On October 12, 2018 Ipsen (Euronext: IPN, ADR: IPSEY) reported that cabozantinib (Cabometyx ), liposomal irinotecan for injection (Onivyde ), lanreotide (Somatuline ) and lanreotide and telotristat (Xermelo ) ), will be the subject of 12 presentations at the 2018 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) conference , to be held from 19 to 23 October 2018 in Munich, Germany (Press release, Ipsen, OCT 12, 2018, View Source [SID1234529877]).
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"Since ESMO (Free ESMO Whitepaper) 2017, Ipsen has had a very dynamic twelve months, with major regulatory breakthroughs for Cabometyx in the treatment of renal and hepatocellular carcinoma, and for Xermelo in the treatment of neuroendocrine tumors. Again this year, Ipsen will have a strong presence at ESMO (Free ESMO Whitepaper) with the presentation of 12 posters detailing important clinical outcomes for patients on hepatocellular carcinoma, kidney cancer, medullary thyroid cancer, pancreatic cancer and neuroendocrine tumors, "said the doctor Alexandre Lebeaut, Executive Vice President, Research and Development and Chief Scientific Officer, Ipsen.
"Our oncology products, including Cabometyx , Onivyde , Somatuline and Xermelo , have been evaluated by numerous scientific teams around the world, either directly by investigators, or by our partners, or by Ipsen. The results of some of these investigations will be unveiled at ESMO (Free ESMO Whitepaper) 2018. We are fundamentally committed to the fight against cancer; our discussions during ESMO (Free ESMO Whitepaper) 2018 will allow us to continue to innovate in oncology to better treat patients, " added Dr. Alexandre Lebeaut .
Cabozantinib (Cabometyx ) will be the subject of 5 posters :
Poster presentation, Sunday, October 21st, 1:15 pm – 2:15 pm, Hall A3
CELESTIAL study
[Poster 702P] Outcomes by baseline alpha-fetoprotein (AFP) levels in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (HCC) (Kelley et al.).
Presenter: RK Kelly [Sponsor: Exelixis].
[Poster 703P] CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC) (Blanc et al.).
Presenter: JF Blanc [Sponsor: Exelixis].
[Poster 704P] Outcomes by Transarterial Prior Chemoembolization (TACE) in Phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) (Yau et al.).
Presenter: T Yau [Sponsor: Exelixis].
Poster presentation, Monday 22 October, 1:15 pm – 2:15 pm, Hall A3
Study COSMIC-021 ( CABOZANTINIB + atézolizumab )
[Poster 872P] Phase 1b study (COSMIC-021) of cabozantinib in combination with atezolizumab in solid tumors: Results of the dose escalation stage in patients with advanced treatment-naive RCC (Agarwal et al.).
Presenter: N Agarwal [Sponsor: Exelixis].
Poster presentation, Sunday October 21st, 1:15 pm – 2:15 pm, Hall A3
Study EXAMINE
[Poster 129TiP] A noninferiority trial of cabozantinib (C) comparing 140 mg vs. 60 mg orally to evaluate patients’ safety (pts) with progressive, metastatic medullary thyroid cancer (TCM) (Krajewska et al.).
Presenter: J Krajewska [Sponsor: Exelixis].
Poster presentation, Sunday, October 21st, 1:15 pm – 2:15 pm, Hall A3
Liposomal irinotecan for injection (Onivyde ) will be presented in 4 presentations :
[Poster 749P] The prognostic value of the Modified Glasgow Prognostic Score (mGPS) in predicting overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5- FU / LV). (Chen, et al.)
Presenter: LT Chen [Sponsor: Ipsen].
[Poster 734P] Liposomal irinotecan (nal-IRI) + 5-fluorouracil / leucovorin (5-FU / LV): Survival analysis from NAPOLI-1. (Chen, et al.)
Presenter: LT Chen [Sponsor: Ipsen].
