Trial Outcomes & Findings for MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma (NCT NCT02592551)

Last Updated: 2022-09-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

24 participants

Primary outcome timeframe

at day 1 after screening and at a surgery within one to six weeks after treatment

Results posted on

2022-09-29

Participant Flow

Participant milestones

Participant milestones
Measure	MEDI4736 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.	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. 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.	Untreated Arm (Control) 4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Overall Study STARTED	9	11	4
Overall Study COMPLETED	8	8	4
Overall Study NOT COMPLETED	1	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	MEDI4736 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.	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. 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.	Untreated Arm (Control) 4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.
Overall Study Not evaluable	1	3	0

Baseline Characteristics

MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MEDI4736 n=9 Participants 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.	MEDI4736 + Tremelimumab n=11 Participants 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.	Untreated Arm (Control) n=4 Participants 4 patients will not receive MEDI4736 or Tremelimumab. no other name: Neither MEDI4736 nor Tremelimumab will be used.	Total n=24 Participants Total of all reporting groups
Age, Continuous	67 years STANDARD_DEVIATION 6 • n=99 Participants	59 years STANDARD_DEVIATION 15 • n=107 Participants	58 years STANDARD_DEVIATION 12 • n=206 Participants	63 years STANDARD_DEVIATION 12 • n=7 Participants
Sex: Female, Male Female	2 Participants n=99 Participants	2 Participants n=107 Participants	2 Participants n=206 Participants	6 Participants n=7 Participants
Sex: Female, Male Male	7 Participants n=99 Participants	9 Participants n=107 Participants	2 Participants n=206 Participants	18 Participants n=7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	3 Participants n=7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=99 Participants	9 Participants n=107 Participants	3 Participants n=206 Participants	21 Participants n=7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants	1 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) White	9 Participants n=99 Participants	11 Participants n=107 Participants	1 Participants n=206 Participants	21 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	2 Participants n=206 Participants	2 Participants n=7 Participants
Prior Chemodtherapy Yes	0 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants	3 Participants n=7 Participants
Prior Chemodtherapy No	9 Participants n=99 Participants	10 Participants n=107 Participants	2 Participants n=206 Participants	21 Participants n=7 Participants

PRIMARY outcome

Timeframe: at day 1 after screening and at a surgery within one to six weeks after treatment

Population: 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).

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	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. 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.
Change in Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg)	8.6 no unit of ratios with same units(%) Interval -1.4 to 29.9	—

SECONDARY outcome

Timeframe: at day 1 after screening and at a surgery within one to six weeks after treatment

Population: 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).

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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	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. 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.
Change in Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells.	-2.1 percentage of inducible T-cell co-stimul Interval -5.2 to 1.0	—

SECONDARY outcome

Timeframe: at day 1 after screening and at a surgery within one to six weeks after treatment

Population: 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).

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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	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. 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.
Change in Tumor Expression Programmed Death-ligand 1 (PD-L1).	0.07 MMI (Mean Mass Intensity) Interval -0.12 to 0.3	—

SECONDARY outcome

Timeframe: at a surgery within one to six weeks after treatment

Population: 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.

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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=7 Participants 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.	MEDI4736 + Tremelimumab n=8 Participants 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.
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.	8 no unit of ratios with same units(%) Interval 3.4 to 9.4	9.7 no unit of ratios with same units(%) Interval 2.0 to 20.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	MEDI4736 + Tremelimumab n=4 Participants 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.
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.	9.7 no unit of ratios with same units(%) Interval 2.0 to 20.9	4.03 no unit of ratios with same units(%) Interval 2.7 to 12.6

SECONDARY outcome

Timeframe: at a surgery within one to six weeks after treatment

Population: 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.

