Browsing by Author "Malhotra, Jyoti"

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    A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)
    (Wiley, 2022) Leal, Ticiana A.; Sharifi, Marina N.; Chan, Nancy; Wesolowski, Robert; Turk, Anita A.; Bruce, Justine Y.; O'Regan, Ruth M.; Eickhoff, Jens; Barroilhet, Lisa M.; Malhotra, Jyoti; Mehnert, Janice; Girda, Eugenia; Wiley, Elizabeth; Schmitz, Natalie; Andrews, Shannon; Liu, Glenn; Wisinski, Kari B.; Medicine, School of Medicine
    Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. Conclusion: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.
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    A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)
    (Wiley, 2022-11) Leal, Ticiana A.; Sharifi, Marina N.; Chan, Nancy; Wesolowski, Robert; Turk, Anita A.; Bruce, Justine Y.; O'Regan, Ruth M.; Eickhoff, Jens; Barroilhet, Lisa M.; Malhotra, Jyoti; Mehnert, Janice; Girda, Eugenia; Wiley, Elizabeth; Schmitz, Natalie; Andrews, Shannon; Liu, Glenn; Wisinski, Kari B.; Medicine, School of Medicine
    Background Inhibitors of poly(ADP‐ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods We conducted a phase I study of talazoparib with carboplatin AUC5‐6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21‐day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4–6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results Forty‐three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment‐related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13‐month median duration of maintenance. Conclusion We have established the recommended phase II dose of Talazoparib at 250mcg on a 3‐ or 7‐day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21‐day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.
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    Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma
    (Elsevier, 2022-12-07) Kapelanski-Lamoureux, Audrey; Chen, Zhouji; Gao, Zu-Hua; Deng, Ruishu; Lazaris, Anthoula; Lebeaupin, Cynthia; Giles, Lisa; Malhotra, Jyoti; Yong, Jing; Zou, Chenhui; de Jong, Ype P.; Metrakos, Peter; Herzog, Roland W.; Kaufman, Randal J.; Pediatrics, School of Medicine
    Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.