[Poster 735P] Real-world dosing patterns of patients (pts) with metastatic pancreatic cancer (mPC) treated with liposomal irinotecan (nal-IRI) in US oncology clinics. (Ahn, et al.)
Presenter: D Ahn [Sponsor: Ipsen].
[Poster 733P] NAPOLI-1 Phase 3 trial outcomes by prior surgery, and disease stage, in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). (Macarulla, et al.)
Presenter: T Macarulla [Sponsor: Shire].
Poster presentation, Sunday, October 21st, 1:15 pm – 2:15 pm, Hall A3
The lanreotide (Somatuline ) will be the subject of 2 presentations :
PRELUDE (TGR)
[Poster 1331P] Tumor growth rate (TGR) when using lanreotide Autogel (LAN) before, during and after peptide receptor radionuclide therapy (PRRT) in advanced neuroendocrine tumors (NETs). (Prasad, et al.)
Presenter: V Prasad [Sponsor: Ipsen].
Poster presentation, Sunday October 21st, 1:15 pm – 2:15 pm, Hall A3
CLARINET (diabetes)
[Poster 1319P] Post-hoc analysis of CLARINET phase III study to investigate the influence of diabetic status on progression-free survival (PFS) of patients with neuroendocrine tumors (NETs) treated with lanreotide (LAN) or placebo (PBO). (Pusceddu, et al.).
Presenter: V Pusceddu [Sponsor: Ipsen].
Poster presentation, Sunday October 21st, 1:15 pm – 2:15 pm, Hall A3
Lanreotide (Somatuline ) and Telotristat (Xermelo ) will be presented :
TELESTAR & TELECAST (LAN patients)
[Poster 4378P] Efficacy and safety of telothrombin (TE) in combination with lanreotide (LAN) in patients with neuroendocrine tumors and carcinoid syndrome (CS) diarrhoea (CSD): Meta-analysis of phase 3 double-blind placebo (PBO) -controlled TELESTAR and TELECAST studies. (Hörsch, et al.).
Presenter: D Hörsch [Sponsor: Ipsen].
About CABOMETYX (cabozantinib)
Cabometyx is a small molecule inhibiting receptors, including VEGFR, MET, AXL and RET, administered orally. In preclinical models, cabozantinib inhibited the activity of these receptors involved in normal cellular function and pathological processes such as angiogenesis, invasive potential, tumor metastasis, and drug resistance.
In February 2016, Exelixis and Ipsen announced the signing of an exclusive licensing agreement for the commercialization and development of cabozantinib, outside the United States, Canada and Japan. This agreement was amended in December 2016 to include marketing rights for Ipsen in Canada.
On April 25, 2016, the FDA approved Cabometyx Tablets for the treatment of patients with advanced renal cell carcinoma who have previously received anti-angiogenic therapy. On September 9, 2016, the European Commission approved Cabometyx Tablets for the treatment of advanced RCC in adults who have previously received vascular endothelial growth factor (VEGF) therapy in the European Union. in Norway and Iceland. Cabometyx has also received approval in Canada, Australia, Switzerland and South Korea. Cabometyx is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once a day.
On December 19, 2017, Exelixis received approval from the US regulatory authorities (FDA) for the new indication of Cabometyx in the first-line treatment of advanced RCC.
On 17 May 2018, Ipsen announced that the European Commission has approved Cabometyx for the first-line treatment of adults with advanced intermediate or high risk renal cell carcinoma in the European Union, Norway and Iceland.
Cabozantinib is not yet approved for the treatment of hepatocellular carcinoma.
Indications: CABOMETYX is indicated for the treatment of advanced renal cell carcinoma:
in adult patients at intermediate or high risk and previously untreated
in adult patients after targeted therapy of vascular endothelial growth factor (VEGF) receptors.
