A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer

Pishvaian, Michael J.; Wang, Hongkun; He, Aiwu Ruth; Hwang, Jimmy J.; Smaglo, Brandon G.; Kim, Sunnie S.; Weinberg, Benjamin A.; Weiner, Louis M.; Marshall, John L.; Brody, Jonathan R.

doi:10.1158/1078-0432.ccr-20-1301

Cited by 29 publications

(22 citation statements)

References 38 publications

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“…A recently published phase 1 to 2 study of veliparib plus modified FOLFOX‐6 in patients with pancreatic cancer ( n = 64) established the RP2D at veliparib 200 mg twice daily plus oxaliplatin 85 mg/m 2 and 5‐FU 2400 mg/m 2 continuous infusion over 46 hours 70 . Again, the 5‐FU bolus was omitted due to prolonged myelotoxicity among the first treated patients, and additional dose reductions of at least one component were necessary in all patients.…”

Section: Completed Clinical Studiesmentioning

confidence: 99%

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

Singh

Bailey

Hübschmann

et al. 2021

Genes Chromosomes & Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP‐ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum‐based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression‐free survival for patients with metastatic PDAC after at least 4 months of platinum‐based chemotherapy. Hopefully, this first biomarker‐directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.

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Section: Completed Clinical Studiesmentioning

confidence: 99%

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

Singh

Bailey

Hübschmann

et al. 2021

Genes Chromosomes & Cancer

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“…Lynch syndrome from mismatch repair (MMR) gene mutations, Peutz-Jeghers syndrome from STK11 mutations) [9]. Moreover, our knowledge about other cancers (e.g., ovary, prostate) underscores the possible therapeutic implications of a broader range of DDR gene mutations [15][16][17][18][19][20], and this concept has recently been extended to PC [40,41]. This highlights the need for genetic screening beyond BRCA: in our opinion it is mandatory to take advantage of a gene panel that cannot exclude essential genes such as ATM, PALB2, RAD50, STK11 and MMR genes [9,31,40].…”

Section: Discussionmentioning

confidence: 99%

“…Studies in cancers other than PC (i.e. ovarian and prostate) have shown that BRCA1 and BRCA2 are not the only genes whose alteration is essential in this context: indeed, the wider concept of HR deficiency, including other genes such as ATM or PALB2, is implicated in the exploitation of synthetic lethality [15][16][17][18][19][20]. Furthermore, new treatment options that take advantage of this mechanism are emerging in addition to PARPi.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer

et al. 2021

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Background Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. Methods We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. Results We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. Conclusions Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients’ eligibility for emerging therapeutic options.

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“…A phase I/II trial of veliparib with FOLFOX (5-FU, oxaliplatin, folinic acid) has demonstrated an acceptable safety profile. The primary endpoint ORR at 26% was met, while the ORR was even higher at 30-58% for patients with a family history suggestive of breast and ovarian cancer syndrome or DDR mutation [170]. This warrants further investigation with a randomized double-arm clinical trial to validate a benefit of adding veliparib to FOLFOX.…”

Section: Pancreatic Cancermentioning

confidence: 91%

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

et al. 2021

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Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

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A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer

Cited by 29 publications

References 38 publications

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

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