A Phase I/II Study of TTI-621 in Combination With Doxorubicin in Patients With Unresectable or Metastatic High-Grade Leiomyosarcoma

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs: Phase I

时间窗: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

An adverse event (AE) was any untoward medical occurrence or worsening of a pre-existing medical condition following or during exposure to pharmaceutical product, whether or not considered causally related to product. A serious adverse event (SAE) was an adverse event occurred during any study at any dose of the investigational products that fulfils one or more of following criteria: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. TEAEs were those events with onset date occurred during on-treatment period. AEs included SAEs and all Non-SAEs. On-treatment period was defined as time from first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer therapy). Participant with at least one TEAE and one serious TEAEs are reported in this outcome measure.

Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 1 Day 1 (C1D1): Phase I

时间窗: Baseline, 30 minutes post dose on Day 1 of Cycle 1

Blood pressure included diastolic blood pressure (DBP) and systolic blood pressure (SBP). Mean change from baseline to 30 minutes post-dose on C1D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C1D1: Phase I

时间窗: Baseline, 60 minutes post dose on Day 1 of Cycle 1

Blood pressure included DBP and SBP. Mean change from baseline to 60 minutes post-dose on C1D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 1 Day 8 (C1D8): Phase I

时间窗: Baseline, 30 minutes post dose on Day 8 of Cycle 1

Blood pressure included DBP and SBP. Mean change from baseline to 30 minutes post-dose on C1D8 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C1D8: Phase I

时间窗: Baseline, 60 minutes post dose on Day 8 of Cycle 1

Blood pressure included DBP and SBP. Mean change from baseline to 60 minutes post-dose on C1D8 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 2 Day 1 (C2D1): Phase I

时间窗: Baseline, 30 minutes post dose on Day 1 of Cycle 2

Blood pressure included DBP and SBP. Mean change from baseline to 30 minutes post-dose on C2D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C2D1: Phase I

时间窗: Baseline, 60 minutes post dose on Day 1 of Cycle 2

Blood pressure included DBP and SBP. Mean change from baseline to 60 minutes post-dose on C2D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 3 Day 1 (C3D1): Phase I

时间窗: Baseline, 30 minutes post dose on Day 1 of Cycle 3

Blood pressure included DBP and SBP. Mean change from baseline to 30 minutes post-dose on C3D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C3D1: Phase I

时间窗: Baseline, 60 minutes post dose on Day 1 of Cycle 3

Blood pressure included DBP and SBP. Mean change from baseline to 60 minutes post-dose on C3D1 were reported in this outcome measure. Baseline was defined as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Blood Pressure at Safety Follow up: Phase I

时间窗: Baseline, Safety follow up (up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

Blood pressure included DBP and SBP. Mean change from baseline to safety follow up visit were reported in this outcome measure. Baseline was considered as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Body Weight at C3D1: Phase I

时间窗: Baseline, Day 1 of Cycle 3

Body weight was measured in kilograms (kg). Baseline was considered as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Body Weight at Cycle 5 Day 1 (C5D1): Phase I

时间窗: Baseline, Day 1 of Cycle 5

Body weight was measured in kilograms. Baseline was considered as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Body Weight at Cycle 7 Day 1 (C7D1): Phase I

时间窗: Baseline, Day 1 of Cycle 7

Body weight was measured in kilograms. Baseline was considered as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Mean Change From Baseline in Body Weight at Safety Follow up: Phase I

时间窗: Baseline, Safety follow up (up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

Body weight was measured in kilograms. Baseline was considered as the last measurement taken prior to the first infusion of study medication (Day 1 of Cycle 1).

Number of Participants With Overall Electrocardiogram (ECG) Abnormalities: Phase I

时间窗: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

Standard 12- lead ECGs, average of triplicate assessments were obtained in participant in supine position and within 10 minutes total time. ECG abnormalities included: PR interval (millisecond \[msec\]): value greater than or equal to (\>=) 220 and change from baseline \>=20; QRS interval (msec) value \>=120; uncorrected QT interval, QT correct by Bazzette's formula (QTcB) interval and QT correct by Frederica formula (QTcF) interval (msec): value greater than (\>) 450, value \> 480, value \> 500, change from baseline \> 30 and \> 60. Baseline was defined as the last assessment prior to the date or time of the first dose of study treatment. In this outcome measure number of participants with overall ECG abnormalities are reported.

Number of Participants With Shift in National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v)5.0 Grade <=2 at Baseline to >=3 Post-baseline in Hematology Parameters: Phase I

时间窗: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

The following hematology laboratory parameters were assessed: hemoglobin, hematocrit, platelets, white blood cells (WBC), neutrophils, lymphocytes, eosinophils, basophils, monocytes, WBC with automated 5-part differential, Red blood cells (RBC), absolute reticulocytes, reticulocytes percentage (%), Mean corpuscular hemoglobin (MCH), Mean corpuscular volume (MCV) and Red cell distribution width (RDW). Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. Baseline was defined as the last assessment prior to the date/time of the first dose of study treatment. Number of participants who had hematology parameter abnormality Grade \<=2 at baseline and shifted to \>=3 post-baseline are reported in this outcome measure. Only non-zero categories for any reporting arm are reported.

Number of Participants With Shift in NCI-CTCAE v5.0 Grade <=2 at Baseline to >=3 Post-baseline in Chemistry Parameters: Phase I

时间窗: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)

The following chemistry parameters were assessed: glucose, sodium, potassium, calcium, chloride, phosphate, bicarbonate, blood urea nitrogen or urea, creatinine, total protein, albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, indirect bilirubin, uric acid, calcium, magnesium, lactate dehydrogenase (LDH). Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death related to adverse event. Baseline was defined as last assessment prior to date/time of first dose of study treatment. Number of participants who had chemistry parameter abnormality Grade\<=2 at baseline and shifted to \>=3 post-baseline are reported in this outcome measure. Only non-zero categories for any reporting arm are reported.

Number of Participants With Dose Modifications: Phase I

时间窗: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 74.1 weeks for ontorpacept and 20.1 weeks for doxorubicin)

Dose modifications included dose reduction, dose omitted, infusion interruption and cycle delayed.

Number of Participants With Treatment Discontinuations: Phase I

时间窗: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 74.1 weeks for ontorpacept and 20.1 weeks for doxorubicin)

Number of participants with treatment discontinuations during the study treatment were reported in this outcome measure.

Objective Response Rate (ORR): Phase I and Phase II

时间窗: From the start of study treatment until disease progression (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)

ORR: percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) based on investigator's assessment per response evaluation criteria in solid tumours RECIST version (v)1.1. BOR: best response recorded from start of treatment until disease progression (PD). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than(\< )10 mm. PR: at least 30 percent (%) decrease in sum of longest diameter of target lesions, taking as reference baseline sum longest diameter. PD: at least 20% increase in sum of longest diameter of target lesions, taking as reference of the smallest sum on study.