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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=3 Participants 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.	MEDI4736 + Tremelimumab n=2 Participants 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.
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	1.2 percentage of (ICOS) + CD4 T cells Interval 0.5 to 3.9	4.5 percentage of (ICOS) + CD4 T cells Interval 2.5 to 6.5

SECONDARY outcome

Timeframe: Untreated group (control): at day 1, MEDI-4736 and Tremelimumab group: at a surgery within one to six weeks after treatment

Population: 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.

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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=2 Participants 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.	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. 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.
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.	4.5 percentage of (ICOS) + CD4 T cells Interval 2.5 to 6.5	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=7 Participants 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.	MEDI4736 + Tremelimumab n=8 Participants 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.
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.	0.31 MMI (Mean Mass Intensity) Interval 0.19 to 0.69	0.18 MMI (Mean Mass Intensity) Interval 0.12 to 0.59

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	MEDI4736 + Tremelimumab n=4 Participants 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.
Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients.	0.18 MMI (Mean Mass Intensity) Interval 0.12 to 0.59	0.24 MMI (Mean Mass Intensity) Interval 0.11 to 1.08

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	MEDI4736 + Tremelimumab n=8 Participants 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.
Median Recurrence-free Survival (RFS)	14 months Interval 3.2 to The upper 95% confidence limit of the survival curve hasn't reached 50%, there is no estimate for the upper confidence limit on the median.	NA months Interval 1.6 to The median RFS was NA because there was more than 50% survival in the group. The upper 95% confidence limit of the survival curve hasn't reached 50%, there is no estimates for the upper confidence limit on the median.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MEDI4736 + Tremelimumab n=8 Participants 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.	MEDI4736 + Tremelimumab n=8 Participants 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.
Median Overall Survival (OS)	14.4 months Interval 1.0 to 27.0	NA months Interval 5.0 to The median survival was NA because there were more than 50% survival in the group. The upper 95% confidence limit of the survival curve hasn't reached 50%, there is no estimates for the upper confidence limit on the median.

Adverse Events

MEDI4736

Serious events: 4 serious events

Other events: 6 other events

Deaths: 7 deaths

MEDI4736 + Tremelimumab

Serious events: 4 serious events

Other events: 7 other events

Deaths: 6 deaths

Untreated Arm (Control)

Serious events: 1 serious events

Other events: 4 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Bryan Burt, MD

Baylor College of Medicine

Phone: 713-798-6376

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	MEDI4736 n=9 participants at risk 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 + Tremelimumab n=11 participants at risk 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.	Untreated Arm (Control) n=4 participants at risk no other name: Neither MEDI4736 nor Tremelimumab will be used.
Cardiac disorders Acute coronary syndrome	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Cardiac disorders Heart failure	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	25.0% 1/4 • Number of events 1 • 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
Cardiac disorders Myocardial infarction	0.00% 0/9 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
General disorders Death NOS	33.3% 3/9 • Number of events 3 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
General disorders Edema limbs	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
General disorders Fatigue	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
General disorders Multi-organ failure	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
General disorders Pain	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
General disorders Sudden death NOS	0.00% 0/9 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	0.00% 0/9 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
Injury, poisoning and procedural complications Fall	0.00% 0/9 • 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	0.00% 0/11 • 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	25.0% 1/4 • Number of events 1 • 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
Investigations Alanine aminotransferase increased	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Investigations Weight loss	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Metabolism and nutrition disorders Anorexia	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/9 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
Nervous system disorders Syncope	0.00% 0/9 • 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	0.00% 0/11 • 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	25.0% 1/4 • Number of events 1 • 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
Renal and urinary disorders Acute kidney injury	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Respiratory, thoracic and mediastinal disorders Dyspnea	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Respiratory, thoracic and mediastinal disorders Respiratory failure	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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
Skin and subcutaneous tissue disorders Rash acneiform	0.00% 0/9 • 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	9.1% 1/11 • Number of events 1 • 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	0.00% 0/4 • 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
Vascular disorders Hypotension	11.1% 1/9 • Number of events 1 • 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	0.00% 0/11 • 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	0.00% 0/4 • 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