolizumab (29-55 days after initiation)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Disease-free Survival (DFS)
Description	DFS is defined as the time from surgical resection to disease recurrence (first disease recurrence or death, whichever comes first) after surgery.The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval.
Time Frame	Until disease recurrence or death (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Change in Blood-based Biomarker Values
Description	Changes in levels of blood-based biomarkers before and after protocol treatment and correlated with clinical outcomes, such as objective response, overall survival, and disease-free survival.
Time Frame	Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Detectability of Tumor Infiltrating Lymphocytes (TILs)
Description	Percentage of patients with detectable TILs, defined as greater than or equal to 0.05% (with each value also being at least twice that of the background unstimulated control value TIL)
Time Frame	End of protocol treatment (Estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Adverse Events
Description	Safety will be evaluated for all treated patients using CTCAE V 4.0.
Time Frame	End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Detectability of Circulating T Cells Specific Against TAA
Description	Proportion of patients with detectable circulating T cells specific against TAA after protocol treatment.
Time Frame	End of protocol treatment (estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Pathologic Response Rate
Description	Pathologic response rate for neoadjuvant pembrolizumab
Time Frame	At surgery (day 29-56)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Change in Immunomodulatory Effects
Description	Determine if the immunomodulatory effects of neoadjuvant pembrolizumab have an impact on the suppressive mechanisms, restoring functional reactivity to important anti-tumor effects cell populations. Functional TAA-specific T cell reactivities will measured at 4 time points.
Time Frame	Baseline (day 0), before surgery (days 29-56), 3-6 weeks after surgery, and after completion of adjuvant pembrolizumab (estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Detectability of Circulating T Cells Meeting New Definition of Detectability
Description	Percentage of patients with circulating T cells meeting the new definition of detectable.
Time Frame	End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Gene Expression of the PD-1/PD-L1 Axis
Description	Elucidate genes associated with function and modulation of the PD-1/PD-L1 axis.
Time Frame	End of protocol treatment ((Estimated at 10.5 months from start depending on treatment components received by patient)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Correlation of Pathologic Response to the Presence of TILs
Description	A Fisher exact test will be used to evaluate the association of the presence of TILs with pathologic tumor response to neoadjuvant therapy.
Time Frame	At surgery (day 29-56)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Correlation of Pathologic Response to the Quality of TILs
Description	A Fisher exact test will be used to evaluate the association of the quality of TILs with pathologic tumor response to neoadjuvant therapy.
Time Frame	At surgery (day 29-56)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Correlation of Pathologic Response to the Quantity of TILs
Description	A Wilcoxon rank sum test will be used to test the association of the quantity of TILs and pathologic response to neoadjuvant therapy.
Time Frame	At surgery (days 29-56)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Patterns of Metastases as Measured by Frequency at Site.
Description	The Kaplan-Meier estimator will be used to estimate median DFS and its confidence interval. The frequencies of metastases by site will be tabulated
Time Frame	Until disease recurrence or death (up to 5 years)]

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Approximately 10.5 months
Adverse Event Reporting Description	30 patients received neoadjuvant therapy. Among them, 25 patients underwent surgery. 17 out of those 25 patients received adjuvant therapy. Therefore, the number of patients at risk was different at different treatment phases.
Arm/Group Title	Pembrolizumab Prior to and After Surgery
Arm/Group Description	Pembrolizumab: Pembrolizumab (prior to surgery) 200 mg IV over 30 min, days 1 & 22, two cycles; followed by surgery; followed by standard adjuvant chemotherapy (per med. oncologist) +/- radiation therapy per institutional standard of care; followed by adjuvant pembrolizumab 200 mg IV over 30 min every 21 days for 4 cycles -Note: Standard radiation therapy in selected patients for standard clinical indications
