Background
Methods
Treatment protocols
Therapy
Echocardiographic and biomarker measurements
Second malignant neoplasms
Treatment Arm | Dexrazoxane | Doxorubicin | Ifosfamide | Etoposide |
---|---|---|---|---|
AOST0121 HER2+ | 3.75 g/m2 | 375 mg/m2 | 51 g/m2 | 1.5 g/m2 |
AOST0121 HER2- | 3.75 g/m2 | 375 mg/m2 | 51 g/m2 | 1.5 g/m2 |
P9754 Pilot 1 Good Response | 4.5 g/m2 | 450 mg/m2 | ||
P9754 Pilot 1 Standard Response | 6 g/m2 | 600 mg/m2 | ||
P9754 Pilot 2 Good Response | 4.5 g/m2 | 450 mg/m2 | 27 g/m2 | |
P9754 Pilot 2 Standard Response | 6 g/m2 | 600 mg/m2 | 45 g/m2 | |
P9754 Pilot 3 Good Response | 4.5 g/m2 | 450 mg/m2 | 27 g/m2 | |
P9754 Pilot 3 Standard Response | 4.5 g/m2 | 450 mg/m2 | 60 g/m2 | 1.5 g/m2 |
Statistical methods
Results
Patients
Study and Treatment Arm | Mean Age at Enrollmenta | Patient Sexb | Total | Expected Weeks | Dexc | Doxorubicin | Trastuzumab | ||
---|---|---|---|---|---|---|---|---|---|
Male | Female | ||||||||
AOST0121 | AOST0121 HER2 Negative | 15.1 (3.6) | 33 (60.0%) | 22 (40.0%) | 55 (100%) | 34 | 3.75 g/m2 | 375 mg/m2 | 70 mg/kg |
AOST0121 HER2 Positive | 13.7 (2.7) | 19 (47.5%) | 21 (52.5%) | 40 (100%) | 34 | 3.75 g/m2 | 375 mg/m2 | ||
P9754 | P9754 Pilot 1 Good Response | 13.5 (5.0) | 16 (47.1%) | 18 (52.9%) | 34 (100%) | 28 | 4.5 g/m2 | 450 mg/m2 | |
P9754 Pilot 1 Standard Response | 13.9 (4.4) | 48 (62.3%) | 29 (37.7%) | 77 (100%) | 29 | 6 g/m2 | 600 mg/m2 | ||
P9754 Pilot 2 Good Response | 13.9 (3.9) | 7 (33.3%) | 14 (66.7%) | 21 (100%) | 28 | 4.5 g/m2 | 450 mg/m2 | ||
P9754 Pilot 2 Standard Response | 13.8 (4.5) | 20 (60.6%) | 13 (39.4%) | 33 (100%) | 31 | 6 g/m2 | 600 mg/m2 | ||
P9754 Pilot 3 Good Response | 14.3 (4.0) | 12 (63.2%) | 7 (36.8%) | 19 (100%) | 28 | 4.5 g/m2 | 450 mg/m2 | ||
P9754 Pilot 3 Standard Response | 13.4 (4.6) | 20 (54.1%) | 17 (45.9%) | 37 (100%) | 36 | 4.5 g/m2 | 450 mg/m2 |
Variable | LV Fractional Shortening Z-scores | LV End-Diastolic Dimension Z-scores | LV End-Diastolic Posterior Wall Thickness Z-scores | LV Thickness to Dimension Ratio Z-scores | End-Diastolic Septal Thickness Z-scores | LV Mass Z-scores | NT-proBNP |
---|---|---|---|---|---|---|---|
Overall | n = 81 | n = 78 | n = 78 | n = 82 | n = 70 | n = 74 | n = 59 |
AOST0121 | n = 8 | n = 5 | n = 5 | n = 9 | n = 5 | n = 5 | n = 15 |
P9754 | n = 73 | n = 73 | n = 73 | n = 73 | n = 65 | n = 69 | n = 44 |
Variable | LV Fractional Shortening Z-scores | LV End-Diastolic Dimension Z-scores | LV End-Diastolic Posterior Wall Thickness Z-scores | LV Thickness to Dimension Ratio Z-scores | End-Diastolic Septal Thickness Z-scores | LV Mass Z-scores | NT-proBNP |
---|---|---|---|---|---|---|---|
Overall | n = 229 | n = 224 | n = 221 | n = 228 | n = 212 | n = 214 | n = 156 |
(n = 148) | (n = 146) | (n = 143) | (n = 146) | (n = 142) | (n = 140) | (n = 97) | |
AOST0121 | n = 90 | n = 85 | n = 83 | n = 89 | n = 83 | n = 82 | n = 42 |
(n = 82) | (n = 80) | (n = 78) | (n = 80) | (n = 78) | (n = 77) | (n = 27) | |
