A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial

Fuchs, Charles S.; Azevedo, Sérgio Jobim; Okusaka, Takuji; Laethem, Jean Luc Van; Lipton, Lara; Riess, Hanno; Szczylik, Cezary; Moore, Malcolm J.; Peeters, Marc; Bodoky, G.; Ikeda, Masafumi; Melichar, Bohuslav; Němeček, Radim; Ohkawa, Shinichi; Świeboda-Sadlej, Anna; Tjulandin, Sergei; Cutsem, Éric Van; Loberg, Robert D.; Haddad, Vincent; Gansert, Jennifer; Bach, Bruce Allen; Carrato, Alfredo

doi:10.1093/annonc/mdv027

Cited by 142 publications

(80 citation statements)

References 23 publications

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“…However, many clinical trials with IGF-1R inhibitors failed to show any significant clinical benefit including hepatocellular carcinoma [25], non-small cell lung cancer [26] and breast cancer [27]. In pancreatic cancer, the combination of gemcitabine and ganitumab, a monoclonal antibody against IGF-1R, showed a significant clinical response in a phase 2 randomized trial [28], but unfortunately this combination did not show any clinical benefit in phase 3 evaluation [29]. Recently, a clinical study demonstrated a correlation between IGF-1R signaling and tumor aggressiveness in PDAC patients [15], and increased exposure to ganitumab was found to be associated with improved overall survival and progression free survival in metastatic PDAC [30].…”

Section: Introductionmentioning

confidence: 99%

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

et al. 2016

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Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and −87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

et al. 2016

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“…In a phase III trial assessing ganitumab in combination with gemcitabine, the study closed early based on a pre-planned futility analysis. The median overall survival was 7.1 mo in the maximum dose ganitumab arm vs. 7.2 mo in the placebo arm (HR 0.97, P=0.397) (98).…”

Section: Igfr Pathway Inhibitorsmentioning

confidence: 94%

Pancreatic cancer from bench to bedside: molecular pathways and treatment options

Kosmidis¹,

Sapalidis²,

Kotidis³

et al. 2016

Ann. Transl. Med.

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In the last forty years the pancreatic cancer treatment has made advances, however; still novel drugs are needed. It is known that the five year survival rate remains around 5%. The best treatment option still remains surgery, if patients are diagnosed early. In the last decade the biology of pancreatic cancer has been vastly explored and novel agents such as; tyrosine kinase agents, or vaccines have been added as a treatment perspective. The big challenge is now to translate this knowledge in better outcomes for patients. In this current review we will present information from pancreatic cancer diagnosis to molecular pathways and treatment options; current and future.

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“…It has been shown to delay growth of human pancreatic cancer and neuroblastoma cells[44, 53]. Ganitumab, an Ab targeted to IGF-1R, was well tolerated in a phase III trial but failed to improve OS in combination with gemcitabine compared to gemcitabine alone in patient s with metastatic pancreatic cancer[54]. Dalotuzumab is a humanized IGF-1R monoclonal antibody that selectively binds to IGF-IR and blocks receptor autophosphorylation and cell proliferation in vitro.…”

Section: Signaling Disruptionmentioning

confidence: 99%

Mechanisms of action of therapeutic antibodies for cancer

Redman

Hill

Aldeghaither

et al. 2015

Molecular Immunology

142

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The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

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A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial

Abstract: ClinicalTrials.gov NCT01231347.

Cited by 142 publications

References 23 publications

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

Pancreatic cancer from bench to bedside: molecular pathways and treatment options

Mechanisms of action of therapeutic antibodies for cancer

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