MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02592551
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 75.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The objective of this study is to determine whether MEDI4736 or combination therapy with MEDI4736 + tremelimumab are associated with favorable alterations of the intratumoral immunologic environment in subjects undergoing resectional surgery for Malignant Pleural Mesothelioma MPM.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma	Drug: MEDI4736; Drug: Tremelimumab; Other: no other name	Phase 2

Detailed Description

Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at which time tumor tissue (at least 2 g) and peripheral blood will be collected for the study. These procedures are performed as standard of care in the treatment of these subjects. The subject will be randomized. Three days to three weeks after the biopsy, subjects will be randomly treated with either MEDI-4736 (15 mg/kg once intravenously) or MEDI-4736 (1500 mg once intravenously) plus tremelimumab (75 mg once intravenously) or a control group in a randomized controlled study design. There will be two treatment arms (MEDI4736 only and combination MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified by receiving previous chemotherapy or not, will be performed and will help to minimize patient selection biases between three arms. Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and Tremelimumab combination therapy. These patients are excluded from fixed based dosing to limit endotoxin exposure from the drug preparations. One to six weeks after the infusion, subjects will undergo resectional surgery, including extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), at which time the tumor will be removed (typically 200-1000 g) and obtained for study. Four patients that do not undergo treatment with MEDI-4736 or tremelimumab will be included as controls. Blood will be obtained after the induction of general anesthesia for both the thoracoscopy procedure and the EPP or P/D resectional procedure, as is routinely done in these procedures. The sixth rib will be obtained at the time of the resection. After the removal of the tumor, standard protocol includes intraoperative heated chemotherapy using a lavage of intracavitary cisplatin in the presence of conserved renal function (Sugarbaker et al., 2013, 2014; Richards et al., 2006).

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Window Of Opportunity Phase II Study Of MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma
• Actual Study Start Date: May 11, 2016
• Actual Primary Completion Date: Aug 6, 2019
• Anticipated Study Completion Date: Sep 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MEDI4736 8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection.	Drug: MEDI4736; MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.; Other Names: durvalumab
Active Comparator: MEDI4736 + Tremelimumab 8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection.	Drug: MEDI4736; MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.; Other Names: durvalumab ; Drug: Tremelimumab; Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.; Other Names: no other name
Placebo Comparator: Untreated arm (control) 4 patients will not receive MEDI4736 or Tremelimumab.	Other: no other name; Neither MEDI4736 nor Tremelimumab will be used.

Outcome Measures

Primary Outcome Measures

1. Change in Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) [at day 1 after screening and at a surgery within one to six weeks after treatment]

   Tissue biomarker immune response of CD8 and Treg to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.

Secondary Outcome Measures

1. Change in Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells. [at day 1 after screening and at a surgery within one to six weeks after treatment]

   Tissue biomarker for the immune response of ICOS+ CD4 T cells to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.

2. Change in Tumor Expression Programmed Death-ligand 1 (PD-L1). [at day 1 after screening and at a surgery within one to six weeks after treatment]

   Tumor expression programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.

3. Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone. [at a surgery within one to six weeks after treatment]

   Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.

4. Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and Untreated Patients. [the untreated group(control) : at day 1, MEDI4736 + Tremelimumab: at a surgery within one to six weeks after treatment (MEDI4736+Tremelimumab) group]

   Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and at day 1 of untread will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.

5. Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone [at a surgery within one to six weeks after treatment]

   Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.

6. Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients. [Untreated group (control): at day 1, MEDI-4736 and Tremelimumab group: at a surgery within one to six weeks after treatment]

   Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after untreated patients will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.

7. Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone. [at a surgery within one to six weeks after treatment]

   Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI-4736 alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.

8. Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients. [Untreated arm (control): at day 1 after screening, MEDI4736 + Tremelimumab group: at a surgery within one to six weeks after treatment]

   Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and before and at day 1 of untreate alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.