P9754 | n = 139 | n = 139 | n = 138 | n = 139 | n = 129 | n = 132 | n = 114 |
(n = 66) | (n = 66) | (n = 65) | (n = 66) | (n = 64) | (n = 63) | (n = 70) |
Echocardiographic measurements
Measurement | Group | N | Mean | 95% Confidence Interval for Mean |
P
b
|
---|---|---|---|---|---|
NT-proBNP2 | All Patients | 59 | 47.3c | (36.3, 61.6)c | < 0.01 |
LV End-Diastolic Posterior Wall Thickness Z-score | All Patients | 78 | −0.29 | (− 0.60, 0.02) | 0.06 |
Female | 30 | − 0.57 | (−1.04, − 0.09) | 0.02 | |
Male | 48 | −0.10 | (− 0.50, 0.30) | 0.63 | |
End-Diastolic Septal Thickness Z-score | All Patients | 70 | −0.84 | (−1.2, − 0.48) | < 0.01 |
Female | 27 | −1.20 | (−1.76, −0.64) | < 0.01 | |
Male | 43 | −0.60 | (−1.06, − 0.15) | 0.01 | |
LV Fractional Shortening Z-score | All Patients | 81 | −0.19 | (−0.54, 0.17) | 0.30 |
Female | 32 | −0.46 | (−1.02, 0.10) | 0.10 | |
Male | 49 | 0.00 | (−0.46, 0.47) | 0.99 | |
LV Mass Z-score | All Patients | 74 | −0.74 | (−1.06, − 0.42) | < 0.01 |
Female | 29 | −1.23 | (−1.71, −0.75) | < 0.01 | |
Male | 45 | −0.39 | (−0.80, 0.01) | 0.06 |
Prediction Factor, Model |
P
a
|
---|---|
Left Ventricular End-Diastolic Dimension Z-Scores | |
Univariate Model | |
Sex | 0.04 |
Final Model | |
Assessment Pointb | 0.77 |
Sex2 | 0.74 |
Assessment Point* Sex Interaction Term | < 0.01 |
Male Slopec | 0.02 |
Female Slopec | 0.02 |
NT pro-BNP, Both Studies Combined | |
Sex | 0.02 |
NT pro-BNP, P9754 | |
Univariate Models | |
Assessment Point | 0.02 |
Sex | 0.02 |
Final Model | |
Assessment Point | < 0.01 |
Sex | < 0.01 |
Assessment Point * Sex Interaction Termd | 0.59 |
NT pro-BNP, AOST0121e | |
Final Model | |
Assessment Pointf | 0.05 |
Sex | 0.03 |
Assessment Point * Sex Interaction Term | 0.03 |
Male Slopec | 0.03 |
Female Slopec,f | 0.08 |
Cardiac biomarker assays
Variable | LV Fractional Shortening Z-scores | LV End-Diastolic Dimension Z-scores | LV End-Diastolic Posterior Wall Thickness Z-scores | LV Thickness to Dimension Ratio Z-scores | End-Diastolic Septal Thickness Z-scores | LV Mass Z-scores | NT-proBNPc |
---|---|---|---|---|---|---|---|
Overall | n = 81 | n = 78 | n = 78 | n = 82 | n = 70 | n = 74 | n = 59 |
\( \overline{x} \) = − 0.19 | \( \overline{x} \) = − 0.49 | \( \overline{x} \) = − 0.29 | \( \overline{x} \) = − 0.23 | \( \overline{x} \) = − 0.84 | \( \overline{x} \) = − 0.74 | GM = 47.3 | |
(− 0.54, 0.17) | (− 0.76, − 0.21) | (− 0.60, 0.02) | (− 0.53, 0.07) | (− 1.2, − 0.48) | (− 1.06, − 0.42) | (36.3, 61.6) | |
P = 0.30 | P < 0.01 | P = 0.06 | P = 0.13 | P < 0.01 | P < 0.01 | P < 0.01 | |
Sex | |||||||
Female | n = 32 | n = 30 | n = 30 | n = 33 | n = 27 | n = 29 | n = 28 |
\( \overline{x} \) = − 0.46 | \( \overline{x} \) = − 0.82 | \( \overline{x} \) = − 0.57 | \( \overline{x} \) = − 0.29 | \( \overline{x} \) = − 1.20 | \( \overline{x} \) = − 1.23 | GM = 63.2 | |
(− 1.02, 0.10) | (−1.24, − 0.40) | (− 1.04, − 0.09) | (− 0.75, 0.16) | (−1.76, − 0.64) | (− 1.71, − 0.75) | (43.8, 91.4) | |
