Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study

SummaryBackground: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

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Safety, Pharmacokinetics, and Preliminary Efficacy of Talazoparib in Japanese Patients With Advanced Solid Tumors: Phase 1 Study

10.21203/rs.3.rs-189395/v1 ◽

2021 ◽

Author(s):

Yoichi Naito ◽

Yasutoshi Kuboki ◽

Masafumi Ikeda ◽

Kenichi Harano ◽

Nobuaki Matsubara ◽

...

Keyword(s):

Antitumor Activity ◽

Adverse Events ◽

Solid Tumors ◽

Neutrophil Count ◽

Phase 1 ◽

Single Agent ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Once Daily

Abstract Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3+3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose level, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. Clinical Trial Register: clinicalTrials.govClinical Registration Number: NCT03343054 (November 17, 2017)

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Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-010-1243-y ◽

2010 ◽

Vol 66 (5) ◽

pp. 935-943 ◽

Cited By ~ 14

Author(s):

Yasuhito Fujisaka ◽

Yasuhide Yamada ◽

Noboru Yamamoto ◽

Toshio Shimizu ◽

Yutaka Fujiwara ◽

...

Keyword(s):

Solid Tumors ◽

Phase 1 ◽

Angiogenesis Inhibitor ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Phase 1 Study

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Phase 1 Study of the Parp Inhibitor E7449 As a Single Agent in Patients with Advanced Solid Tumors or B-Cell Lymphoma

Annals of Oncology ◽

10.1093/annonc/mdu331.13 ◽

2014 ◽

Vol 25 ◽

pp. iv151 ◽

Cited By ~ 1

Author(s):

R. Plummer ◽

D. Dua ◽

N. Cresti ◽

A. Suder ◽

Y. Drew ◽

...

Keyword(s):

B Cell ◽

Solid Tumors ◽

Cell Lymphoma ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

B Cell Lymphoma ◽

Advanced Solid Tumors ◽

Phase 1 Study

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A Phase 1 Study of Necitumumab (Anti-Egfr Monoclonal Antibody) in Japanese Patients with Advanced Solid Tumors

Annals of Oncology ◽

10.1093/annonc/mdu435.108 ◽

2014 ◽

Vol 25 ◽

pp. v70 ◽

Cited By ~ 3

Author(s):

Hiroshi Nokihara ◽

Noboru Yamamoto ◽

Yosuke Tamura ◽

Yuko Tanabe ◽

Kazunori Honda ◽

...

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Phase 1 ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Phase 1 Study

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Abstract LB-406: Phase 1 study of the Smac mimetic TL32711 in adult subjects with advanced solid tumors and lymphoma to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity

10.1158/1538-7445.am2011-lb-406 ◽

2011 ◽

Cited By ~ 12

Author(s):

Ravi K. Amaravadi ◽

Russell J. Schilder ◽

Grace K. Dy ◽

Wen W. Ma ◽

Gerald J. Fetterly ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumors ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Smac Mimetic

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A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3013 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3013-3013 ◽

Cited By ~ 13

Author(s):

Michael Friedlander ◽

Tarek Meniawy ◽

Ben Markman ◽

Linda R. Mileshkin ◽

Paul R. Harnett ◽

...

Keyword(s):

Pancreatic Cancer ◽

Monoclonal Antibody ◽

Solid Tumors ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Multiple Tumor ◽

Study Results

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.

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A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.48 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 48-48 ◽

Cited By ~ 7

Author(s):

Michael Friedlander ◽

Tarek Meniawy ◽

Ben Markman ◽

Linda R. Mileshkin ◽

Paul Harnett ◽

...

Keyword(s):

Monoclonal Antibody ◽

Autoimmune Hepatitis ◽

Solid Tumors ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

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