Abstract
Purpose: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-inhuman study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. Patients and Methods: A 3 þ 3 dose escalation for different mivebresib dosing schedules [daily, Monday/ Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Results: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9). Conclusions: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6309-6319 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 25 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 1 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
First-in-human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/ refractory solid tumors. / Piha-Paul, Sarina A.; Sachdev, Jasgit C.; Barve, Minal; LoRusso, Patricia; Szmulewitz, Russell; Patel, Sapna Pradyuman; Lara, Primo N.; Chen, Xiaotian; Hu, Beibei; Freise, Kevin J.; Modi, Dimple; Sood, Anjla; Hutti, Jessica E.; Wolff, Johannes; O'Neil, Bert H.
In: Clinical Cancer Research, Vol. 25, No. 21, 01.11.2019, p. 6309-6319.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - First-in-human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/ refractory solid tumors
AU - Piha-Paul, Sarina A.
AU - Sachdev, Jasgit C.
AU - Barve, Minal
AU - LoRusso, Patricia
AU - Szmulewitz, Russell
AU - Patel, Sapna Pradyuman
AU - Lara, Primo N.
AU - Chen, Xiaotian
AU - Hu, Beibei
AU - Freise, Kevin J.
AU - Modi, Dimple
AU - Sood, Anjla
AU - Hutti, Jessica E.
AU - Wolff, Johannes
AU - O'Neil, Bert H.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-inhuman study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. Patients and Methods: A 3 þ 3 dose escalation for different mivebresib dosing schedules [daily, Monday/ Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Results: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9). Conclusions: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.
AB - Purpose: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-inhuman study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. Patients and Methods: A 3 þ 3 dose escalation for different mivebresib dosing schedules [daily, Monday/ Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Results: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9). Conclusions: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.
UR - http://www.scopus.com/inward/record.url?scp=85074379082&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074379082&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0578
DO - 10.1158/1078-0432.CCR-19-0578
M3 - Article
C2 - 31420359
AN - SCOPUS:85074379082
VL - 25
SP - 6309
EP - 6319
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 21
ER -