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

Sarina A. Piha-Paul, Jasgit C. Sachdev, Minal Barve, Patricia LoRusso, Russell Szmulewitz, Sapna Pradyuman Patel, Primo N. Lara, Xiaotian Chen, Beibei Hu, Kevin J. Freise, Dimple Modi, Anjla Sood, Jessica E. Hutti, Johannes Wolff, Bert H. O'Neil

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)6309-6319
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2019

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Neoplasms
Proteins
Safety
Thrombocytopenia
Fatigue
Prostatic Neoplasms
Appointments and Schedules
Dysgeusia
Appetite
Aspartate Aminotransferases
Nausea
Disease-Free Survival
Anemia
Breast
Neck
Pharmacokinetics
Head
Confidence Intervals
Apoptosis
Hypertension

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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 journalArticle

Piha-Paul, SA, Sachdev, JC, Barve, M, LoRusso, P, Szmulewitz, R, Patel, SP, Lara, PN, Chen, X, Hu, B, Freise, KJ, Modi, D, Sood, A, Hutti, JE, Wolff, J & O'Neil, BH 2019, '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', Clinical Cancer Research, vol. 25, no. 21, pp. 6309-6319. https://doi.org/10.1158/1078-0432.CCR-19-0578
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. / 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. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 21. pp. 6309-6319.
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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 {\th} 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.",
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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.

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