All Cause Mortality
	Pembrolizumab Prior to and After Surgery
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Serious Adverse Events
	Pembrolizumab Prior to and After Surgery
	Affected / at Risk (%)	# Events
Total	6/30 (20%)
Cardiac disorders
Supraventricular tachycardia	1/25 (4%)
Gastrointestinal disorders
Abdominal pain	1/17 (5.9%)
Injury, poisoning and procedural complications
Infusion related reaction	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Lung infection	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders - Other	1/17 (5.9%)
Vascular disorders
Thromboembolic event	1/25 (4%)
Other (Not Including Serious) Adverse Events
	Pembrolizumab Prior to and After Surgery
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anemia	7/30 (23.3%)
Cardiac disorders
Atrial fibrillation	6/25 (24%)
Sinus bradycardia	1/30 (3.3%)
Sinus tachycardia	1/17 (5.9%)
Supraventricular tachycardia	1/25 (4%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	1/30 (3.3%)
Endocrine disorders
Endocrine disorders - Other	5/30 (16.7%)
Hyperthyroidism	2/30 (6.7%)
Hypothyroidism	5/30 (16.7%)
Eye disorders
Dry eye	1/30 (3.3%)
Eye disorders - Other	2/30 (6.7%)
Watering eyes	2/30 (6.7%)
Gastrointestinal disorders
Abdominal distension	1/17 (5.9%)
Abdominal pain	2/17 (11.8%)
Bloating	1/30 (3.3%)
Colitis	1/30 (3.3%)
Constipation	4/30 (13.3%)
Diarrhea	12/30 (40%)
Dyspepsia	1/30 (3.3%)
Dysphagia	1/17 (5.9%)
Gastroesophageal reflux disease	2/30 (6.7%)
Gastrointestinal disorders - Other	2/30 (6.7%)
Hemorrhoidal hemorrhage	1/17 (5.9%)
Hemorrhoids	1/30 (3.3%)
Mucositis oral	2/30 (6.7%)
Nausea	4/30 (13.3%)
Vomiting	1/30 (3.3%)
General disorders
Chills	2/30 (6.7%)
Edema limbs	3/30 (10%)
Fatigue	12/30 (40%)
Fever	1/30 (3.3%)
Flu like symptoms	2/30 (6.7%)
Gait disturbance	1/17 (5.9%)
General disorders and administration site conditions - Other	1/30 (3.3%)
Non-cardiac chest pain	3/30 (10%)
Pain	2/30 (6.7%)
Infections and infestations
Bronchial infection	2/30 (6.7%)
Lung infection	2/25 (8%)
Scrotal infection	1/17 (5.9%)
Skin infection	2/25 (8%)
Injury, poisoning and procedural complications
Fall	1/30 (3.3%)
Infusion related reaction	1/30 (3.3%)
Postoperative thoracic procedure complication	4/25 (16%)
Investigations
Alanine aminotransferase increased	2/30 (6.7%)
Alkaline phosphatase increased	3/30 (10%)
Aspartate aminotransferase increased	2/30 (6.7%)
Blood bilirubin increased	1/30 (3.3%)
Creatinine increased	3/30 (10%)
Neutrophil count decreased	1/30 (3.3%)
Platelet count decreased	2/30 (6.7%)
Weight gain	1/17 (5.9%)
Weight loss	1/30 (3.3%)
Metabolism and nutrition disorders
Anorexia	5/30 (16.7%)
Dehydration	1/17 (5.9%)
Hypercalcemia	1/17 (5.9%)
Hyperglycemia	3/30 (10%)
Hyperuricemia	1/17 (5.9%)
Hypoalbuminemia	6/30 (20%)
Hypocalcemia	1/30 (3.3%)
Hypokalemia	6/30 (20%)
Hypomagnesemia	8/30 (26.7%)
Hyponatremia	7/30 (23.3%)
Hypophosphatemia	3/30 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/30 (16.7%)
Bone pain	1/30 (3.3%)
Joint effusion	1/30 (3.3%)
Muscle weakness lower limb	1/17 (5.9%)
Myalgia	1/30 (3.3%)
Pain in extremity	1/30 (3.3%)
Nervous system disorders
Concentration impairment	1/30 (3.3%)
Dizziness	5/30 (16.7%)
Dysgeusia	2/30 (6.7%)
Headache	4/30 (13.3%)
Paresthesia	2/30 (6.7%)
Peripheral sensory neuropathy	2/17 (11.8%)
Tremor	1/17 (5.9%)
Psychiatric disorders
Agitation	1/30 (3.3%)
Anxiety	3/30 (10%)
Confusion	1/30 (3.3%)
Insomnia	6/30 (20%)
Renal and urinary disorders
Renal and urinary disorders - Other	1/30 (3.3%)
Reproductive system and breast disorders
Reproductive system and breast disorders - Other	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/17 (5.9%)
Atelectasis	3/25 (12%)
Bronchopulmonary hemorrhage	1/17 (5.9%)
Cough	3/30 (10%)
Dyspnea	6/30 (20%)
Epistaxis	1/30 (3.3%)
Hypoxia	4/25 (16%)
Nasal congestion	2/17 (11.8%)
Pneumonitis	2/17 (11.8%)
Productive cough	1/17 (5.9%)
Pulmonary hypertension	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders - Other	2/17 (11.8%)
Upper respiratory infection	2/17 (11.8%)
Wheezing	2/30 (6.7%)
Skin and subcutaneous tissue disorders
Dry skin	1/30 (3.3%)
Pruritus	4/30 (13.3%)
Rash maculo-papular	5/30 (16.7%)
Skin and subcutaneous tissue disorders - Other	3/30 (10%)
Skin induration	1/17 (5.9%)
Surgical and medical procedures
Surgical and medical procedures - Other	1/25 (4%)
Vascular disorders
Hypertension	3/17 (17.6%)
Hypotension	1/30 (3.3%)
Thromboembolic event	2/25 (8%)

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.