Takeda Announces Publication of Final Data from ICLUSIG® (ponatinib) Pivotal Phase 2 PACE Trial in Blood
Final five-year results show ICLUSIG continued to provide clinically meaningful responses, with depth and lasting duration, irrespective of dose reductions, in heavily pre-treated chronic-phase chronic myeloid leukemia patients
March 26, 2018 15:30 KST
CAMBRIDGE, MASS. & OSAKA, JAPAN--(Business Wire / Korea Newswire) March 26, 2018 -- Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that final data from the pivotal Phase 2 PACE clinical trial of ICLUSIG (ponatinib) in refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) were published in Blood. The manuscript is available online today and will be included in a future print edition of Blood. The final five-year results support ICLUSIG as an effective treatment option for patients with chronic-phase CML (CP-CML) whose prior therapies have failed. ICLUSIG, a tyrosine kinase inhibitor (TKI) with potent activity against native and mutant forms of BCR-ABL1 (an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL), received full approval from the U.S. Food and Drug Administration in 2016. ICLUSIG is indicated for the treatment of adult patients with CML or Ph+ ALL for whom no other TKI is indicated, including those with T315I-positive CML or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
“The PACE trial is among the longest and largest studies of patients with CP-CML who have received two or three prior TKIs, and the findings provide treating physicians with important updated information about the clinical benefits and safety profile of ICLUSIG,” said Jorge Eduardo Cortes, M.D., Deputy Chair and Professor of Medicine, Department of Leukemia, MD Anderson Cancer Center. “These final PACE results demonstrate that ICLUSIG provides lasting clinically meaningful responses, irrespective of dose reductions, in this population.”
“The publication of these data is an important milestone for the ICLUSIG clinical program as it shows that ICLUSIG continues to be an effective treatment option for appropriate patients whose prior TKIs have failed, including patients with the T315I mutation, for whom no other TKI is indicated,” said Frank Neumann, M.D., Ph.D., Senior Medical Director, Global Clinical Lead, ICLUSIG, Takeda. “While the PACE study analysis did not evaluate the impact of initiating therapy with a lower dose on adverse events and response rates, this important question is being addressed by the ongoing prospective dose-ranging OPTIC (Optimizing Ponatinib Treatment in CML) trial (NCT02467270).”
The pivotal Phase 2 PACE trial, which supported the FDA Accelerated Approval Program, evaluated the efficacy and safety of ICLUSIG at a starting dose of 45 mg once daily in 449 patients with CML (270 CP-CML, 85 accelerated-phase CML (AP-CML), 62 blast-phase CML (BP-CML) or Ph+ ALL (n=32) resistant/intolerant to prior TKI therapy, or with the T315I mutation, of which 444 were evaluable for efficacy analyses. The final results reflect a data analysis as of February 6, 2017, with median follow-up of 37.3 months for all patients and 56.8 months for CP-CML patients.
As reported in Blood, the final 5-year results demonstrated:
· Among 267 heavily pre-treated CP-CML patients (>90% had received at least 2 prior approved TKIs), 159 (60 percent) achieved MCyR at any time, of whom 144 (54 percent of evaluable CP-CML patients) achieved complete cytogenic response (CCyR). Further depth of response was attained where 108 (40 percent) patients achieved major molecular response (MMR) and 64 (24 percent) achieved molecular response 4.5 (MR4.5).
· Among CP-CML patients, 82 percent and 59 percent of those who achieved major cytogenic response (MCyR) by 12 months and MMR at any time, respectively, were estimated to maintain these responses at five years, based on Kaplan-Meier methods.
· Responses achieved by CP-CML patients in PACE correlated with long-term outcomes, with estimated progression-free survival (PFS)/overall survival (OS) rates at five years of 53 percent/73 percent overall, and with comparable rates in the resistant/intolerant and T315I cohorts.
