PMID- 27284481 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20160610 LR - 20220410 IS - 2078-6891 (Print) IS - 2219-679X (Electronic) IS - 2078-6891 (Linking) VI - 7 IP - 3 DP - 2016 Jun TI - Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial. PG - 469-78 LID - 10.21037/jgo.2016.01.03 [doi] AB - BACKGROUND: Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer. METHODS: Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle >/=2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities. RESULTS: Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS. CONCLUSIONS: This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy. FAU - Scheithauer, Werner AU - Scheithauer W AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Ramanathan, Ramesh K AU - Ramanathan RK AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Moore, Malcolm AU - Moore M AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Macarulla, Teresa AU - Macarulla T AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Goldstein, David AU - Goldstein D AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Hammel, Pascal AU - Hammel P AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Kunzmann, Volker AU - Kunzmann V AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Liu, Helen AU - Liu H AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - McGovern, Desmond AU - McGovern D AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Romano, Alfredo AU - Romano A AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. FAU - Von Hoff, Daniel D AU - Von Hoff DD AD - 1 Medizinische Universitat Wien, Wien, Austria ; 2 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA ; 3 BC Cancer Agency, Vancouver, British Columbia, Canada ; 4 Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain ; 5 Prince of Wales Hospital, Sydney, NSW, Australia ; 6 Hopital Beaujon, Clichy, France ; 7 Universitatsklinikum Wurzburg, Wurzburg, Germany ; 8 Celgene Corporation, Summit, New Jersey, USA ; 9 Celgene Corporation, Boudry, Switzerland ; 10 Translational Genomics Research Institute and Honor Health, Scottsdale, Arizona, USA. LA - eng PT - Journal Article PL - China TA - J Gastrointest Oncol JT - Journal of gastrointestinal oncology JID - 101557751 PMC - PMC4880765 OTO - NOTNLM OT - Pancreatic cancer OT - dose delay OT - dose reduction OT - gemcitabine (Gem) OT - nab-paclitaxel (nab-P) COIS- Conflicts of Interest: WS-reports grants, personal fees (for consultant, advisory board & invited speaker activities) and non-financial support (study medication drug supply) from Celgene Corporation, during the conduct of the study; RKR-reports grants and personal fees from Celgene Corporation, outside the submitted work; MM-reports grants from Celgene Corporation, during the conduct of the study; personal fees from Celgene Corporation outside the submitted work; TG-nothing to disclose; DG-reports grants from Celgene Corporation, during the conduct of the study; grants from Pfizer, grants from Amgen, outside the submitted work; PH-reports consulting for Celgene Corporation during the conduct of the study; VK-reports honoraria for consulting and lectures by Celgene Corporation; HL-reports employment, stock ownership from Celgene Corporation; DM-reports employment, stock ownership from Celgene Corporation; AR-reports employment, stock ownership from Celgene Corporation; DDVH-reports consultant, honoraria, and research funding, Celgene Corporation. EDAT- 2016/06/11 06:00 MHDA- 2016/06/11 06:01 PMCR- 2016/06/01 CRDT- 2016/06/11 06:00 PHST- 2016/06/11 06:00 [entrez] PHST- 2016/06/11 06:00 [pubmed] PHST- 2016/06/11 06:01 [medline] PHST- 2016/06/01 00:00 [pmc-release] AID - jgo-07-03-469 [pii] AID - 10.21037/jgo.2016.01.03 [doi] PST - ppublish SO - J Gastrointest Oncol. 2016 Jun;7(3):469-78. doi: 10.21037/jgo.2016.01.03.