9. Median Recurrence-free Survival (RFS) [Participants will be followed up until disease recurrence or censor for 2 year after surgery]

   RFS based on the Kaplan-Meier method is defined as the time between treatment and disease recurrence or censored and participants in either MEDI-4736 alone or MEDI-4736 plus Tremelimumab will be followed up for 2 years after surgery.

10. Median Overall Survival (OS) [Participants will be followed up until death or censor for 2 year after surgery]

    OS based on the Kaplan-Meier method is defined as the time between treatment and death or censored and participants in either MEDI-4736 alone or MEDI-4736+Tremelimumab will be followed up for 2 years after surgery.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations

2. Age >/= 18 years at time of study entry

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

4. Adequate normal organ and marrow function as defined below:

Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (> 1500 per mm3) Platelet count ≥ 100 × 109/L (>100,000 per mm3) Serum bilirubin ≤ 1.5× institutional upper limit of normal (ULN)AST<3.0 Creatinine clearance >50mL/miN Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if documented liver metastasis are present); Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation;

Males:

Creatinine CL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) × (140 - Age) × 0.85 72 × serum creatinine (mg/dL)

1. Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: ≥60 years old and no menses for >/=1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

2. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

3. Surgically resectable MPM with no disease extension beyond the ipsilateral hemithorax

4. Planned resectional surgery for MPM [extrapleural pneumonectomy (EPP) or pleurectomy and decortication (P/D)]

5. Any MPM histology (epithelial, mixed, sarcomatoid)

6. N0 or N1 nodal disease as present on perioperative chest CT and/or PET CT.

7. N2 nodal disease if no progression after 2 cycles of standard chemotherapy. Progression will be considered if additional N1 or N2 disease develop during chemotherapy

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) or previous enrollment or randomization in the present study

2. Participation in another clinical study with an investigational product during the last 3 months

3. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736

4. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 30 days prior to the first dose of study drug, and 30 days prior to the first dose of study drug for subjects who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C).

5. Current or prior use of immunosuppressive medication within 28 days before the infusion with MEDI4736 or MEDI4736 + tremelimumab and through 90 days post infusion, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

6. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.

7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1

8. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.

9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

10. History of primary immunodeficiency

11. History of allogeneic organ transplant

12. History of hypersensitivity to MEDI4736 or any excipient

13. History of hypersensitivity to tremelimumab or the combination of MEDI4736 + tremelimumab

14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent

15. Known history of previous clinical diagnosis of tuberculosis

16. History of leptomeningeal carcinomatosis

17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 6 months of receiving MEDI4736 or MEDI + tremelimumab

18. Receipt of drugs with laxative properties and herbal or natural remedies for constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab

19. Receipt of sunitinib within 3 months of receiving tremelimumab

20. Female subjects who are pregnant, breastfeeding, or male or female subjects of reproductive potential who are not employing an effective method of birth control

21. Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study treatment or interpretation of subject safety or study results

22. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.

23. Subjects with uncontrolled seizures

24. N3 nodal disease

25. History of interstitial lung disease/pneumonitis

26. No tissue is obtainable at the time of thoracoscopy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baylor St Lukes	Houston	Texas	United States	77030

Sponsors and Collaborators

• Baylor College of Medicine

Investigators

• Principal Investigator: Bryan Burt, MD, Baylor College of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 17, 2019

More Information

Publications

None provided.

• Responsible Party: Bryan Burt, MD, Principal Investigator, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT02592551
• Other Study ID Numbers: H-36952
• First Posted: Oct 30, 2015
• Last Update Posted: Jan 27, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Mesothelioma; Mesothelioma, Malignant; Durvalumab; Tremelimumab

Study Results

Participant Flow

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab	Untreated Arm (Control)
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.	4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Period Title: Overall Study
STARTED	9	11	4
COMPLETED	8	8	4
NOT COMPLETED	1	3	0