Dosage and method of administration: The recommended dose of CABOMETYX is 60 mg once daily. Treatment should be continued as long as a clinical benefit is observed for the patient or until the occurrence of unacceptable toxicity. Management of adverse reactions suspected to be treatment-related may require temporary discontinuation of CABOMETYX therapy and / or dose reduction. For more information on changing the dose, please refer to the Summary of Product Characteristics. CABOMETYX is supplied in tablet form for oral administration. The tablets should be swallowed whole, without crushing them. Patients should be informed that
Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in the Summary of Product Characteristics.
Special warnings and precautions for use:
Monitor the toxicity carefully during the first 8 weeks of treatment. Adverse events that usually occur early are: hypocalcemia, hypokalemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia (PIP) syndrome, proteinuria, and gastrointestinal (GI) episodes. Perforations and fistulas: Serious cases of gastrointestinal perforation (GI) and fistulas, sometimes fatal, have been observed with cabozantinib. Patients with inflammatory bowel disease, gastrointestinal tumor infiltration or complications of anterior digestive surgery should be evaluated prior to initiation of treatment and monitored.
Complications of Wound Healing: Treatment with cabozantinib should be stopped at least 28 days before scheduled surgery, including dental surgery.
Hypertension: monitor blood pressure (BP); reduce the dose if hypertension persists and stop treatment in case of uncontrolled hypertension or hypertensive crisis
Palmaroplantar erythrodysaesthesia (PPP) syndrome: discontinue treatment if severe PPES occurs.
Proteinuria: Stop treatment in patients with nephrotic syndrome.
Posterior Reversible Leukoencephalopathy Syndrome (LEPR): Stop treatment in patients with LEPR.
QT prolongation: Use with caution in patients with a history of QT prolongation in patients taking antiarrhythmic drugs or in patients with pre-existing cardiac disease.
Excipients: Do not administer in patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome
Interactions: Cabozantinib is a substrate of CYP3A4. Potent inhibitors of CYP3A4 may cause increased plasma concentrations of cabozantinib (eg, ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice). Concomitant administration of CYP3A4 inducers may result in decreased plasma concentration of cabozantinib (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort). Cabozantinib may increase plasma concentrations of P-glycoprotein substrates (eg, fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan). Inhibitors of MRP2 may result in increases in plasma concentrations of cabozantinib (eg, cyclosporine, efavirenz, emtricitabine). Bile salt chelating agents may have an effect on absorption or reabsorption, potentially reducing the exposure of cabozantinib. No dose adjustment with concomitant administration of gastric pH modifiers. An interaction associated with the displacement of plasma proteins is possible with warfarin. In this case, the INR values must be monitored. Bile salt chelating agents may have an effect on absorption or reabsorption, potentially reducing the exposure of cabozantinib. No dose adjustment with concomitant administration of gastric pH modifiers. An interaction associated with the displacement of plasma proteins is possible with warfarin. In this case, the INR values must be monitored. Bile salt chelating agents may have an effect on absorption or reabsorption, potentially reducing the exposure of cabozantinib. No dose adjustment with concomitant administration of gastric pH modifiers. An interaction associated with the displacement of plasma proteins is possible with warfarin. In this case, the INR values must be monitored.
Women of childbearing potential / contraception in men and women: Use an effective method of contraception (oral contraception combined with a mechanical method) in male and female patients and their partners during treatment and for at least 4 months after treatment. stop treatment.
Pregnancy and breast-feeding: CABOMETYX should not be used during pregnancy unless the clinical condition of the woman justifies it. Breast – feeding – Do not breastfeed during treatment and for at least 4 months after stopping treatment.
Driving and using machines: Caution is required.