· Dose reductions were implemented in October 2013 to decrease the risk of vascular occlusive events (VOEs), including arterial occlusive events (AOEs). A previous post hoc analysis of PACE data suggested that AOEs may be dose-related, with each 15-mg reduction in average daily dose intensity predicted to lead to an approximately 33 percent reduction in the risk of AOEs. Among PACE CP-CML patients who were in MCyR or MMR as of October 2013 and had their dose reduced (including those who had their dose reduced to 15 mg per day), ≥90 percent maintained response 40 months after pre-emptive dose reductions.
· The ICLUSIG label contains Boxed Warning for arterial occlusions, venous thromboembolism, heart failure and hepatotoxicity.
· Individual serious AEs reported in ≥5 percent of CP-CML patients were pancreatitis (7 percent), atrial fibrillation (6 percent), pneumonia (6 percent) and angina pectoris (5 percent). In the overall population, serious AEs reported in ≥5 percent of patients (excluding disease progression) were pneumonia (7 percent) and pancreatitis (6 percent); atrial fibrillation and angina pectoris were reported in 4 percent and 3 percent of patients, respectively.
· The most common any-grade treatment-emergent adverse events (TEAEs) observed in CP-CML patients (with frequency ≥40 percent) were rash (47 percent), abdominal pain (46 percent), thrombocytopenia (46 percent), headache (43 percent), dry skin (42 percent) and constipation (41 percent). The most common grade 3/4 TEAEs in CP-CML patients (with frequency ≥10% [n≥27]) were thrombocytopenia (35 percent), neutropenia (17 percent), hypertension (14 percent), increased lipase (13 percent), abdominal pain (10 percent) and anemia (10 percent).
· The cumulative incidences of treatment-emergent AOEs, including cardiovascular, cerebrovascular and peripheral vascular events, continued to increase over time; 31 percent of CP-CML patients and 25 percent of the overall population reported at least one AOE. The exposure-adjusted incidence of newly occurring AOEs remained relatively constant throughout the study period in both CP-CML patients and all patients. Categorization of AOEs included a broad collection of MedDRA preferred terms; no individual preferred term occurred in >10 percent of patients.
· For advanced phase CML patients included in PACE, major hematologic response (MaHR) was achieved by 51 (61 percent) patients with AP-CML and 19 (31 percent) patients with BP-CML. Among patients with Ph+ ALL, MaHR was achieved by 13 (41 percent) patients.
About CML, ALL and the Philadelphia Chromosome
Leukemia is a blood cancer that forms in a person’s bone marrow. Chronic Myeloid Leukemia (CML) is one of four main types of leukemia; it is a result of a genetic mutation that takes place in early, immature versions of myeloid cells, which form red blood cells, platelets and most types of white blood cells. Subsequently, an abnormal gene called BCR-ABL1 forms, turning the damaged cell into a CML cell. CML typically progresses slowly, but it can also change into a fast-growing acute leukemia that is hard to treat. Chronic phase (CP) is the earliest phase of CML. Patients in CP have unusually high levels of white blood cells. Symptoms are generally mild and may include fatigue, weakness, shortness of breath, fullness or early satiety and weight loss.
Acute Lymphoblastic Leukemia (ALL) starts from the early version of white blood cells, called lymphocytes, in the bone marrow (the soft inner part of the bones, where new blood cells are made). The term “acute” means that the leukemia can progress quickly, and if not treated, would probably be fatal within a few months.
The Philadelphia chromosome is an abnormal chromosome formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR-ABL1 and is associated with CML and Ph+ ALL.
About ICLUSIG® (ponatinib) Tablets
ICLUSIG is a kinase inhibitor that targets BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1. ICLUSIG targets native BCR-ABL1, as well as similar proteins that carry treatment-resistant mutations, including the T315I mutation, which has been associated with resistance to other approved TKIs. ICLUSIG received full approval from the FDA in November 2016, and is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.