Baseline Characteristics

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab	Untreated Arm (Control)	Total
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.	4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.	Total of all reporting groups
Overall Participants	9	11	4	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (6)	59 (15)	58 (12)	63 (12)
Sex: Female, Male (Count of Participants)
Female	2 22.2%	2 18.2%	2 50%	6 25%
Male	7 77.8%	9 81.8%	2 50%	18 75%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 18.2%	1 25%	3 12.5%
Not Hispanic or Latino	9 100%	9 81.8%	3 75%	21 87.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 25%	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	9 100%	11 100%	1 25%	21 87.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	2 50%	2 8.3%
Prior Chemodtherapy (Count of Participants)
Yes	0 0%	1 9.1%	2 50%	3 12.5%
No	9 100%	10 90.9%	2 50%	21 87.5%

Outcome Measures

1. Primary Outcome

Title	Change in Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg)
Description	Tissue biomarker immune response of CD8 and Treg to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.
Time Frame	at day 1 after screening and at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

The primary objective was the comparison of CD8/Treg before and after treatment with combination MEDI-4736 and Tremelimumab group. Therefore, the analysis population was from one arm (MEDI4736+Tremelimumab).

Arm/Group Title	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	8
Median (Inter-Quartile Range) [no unit of ratios with same units(%)]	8.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab
	Comments	Compare in ratios of intratumoral cytotoxic T cells to regulatory T cells (CD8/Treg) between pre and post of MEDI4736+Tremelimumab
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	Wilcoxon signed rank test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	8.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells.
Description	Tissue biomarker for the immune response of ICOS+ CD4 T cells to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.
Time Frame	at day 1 after screening and at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

The objective was the comparison of percentage of inducible T-cell co-stimulator (ICOS) + CD4 T cells before and after treatment with combination MEDI-4736 and Tremelimumab group. Therefore, the analysis population was from one arm (MEDI4736+Tremelimumab).

Arm/Group Title	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	8
Median (Inter-Quartile Range) [percentage of inducible T-cell co-stimul]	-2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab
	Comments
	Type of Statistical Test	Other
	Comments	Compare the tissue biomarker for the immune response of ICOS+ CD4 T cells to before and after MEDI-4736 and Tremelimumab
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Wilcoxon signed rank test
	Comments

3. Secondary Outcome

Title	Change in Tumor Expression Programmed Death-ligand 1 (PD-L1).
Description	Tumor expression programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.
Time Frame	at day 1 after screening and at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

The objective was the comparison of tumor expression programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab group. Therefore, the analysis population was from one arm (MEDI4736+Tremelimumab).

Arm/Group Title	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	8
Median (Inter-Quartile Range) [MMI (Mean Mass Intensity)]	0.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab
	Comments	Compare tumor expression programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.461
	Comments
	Method	Wilcoxon signed rank test
	Comments

4. Secondary Outcome

Title	Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone.
Description	Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.
Time Frame	at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

one participant who was assigned to MEDI4736 alone group completed the study procedures but the tumor sample was too small to analyze in the lab.

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	7	8
Median (Inter-Quartile Range) [no unit of ratios with same units(%)]	8	9.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab, MEDI4736 + Tremelimumab
	Comments	Compare tissue biomarker immune response of CD8 and Treg (ratio of CD8/treg) after MEDI-4736 and Tremelimumab, and after MEDI4736 alone
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.954
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and Untreated Patients.
Description	Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and at day 1 of untread will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.
Time Frame	the untreated group(control) : at day 1, MEDI4736 + Tremelimumab: at a surgery within one to six weeks after treatment (MEDI4736+Tremelimumab) group

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MEDI4736 + Tremelimumab	Untreated Arm (Control)
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.	4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Measure Participants	8	4
Median (Inter-Quartile Range) [no unit of ratios with same units(%)]	9.7	4.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab, MEDI4736 + Tremelimumab
	Comments	Compare tissue biomarker immune response of CD8 and Treg(ratio of CD8/Treg) after MEDI-4736 and Tremelimumab, and at day 1 of untread control group
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.799
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone
Description	Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.
Time Frame	at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

Percentages of ICOS(+) CD8 T cells were obtained in only three patients who have enough amount of live single cells in post-treatment tumor samples in MEDI4736 group and in two patient in MEDI4736+Tremelimumab group.