Side effects : The most common serious side effects are diarrhea, PPMS, pulmonary embolism, fatigue and hypomagnesemia. Very common (> 1/10):anemia, lymphopenia, neutropenia, thrombocytopenia, hypothyroidism, dehydration, decreased appetite, hyperglycemia, hypoglycemia, hypophosphatemia, hypoalbuminemia, hypomagnesaemia, hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hyperbilirubinemia, peripheral sensory neuropathy, dysgeusia, headache, vertigo, dysphonia, dyspnea, cough, diarrhea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, oral pain, dry mouth, SEPP, dermatitis acneiform, erythema, maculopapular rash, dry skin, alopecia, change in hair color, pain in the extremities, muscle spasms, arthralgia, proteinuria, fatigue, inflammation of the mucous membranes, asthenia, weight loss, elevations of ALT,AST and ALP serum, elevations of bilirubin, elevation of creatinine, elevation of triglycerides, decrease of white blood cells, elevation of GGT, elevation of amylase, elevation of blood cholesterol, elevation of lipase.Frequent (> 1/100 to <1/10) : abscess, tinnitus, pulmonary embolism, pancreatitis, upper abdominal pain, gastroesophageal reflux disease, hemorrhoids, pruritus, peripheral edema, wound complications. Rare (> 1/1000 to <1/100): convulsion, anal fistula, cholestatic hepatitis, osteonecrosis of the jaw. Selected adverse effects: GI perforations, fistulas, hemorrhage, LEPR. Prescribers should refer to the SPC for complete information on side effects.
For more information, see the product information regularly updated on the European Medicines Agency website www.ema.europa.eu
ABOUT ONIVYDE (In the US: Liposomal Irinotecan for Injection – Outside the US: Liposomal Irinotecan)
ONIVYDE is an encapsulation formulation of irinotecan, available as a single dose vial at 43 mg / 10 mL. This long-circulating liposomal form is intended to increase the duration of exposure of the tumor to irinotecan and SN-38, its active metabolite.
Ipsen has obtained the exclusive marketing rights for the current indications and potential future indications of ONIVYDE in the United States as well as the current license agreements for marketing rights with Servier outside the United States and with PharmEngine for Taiwan.
ONIVYDE is approved by the US regulatory authorities (FDA) in combination with fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with metastatic pancreatic adenocarcinoma whose disease has progressed following treatment with gemcitabine. Limitations: ONIVYDE is not indicated as monotherapy for the treatment of patients with metastatic pancreatic adenocarcinoma.
Important safety information – United States
Warning (Boxed Warnings): Severe Neutropenia and Severe Diarrhea
Neutropenic sepsis with fatal outcome occurs in 0.8% of patients treated with ONIVYDE. Severe or life-threatening febrile neutropenia or sepsis is observed in 3% of cases, and severe or life-threatening neutropenia in 20% of patients receiving ONIVYDE therapy in combination with 5- FU and LV. Refrain from any treatment with ONIVYDE in the presence of an absolute neutrophil count of less than 1500 / mm3 or febrile neutropenia. Periodically monitor the blood count during treatment.
Cases of severe diarrhea were observed in 13% of patients treated with ONIVYDE in combination with 5-FU / LV. Never prescribe ONIVYDE in patients with intestinal obstruction. Refrain from any treatment with ONIVYDE for grade 2 to 4 diarrhea. Give loperamide in case of late diarrhea regardless of severity. Administer atropine, if not contraindicated in case of early diarrhea, whatever the severity.
Cons-indications
ONIVYDE is contraindicated in patients with a history of severe hypersensitivity to ONIVYDE or irinotecan HCI.
Warnings and precautions for use:
Severe Neutropenia: See Warning. During treatment with ONIVYDE / 5-FU / LV, the incidence of grade 3 and 4 neutropenia is increased in Asian-type subjects (18/33 [55%]) compared with Caucasian (13/73 [18%]). Febrile neutropenia and neutropenic sepsis were observed in 6% of Asian patients versus 1% of Caucasian patients.
Severe diarrhea: See Warning. Late diarrhea (occurring> 24 hours after chemotherapy [9%]) and early diarrhea (occurring ≤ 24 hours after chemotherapy [3%], sometimes with other symptoms related to a cholinergic reaction), severe or life-threatening have been found.