P = 0.10 | P < 0.01 | P = 0.02 | P = 0.20 | P < 0.01 | P < 0.01 | P = 0.02 | |
Male | n = 49 | n = 48 | n = 48 | n = 49 | n = 43 | n = 45 | n = 31 |
\( \overline{x} \) = 0.00 | \( \overline{x} \) = − 0.26 | \( \overline{x} \) = − 0.10 | \( \overline{x} \) = − 0.18 | \( \overline{x} \) = − 0.60 | \( \overline{x} \) = − 0.39 | GM = 36.1 | |
(− 0.46, 0.47) | (− 0.60, 0.08) | (− 0.50, 0.30) | (− 0.57, 0.21) | (− 1.06, − 0.15) | (−0.80, 0.01) | (25.3, 51.6) | |
P = 0.99 | P = 0.14 | P = 0.63 | P = 0.36 | P = 0.01 | P = 0.06 | P < 0.01 | |
Study | |||||||
AOST0121 | n = 8 | n = 5 | n = 5 | n = 9 | n = 5 | n = 5 | n = 15 |
\( \overline{x} \) = − 0.70 | \( \overline{x} \) = − 0.61 | \( \overline{x} \) = − 0.64 | \( \overline{x} \) = 0.10 | \( \overline{x} \) = −3.82 | \( \overline{x} \) = − 0.86 | GM = 60.5 | |
(−2.06, 0.67) | (−1.82, 0.59) | (− 2.06, 0.78) | (−0.97, 1.17) | (−5.05, − 2.59) | (−2.23, 0.50) | (35.0, 104.6) | |
P = 0.31 | P = 0.31 | P = 0.37 | P = 0.85 | P < 0.01 | P = 0.21 | P = 0.07 | |
P9754 | n = 73 | n = 73 | n = 73 | n = 73 | n = 65 | n = 69 | n = 44 |
\( \overline{x} \) = −0.15 | \( \overline{x} \) = − 0.48 | \( \overline{x} \) = − 0.27 | \( \overline{x} \) = − 0.26 | \( \overline{x} \) = − 0.63 | \( \overline{x} \) = − 0.73 | GM = 43.9 | |
(−0.52, 0.22) | (−0.76, − 0.20) | (−0.59, 0.04) | (− 0.57, 0.05) | (− 0.96, − 0.31) | (− 1.07, − 0.40) | (32.4, 59.3) | |
P = 0.43 | P < 0.01 | P = 0.09 | P = 0.10 | P < 0.01 | P < 0.01 | P < 0.01 | |
Assessment Pointd | |||||||
0 to 37 days | n = 48 | n = 48 | n = 45 | n = 45 | n = 40 | n = 38 | n = 30 |
\( \overline{x} \) = −0.18 | \( \overline{x} \) = −0.38 | \( \overline{x} \) = − 0.40 | \( \overline{x} \) = − 0.43 | \( \overline{x} \) = − 0.39 | \( \overline{x} \) = − 0.67 | GM = 32.6 | |
(−0.72, 0.35) | (−0.75, − 0.01) | (−0.85, 0.05) | (− 0.90, 0.03) | (− 0.80, 0.03) | (− 1.13, − 0.20) | (18.4, 57.7) | |
P = 0.49 | P = 0.05 | P = 0.08 | P = 0.06 | P = 0.07 | P < 0.01 | P = 0.01 | |
38 to 81 days | n = 42 | n = 40 | n = 38 | n = 41 | n = 36 | n = 32 | n = 32 |
\( \overline{x} \) = −0.13 | \( \overline{x} \) = −0.60 | \( \overline{x} \) = 0.15 | \( \overline{x} \) = 0.15 | \( \overline{x} \) = −0.82 | \( \overline{x} \) = −0.43 | GM = 45.2 | |
(−0.70, 0.43) | (−1.00, − 0.21) | (−0.33, 0.64) | (− 0.33, 0.63) | (− 1.24, − 0.40) | (−0.93, 0.07) | (26.4, 77.3) | |
P = 0.64 | P < 0.01 | P = 0.53 | P = 0.53 | P < 0.01 | P = 0.09 | P = 0.01 | |
> 81 days | n = 39 | n = 37 | n = 37 | n = 40 | n = 29 | n = 36 | n = 34 |
\( \overline{x} \) = −0.24 | \( \overline{x} \) = −0.51 | \( \overline{x} \) = − 0.57 | \( \overline{x} \) = − 0.35 | \( \overline{x} \) = − 1.46 | \( \overline{x} \) = − 1.06 | GM = 67.6 | |
(−0.82, 0.34) | (−0.91, − 0.10) | (− 1.05, − 0.09) | (−0.83, 0.12) | (− 1.91, − 1.02) | (−1.53, − 0.60) | (39.9, 114.5) | |
P = 0.41 | P = 0.01 | P = 0.02 | P = 0.14 | P < 0.01 | P < 0.01 | P = 0.11 |