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	3	2
Median (Inter-Quartile Range) [percentage of (ICOS) + CD4 T cells]	1.2	4.5

7. Secondary Outcome

Title	Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients.
Description	Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after untreated patients will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.
Time Frame	Untreated group (control): at day 1, MEDI-4736 and Tremelimumab group: at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

Percentages of ICOS(+) CD8 T cells were obtained in only two patients who have enough amount of live single cells in post-treatment tumor samples in MEDI4736+Tremelimumab group. No patients in the untreated arm had enough cells.

Arm/Group Title	MEDI4736 + Tremelimumab	Untreated Arm (Control)
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.	4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Measure Participants	2	0
Median (Inter-Quartile Range) [percentage of (ICOS) + CD4 T cells]	4.5

8. Secondary Outcome

Title	Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone.
Description	Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI-4736 alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.
Time Frame	at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	7	8
Median (Inter-Quartile Range) [MMI (Mean Mass Intensity)]	0.31	0.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab, MEDI4736 + Tremelimumab
	Comments	Compare tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI-4736 alone
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.418
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients.
Description	Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and before and at day 1 of untreate alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.
Time Frame	Untreated arm (control): at day 1 after screening, MEDI4736 + Tremelimumab group: at a surgery within one to six weeks after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MEDI4736 + Tremelimumab	Untreated Arm (Control)
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.	4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Measure Participants	8	4
Median (Inter-Quartile Range) [MMI (Mean Mass Intensity)]	0.18	0.24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MEDI4736 + Tremelimumab, MEDI4736 + Tremelimumab
	Comments	Compare tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and before and at day 1 of untreated
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.932
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Median Recurrence-free Survival (RFS)
Description	RFS based on the Kaplan-Meier method is defined as the time between treatment and disease recurrence or censored and participants in either MEDI-4736 alone or MEDI-4736 plus Tremelimumab will be followed up for 2 years after surgery.
Time Frame	Participants will be followed up until disease recurrence or censor for 2 year after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	8	8
Median (95% Confidence Interval) [months]	14	NA

11. Secondary Outcome

Title	Median Overall Survival (OS)
Description	OS based on the Kaplan-Meier method is defined as the time between treatment and death or censored and participants in either MEDI-4736 alone or MEDI-4736+Tremelimumab will be followed up for 2 years after surgery.
Time Frame	Participants will be followed up until death or censor for 2 year after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MEDI4736	MEDI4736 + Tremelimumab
Arm/Group Description	8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.	8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.
Measure Participants	8	8
Median (95% Confidence Interval) [months]	14.4	NA