Diffuse interstitial lung disease (PID): Irinotecan HCI can cause severe and fatal PID. Treatment with ONIVYDE should be discontinued immediately if dyspnea, progressive dyspnea, cough, and fever develop. Discontinue any treatment with ONIVYDE in patients for whom the diagnosis of diffuse interstitial lung disease has been confirmed.
Reactions to ‘ severe hypersensitivity: Irinotecan HCl may cause severe hypersensitivity reactions including anaphylactic reactions. Permanently discontinue treatment with ONIVYDE in patients with severe hypersensitivity reactions.
Embryonic and fetal toxicity: ONIVYDE has a risk of fetal toxicity, when it is administered in pregnant women. Women of childbearing potential should be informed that they should receive effective contraception during treatment with ONIVYDE, and for 1 month after stopping treatment.
Side effects
The most common adverse events (≥ 20%) were: diarrhea (59%), fatigue / asthenia (56%), vomiting (52%), nausea (51%), loss of appetite (44%), stomatitis (32%) and pyrexia (23%).
The most common Grade 3/4 adverse events (≥ 10%) were: diarrhea (13%), fatigue / asthenia (21%) and vomiting (11%).
Adverse events led to permanent discontinuation of ONIVYDE in 11% of patients treated with ONIVYDE / 5-FU / LV. The most common side effects that led to discontinuation of ONIVYDE were: diarrhea, vomiting and sepsis.
ONIVYDE dose reductions related to an adverse event occurred in 33% of patients who received ONIVYDE / 5-FU / LV. The most common adverse events that led to a dose reduction were neutropenia, diarrhea, nausea and anemia.
ONIVYDE treatment was discontinued or delayed due to adverse events in 62% of patients treated with ONIVYDE / 5-FU / LV. The most common adverse events leading to discontinuation or delayed treatment were neutropenia, diarrhea, nausea and anemia.
The most common laboratory laboratory abnormalities (≥ 20%) were: anemia (97%), lymphopenia 81%), neutropenia (52%), elevations of ALT (51%), hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia (35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia (29%), and hyponatremia (27%).
Drugs interactions
It is recommended that inducers of the CYP3A4 enzyme should not be used as much as possible and that any concomitant therapy should be substituted with therapies that have no effect on enzyme expression at least 2 weeks before administering ONIVYDE. .
It is advisable not to use CYP3A4 or UGT1A1 inhibitors as much as possible, and to discontinue any combination with CYP3A4 inhibitors at least 1 week before starting treatment.
Use in special populations
Pregnancy and Women of Childbearing Age: See WARNINGS and PRECAUTIONS. Men whose partners are women of reproductive age should use condoms during treatment with ONIVYDE, and for 4 months after stopping treatment.
Nursing Women: Women should not breastfeed during treatment and in the month following the last administration of ONIVYDE.
Please refer to the Complete Prescription Information for ONIVYDE in the United States.
ABOUT SOMATULINE
The active substance in Somatuline Autogel / Depot, lanreotide, is a somatostatin analogue that inhibits the secretion of growth hormone and certain hormones secreted by the digestive system.
The main indications of Somatuline and Somatuline Autogel are:
Treatment of acromegaly when circulating levels of growth hormone and insulin-like growth factor type 1 are not normalized after surgery and / or radiotherapy or in patients with no choice but medical treatment.
Treatment of symptoms associated with carcinoid syndrome in patients with neuroendocrine tumors (NET) (except in the United States).
Antiproliferative treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET).
Important Safety Information – United States
Contraindications:
Somatuline is contraindicated in patients with hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following lanreotide administration.
Warnings and precautions for use:
Cholelithiasis and Biliary Mud: Somatuline can reduce motility of the gallbladder and contribute to the formation of gallstones. Periodic monitoring may be necessary.
