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A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations.
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| Zeitschriftentitel: | Journal of Clinical Oncology |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Journal of Clinical Oncology, 35, 2017, 15_suppl, S. 2527-2527 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
|
| Schlagwörter: |
| author_facet |
Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. |
|---|---|
| author |
Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. |
| spellingShingle |
Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. Journal of Clinical Oncology A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. Cancer Research Oncology |
| author_sort |
dhawan, mallika sachdev |
| spelling |
Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2527 <jats:p> 2527 </jats:p><jats:p> Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874. </jats:p> A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. Journal of Clinical Oncology |
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| title |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_unstemmed |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_full |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_fullStr |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_full_unstemmed |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_short |
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_sort |
a phase i study of carboplatin and talazoparib in patients with and without dna repair mutations. |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2527 |
| publishDate |
2017 |
| physical |
2527-2527 |
| description |
<jats:p> 2527 </jats:p><jats:p> Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874. </jats:p> |
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| author | Dhawan, Mallika Sachdev, Bartelink, Imke Heleen, Aggarwal, Rahul Raj, Leng, Jim, Kelley, Robin Kate, Melisko, Michelle E., Ryan, Charles J., Thomas, Scott, Munster, Pamela N. |
| author_facet | Dhawan, Mallika Sachdev, Bartelink, Imke Heleen, Aggarwal, Rahul Raj, Leng, Jim, Kelley, Robin Kate, Melisko, Michelle E., Ryan, Charles J., Thomas, Scott, Munster, Pamela N., Dhawan, Mallika Sachdev, Bartelink, Imke Heleen, Aggarwal, Rahul Raj, Leng, Jim, Kelley, Robin Kate, Melisko, Michelle E., Ryan, Charles J., Thomas, Scott, Munster, Pamela N. |
| author_sort | dhawan, mallika sachdev |
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| description | <jats:p> 2527 </jats:p><jats:p> Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874. </jats:p> |
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| spelling | Dhawan, Mallika Sachdev Bartelink, Imke Heleen Aggarwal, Rahul Raj Leng, Jim Kelley, Robin Kate Melisko, Michelle E. Ryan, Charles J. Thomas, Scott Munster, Pamela N. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2527 <jats:p> 2527 </jats:p><jats:p> Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874. </jats:p> A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. Journal of Clinical Oncology |
| spellingShingle | Dhawan, Mallika Sachdev, Bartelink, Imke Heleen, Aggarwal, Rahul Raj, Leng, Jim, Kelley, Robin Kate, Melisko, Michelle E., Ryan, Charles J., Thomas, Scott, Munster, Pamela N., Journal of Clinical Oncology, A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations., Cancer Research, Oncology |
| title | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_full | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_fullStr | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_full_unstemmed | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_short | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| title_sort | a phase i study of carboplatin and talazoparib in patients with and without dna repair mutations. |
| title_unstemmed | A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations. |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2527 |