Adverse Events

Time Frame	Adverse events were assessed by the study schedule on the day of infusion and followed up until 4 weeks after hospital discharge, the maximum duration of 24 months
Arm/Group Title	MEDI4736		MEDI4736 + Tremelimumab		Untreated Arm (Control)
Arm/Group Description	MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.		MEDI4736: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. Tremelimumab: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.		no other name: Neither MEDI4736 nor Tremelimumab will be used.
All Cause Mortality
	MEDI4736		MEDI4736 + Tremelimumab		Untreated Arm (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/9 (77.8%)		6/11 (54.5%)		3/4 (75%)
Serious Adverse Events
	MEDI4736		MEDI4736 + Tremelimumab		Untreated Arm (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)		4/11 (36.4%)		1/4 (25%)
Cardiac disorders
Acute coronary syndrome	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Heart failure	1/9 (11.1%)	1	0/11 (0%)	0	1/4 (25%)	1
Myocardial infarction	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
General disorders
Death NOS	3/9 (33.3%)	3	1/11 (9.1%)	1	0/4 (0%)	0
Edema limbs	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Fatigue	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Multi-organ failure	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Pain	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Sudden death NOS	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Injury, poisoning and procedural complications
Fall	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Investigations
Alanine aminotransferase increased	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Weight loss	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Metabolism and nutrition disorders
Anorexia	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Hyperglycemia	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Nervous system disorders
Syncope	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Renal and urinary disorders
Acute kidney injury	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Respiratory failure	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Rash acneiform	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Vascular disorders
Hypotension	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	MEDI4736		MEDI4736 + Tremelimumab		Untreated Arm (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)		7/11 (63.6%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	5/9 (55.6%)	5	3/11 (27.3%)	3	4/4 (100%)	4
Febrile neutropenia	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Cardiac disorders
Atrial fibrillation	1/9 (11.1%)	1	0/11 (0%)	0	1/4 (25%)	1
Sinus bradycardia	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Supraventricular tachycardia	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Ventricular arrhythmia	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Ventricular tachycardia	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Abdominal pain	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Constipation	3/9 (33.3%)	3	1/11 (9.1%)	1	2/4 (50%)	2
Dyspepsia	1/9 (11.1%)	1	0/11 (0%)	0	1/4 (25%)	1
Nausea	3/9 (33.3%)	3	1/11 (9.1%)	1	2/4 (50%)	2
Salivary duct inflammation	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
General disorders
Edema limbs	2/9 (22.2%)	2	1/11 (9.1%)	1	1/4 (25%)	1
Fatigue	1/9 (11.1%)	1	2/11 (18.2%)	2	2/4 (50%)	2
Fever	1/9 (11.1%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Infections and infestations
Mucosal infection	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Skin infection	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Investigations
Activated partial thromboplastin time prolonged	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Alanine aminotransferase increased	2/9 (22.2%)	2	2/11 (18.2%)	2	2/4 (50%)	2
Alkaline phosphatase increased	2/9 (22.2%)	2	0/11 (0%)	0	2/4 (50%)	2
Aspartate aminotransferase increased	2/9 (22.2%)	2	0/11 (0%)	0	1/4 (25%)	1
Blood bilirubin increased	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Creatinine increased	2/9 (22.2%)	2	0/11 (0%)	0	0/4 (0%)	0
Fibrinogen decreased	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Lymphocyte count decreased	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Platelet count decreased	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Urine output decreased	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Weight gain	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Weight loss	0/9 (0%)	0	0/11 (0%)	0	2/4 (50%)	2
White blood cell decreased	1/9 (11.1%)	1	0/11 (0%)	0	1/4 (25%)	1
Metabolism and nutrition disorders
Acidosis	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Anorexia	0/9 (0%)	0	0/11 (0%)	0	2/4 (50%)	2
Dehydration	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Hypercalcemia	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Hyperglycemia	6/9 (66.7%)	6	3/11 (27.3%)	3	4/4 (100%)	4
Hyperkalemia	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Hypernatremia	1/9 (11.1%)	1	0/11 (0%)	0	1/4 (25%)	1
Hypoalbuminemia	1/9 (11.1%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Hypocalcemia	2/9 (22.2%)	2	2/11 (18.2%)	2	0/4 (0%)	0
Hypomagnesemia	0/9 (0%)	0	2/11 (18.2%)	2	0/4 (0%)	0
Hyponatremia	1/9 (11.1%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Chest wall pain	1/9 (11.1%)	1	2/11 (18.2%)	2	1/4 (25%)	1
Generalized muscle weakness	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Nervous system disorders
Dizziness	0/9 (0%)	0	1/11 (9.1%)	1	1/4 (25%)	1
Paresthesia	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Psychiatric disorders
Anxiety	0/9 (0%)	0	0/11 (0%)	0	2/4 (50%)	2
Delirium	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Insomnia	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Restlessness	0/9 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Renal and urinary disorders
Acute kidney injury	0/9 (0%)	0	1/11 (9.1%)	1	1/4 (25%)	1
Chronic kidney disease	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Reproductive system and breast disorders
Breast pain	1/9 (11.1%)	1	0/11 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Dyspnea	2/9 (22.2%)	2	1/11 (9.1%)	1	1/4 (25%)	1
Hypoxia	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Pleural effusion	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Sore throat	0/9 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Vascular disorders
Hypotension	1/9 (11.1%)	1	0/11 (0%)	0	3/4 (75%)	3

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.