Hypoglycemia and Hyperglycemia: Pharmacological studies show that Somatuline, like somatostatin and other somatostatin analogues, inhibit the secretion of insulin and glucagon. Blood glucose levels should be monitored at initiation of Somatuline therapy or when there is a change in dose, and antidiabetic therapy should be adjusted accordingly.
Cardiac abnormalities: Somatuline may slow down the heart rate. In 81 patients with baseline heart rate greater than or equal to 60 beats per minute (bpm) treated with Somatuline DEPOT in the pivotal TNE-GEP study, the incidence of heart rate below 60 bpm was 23% (19/81) with Somatuline versus 16% (15/94) with placebo; 10 patients (12%) had heart rates below 60 bpm on multiple visits. The incidence of documented heart rate episodes below 50 bpm, as well as the incidence of reported bradycardia as an adverse event, was 1% in each treatment group.
In patients without underlying heart disease, Somatuline may cause a slowing of the heart rate without necessarily reaching the threshold of bradycardia. In patients with pre-treatment cardiac disorders, sinus bradycardia may occur. Precautions should be taken when initiating therapy in patients with bradycardia.
Drug Interactions: The gastrointestinal pharmacological effects of Somatuline may decrease intestinal absorption of concomitant medications. Concomitant administration of Somatuline Depot may decrease the relative bioavailability of cyclosporine and may necessitate adjustment of the cyclosporine dose to maintain therapeutic levels.
Side effects :
In the pivotal TNE-GEP study, the most common adverse events (incidence greater than 10% and more frequent than placebo) in patients treated with Somatuline DEPOT compared to placebo were: abdominal pain (34 % versus 24%), musculoskeletal pain (19% versus 13%), vomiting (19% versus 9%), headache (16% versus 11%), injection site reactions (15% versus 7 hyperglycemia (14%)). % versus 5%), hypertension (14% versus 5%) and cholelithiasis (14% versus 7%).
You can also report suspected adverse reactions to the FDA at 1-800-FDA-1088 or Ipsen Biopharmaceuticals, Inc. at 1-888-980-2889.
For a summary of Somatuline Depot product features, click here.
ABOUT XERMELO (ETHYL TELTROISTAT)
Xermelo is a new oral tryptophan hydroxylase (TPH) inhibitor. By inhibiting the TPH enzyme, a limiting step in serotonin synthesis, the compound has been designed to reduce serotonin production in neuroendocrine tumors.
On October 22, 2014, Ipsen and Lexicon announced the signing of an exclusive license agreement whereby Ipsen will market Xermelo (telotristat ethyl) in all territories outside the United States and Japan, where Lexicon retains its rights. On February 28, 2017, Lexicon received approval from the US Food and Drug Administration (FDA) for Xermelo as the first and only FDA-approved oral treatment in patients with tumors metastatic neuroendocrine with carcinoid syndrome-associated diarrhea, in combination with a somatostatin analogue (SSA) in patients inadequately controlled by SSA.
General information about the safety of Xermelo
In clinical trials, more than 230 patients with carcinoid syndrome were treated with Xermelo. The placebo-controlled safety analyzes are based on cumulative 12-week double-blind placebo-controlled data in the 2 phase 3 studies. In this safety data set, 71 patients received placebo and 70 patients received Xermelo 250 mg three times daily. The most commonly reported adverse reactions in patients treated with telotristyl ethyl were abdominal pain (26%), gamma-glutamyl transferase (11%) and fatigue (10%). They were usually of mild or moderate intensity. The most common adverse reaction to
Trademarks:
ONIVYDE is a registered trademark of Ipsen Biopharm Limited.
CABOMETYX (cabozantinib), XERMELO (telotristyl ethyl) and DECAPEPTYL (triptorelin) are not marketed by Ipsen in the United States. Approved indications may vary by country. CABOMETYX is marketed by Exelixis, Inc. in the United States. Ipsen has the exclusive commercialization and clinical development rights of CABOMETYX outside the United States and Japan.