Clinically Meaningful Responses to Sequential Gemcitabine-Based Chemotherapy Regimens in a Patient with Metastatic Pancreatic Cancer

Klimant, Eiko; Markman, Maurie; Albu, Daniela M.

doi:10.1159/000346836

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…However, the metabolic response of hepatic lesions was heterogeneous with some lesions showing no response to therapy, even in patients where other lesions responded with complete loss of metabolic activity. This disparity in response observed between primary and metastatic lesions can be observed by FDG-PET imaging in some patients receiving standard chemotherapy alone (28-30). Here, we have used FDG-PET/CT imaging to demonstrate and quantify heterogeneity in metabolic responses observed with therapy in PDA.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Beatty

Torigian

Chiorean

et al. 2013

Clinical Cancer Research

401

284

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Purpose This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunological correlatives, and anti-tumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). Experimental Design Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1000 mg/m2 gemcitabine once weekly for 3 weeks with infusion of CP-870,893 at 0.1 mg/kg or 0.2 mg/kg on day 3 of each 28 day cycle. Results CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4 cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B cell expression of co-stimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) demonstrated >25% decrease in FDG uptake within primary pancreatic lesions in 6 of 8 patients; however, responses observed in metastatic lesions were heterogeneous with some lesions responding with complete loss of FDG uptake while other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; p = 0.007). Conclusions CP-870,893 in combination with gemcitabine was well-tolerated and associated with anti-tumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.

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Section: Discussionmentioning

confidence: 99%

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Beatty

Torigian

Chiorean

et al. 2013

Clinical Cancer Research

401

284

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“…Chue et al [249] reported of a patient with metastatic PDAC who responded extremely well to (five years from diagnosis until report published) treatment with metronomic dosing of POLF (pa clitaxel+oxaliplatin+leucovorin+5-FU) and a gemcitabine-based regimen, including oxaliplatin and leucovorin/5-FU with intemittent cetuximab (EGFR inhibitor). It is noted that the patient's tumour showed no KRAS mutation indicating that wild-type KRAS responds to cetuximad and contributes to patient's unusual long survival [248] Klimant et al [250] presented a case of a patient with PDAC metastatic to the liver who experienced gemcitabine-based chemotherapy. The regimens included cycles of gemcitabine and oxaliplatin (GEMOX), followed by cycles gemcitabine, docetaxel and capecitabine and then cycles of gemcitabine and nab-paclitaxel, with an exceptional response 2 years from the initiation of chemotherapy for metastatic pancreatic cancer [250].…”

Section: Exceptional Respondersmentioning

confidence: 99%

“…It is noted that the patient's tumour showed no KRAS mutation indicating that wild-type KRAS responds to cetuximad and contributes to patient's unusual long survival [248] Klimant et al [250] presented a case of a patient with PDAC metastatic to the liver who experienced gemcitabine-based chemotherapy. The regimens included cycles of gemcitabine and oxaliplatin (GEMOX), followed by cycles gemcitabine, docetaxel and capecitabine and then cycles of gemcitabine and nab-paclitaxel, with an exceptional response 2 years from the initiation of chemotherapy for metastatic pancreatic cancer [250]. Although genetic testing were not performed in this patient, patient's exceptional response to these treatments may lead to the conclusion that this patients' tumour may have had a unique genetic and molecular makeup.…”

Section: Exceptional Respondersmentioning

confidence: 99%

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

Korhan¹,

Verkerk²,

Critchley³

2017

Integr Mol Med

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Pancreatic ductal adenocarcinoma (PDAC) arises from epithelia of pancreas. Despite its low incidence, it is the most lethal cancer type. Although the poor outcome is largely secondary to the high proportion of patients who are diagnosed with advanced disease, the prognosis of PDAC is also influenced by the inherent biological aggressiveness and the high metastatic potential of this malignancy. Treatment options remain limited with little progress over the last decades. Some improvements in surgical outcome occur in patients who also receive chemotherapy and/or radiotherapy, however, the impact on long-term survival has been minimal owing to the intense resistance of PDAC to all extent treatments regimen. Hence, there is an urgent need to 1) gain better understanding of the biology of PDAC; 2) to develop early detection and prevention programs; 3) to identify new therapeutic strategies to improve quality of life and survivorship. In this review, first, we will summarise the state of knowledge of PDAC pathogenesis with a particular the focus on the molecular characteristics causing therapeutic resistance. Then, we will briefly review current and emerging approaches in the PDAC care. Lastly, we will highlight the integrative approaches in the light of new experimental and clinical research conducted with the aim of moving towards personalised therapy in patients with PDAC.

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“…The origin of this study derives from the observation of fınding the occasional "exceptional response" (objective response; i.e., durable) in otherwise negative phase II clinical trials of new agents, or with agents used in the clinic. 4,5 It is not uncommon to fınd in such studies, or sometimes in clinical practice, a few patients whose tumors seem to respond to an agent that does not exhibit any sign of benefıt in the majority of patients treated for a specifıc cancer diagnosis. This study ( Fig.…”

Section: Exceptional Responders Initiativementioning

confidence: 99%

National Cancer Institute's Precision Medicine Initiatives for the New National Clinical Trials Network

Abrams

Conley

Mooney

et al. 2014

American Society of Clinical Oncology Educational Book

145

124

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The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. The National Cancer Institute's (NCI) new National Clinical Trials Network (NCTN) is well positioned to conduct such trials. The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative-why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial-can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial-will targeted epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer-is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.

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Clinically Meaningful Responses to Sequential Gemcitabine-Based Chemotherapy Regimens in a Patient with Metastatic Pancreatic Cancer

Cited by 6 publications

References 11 publications

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

National Cancer Institute's Precision Medicine Initiatives for the New National Clinical Trials Network

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