In the U.S., ICLUSIG is indicated for:
· Treatment of adult patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
· Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic-phase, accelerated-phase, or blast-phase) or T315I-positive Ph+ ALL.
Limitations of use:
ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.
To learn more about ICLUSIG, visit www.ICLUSIG.com or call 1-844-T1POINT (1-844-817-6468). For additional information on the ponatinib clinical trials, please visit www.clinicaltrials.gov.
IMPORTANT SAFETY INFORMATION (US)
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning.
· Arterial occlusion has occurred in at least 35% of ICLUSIG® (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
· Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
· Heart Failure, including fatalities occurred in 9% of ICLUSIG treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
· Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.
WARNINGS AND PRECAUTIONS
Arterial Occlusions: Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of ICLUSIG-treated patients from the phase 1 and phase 2 trials. In the phase 2 trial, 33% (150/449) of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193, 526, and 478 days, respectively. Patients with and without cardiovascular risk factors, some age 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing arterial occlusive events, interrupt or stop ICLUSIG.
Venous Thromboembolism: Venous thromboembolic events occurred in 6% (25/449) of ICLUSIG-treated patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of ICLUSIG-treated patients (29/449). Nine percent of patients (39/449) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (14 patients each; 3%). Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.
Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in a patient within one week of starting ICLUSIG. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.
Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of ICLUSIG-treated patients. Fifty-three patients (12%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during ICLUSIG use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.
Pancreatitis: Pancreatitis occurred in 7% (31/449, 6% serious or grade 3/4) of ICLUSIG-treated patients. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449). The median time to onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with ICLUSIG and evaluate patients for pancreatitis. Do not consider restarting ICLUSIG until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.
Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent ICLUSIG 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
Neuropathy: Peripheral and cranial neuropathy have occurred in ICLUSIG-treated patients. Overall, 20% (90/449) of ICLUSIG-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness (2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of ICLUSIG-treated patients (<1%, 3/449 - grade 3/4). Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting ICLUSIG and evaluate if neuropathy is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of ICLUSIG-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.
Hemorrhage: Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with ICLUSIG. Hemorrhage occurred in 28% (124/449) of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449) each. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.
Fluid Retention: Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with ICLUSIG. One instance of brain edema was fatal. For fluid retention events occurring in >2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, <1%).
In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).
Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.
Cardiac Arrhythmias: Arrhythmias occurred in 19% (86/449) of ICLUSIG-treated patients, of which 7% (33/449) were grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being grade 3 or greater. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of ICLUSIG-treated patients.
Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%). For 27 patients, the event led to hospitalization.
In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt ICLUSIG and evaluate.
Myelosuppression: Myelosuppression was reported as an adverse reaction in 59% (266/449) of ICLUSIG-treated patients and grade 3/4 myelosuppression occurred in 50% (226/449) of patients. The incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML.
Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.
Tumor Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (31/449) of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with ICLUSIG.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Postmarketing cases of reversible posterior leukoencephalopathy syndrome (RPLS—also known as Posterior Reversible Encephalopathy Syndrome (PRES)) have been reported in ICLUSIG-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present and diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. If RPLS is diagnosed, interrupt ICLUSIG treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.
Compromised Wound Healing and Gastrointestinal Perforation: Since ICLUSIG may compromise wound healing, interrupt ICLUSIG for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.
Most Common Adverse Reactions: Overall, the most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-T-1POINT (1-844-817-6468) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Strong CYP3A Inhibitors: Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.
Strong CYP3A Inducers: Avoid concurrent use.
Use in Specific Populations
Females and Males of Reproductive Potential: ICLUSIG can cause fetal harm when administered to pregnant women. Advise females to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. Ponatinib may impair fertility in females and it is not known if these effects are reversible. Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for six days after last dose.
For US Prescribing Information: http://www.iclusig.com/pi
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries.
For more information, visit https://www.takeda.com/newsroom/.
Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.
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