15/05/2015. No conflict of interest for this presentation. The first in-class phosphotidlyinositol3-kinase delta (PI3K delta) inhibitor

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1 Disclosure Idelalisib - A Review No conflict of interest for this presentation Pamela Rudkin PhC Hematology Oncology Pharmacist General Hospital Site Eastern Health Care Corporation Objectives At the completion of this presentation, the participant will be able to: o Explain the mechanism of action of idelalisib oidentify the current approved indications idelalisib o Discuss the clinical trial results for idelalisib odescribe the administration and dosing for idelalisib orecognize the main toxicities of idelalisiband their management Idelalisib Mechanism of Action The first in-class phosphotidlyinositol3-kinase delta (PI3K delta) inhibitor Approved Indications Health Canada approved Notice of Compliance in combination with rituximab for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL). Notice of Compliance with Conditions as a monotherapy for the treatment of patients with follicular lymphoma (FL) who have received at least two prior systemic regimens and are refractory to both rituximab and an alkylating agent. 1

2 Idelalisib Clinical Trial Results Phase 3 trial CLL Phase 2 trial inhl Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia Background: oin patients with CLL and co-existing medical conditions /elderly, effective therapies with acceptable side effect profiles are needed Question: oin patients with relapsed CLL, what is the difference in progression-free survival of rituximab plus idelalisib versus rituximab plus placebo? Design: o Multicentre, randomized, double blind, placebo controlled, Phase 3 Allocation: o not stated Blinding: o Double blinded Setting: o 90 centers in the US and Europe Patients: o Included CLL that had progressed in previous 24 months and were unable to receive cytotoxic agents o N=220 patients, median 71 years; 78% were >65, 65% male, 90% white Intervention: o Rituximab for total of 8 infusions (all patients) plus oral idelalisib 150mg BID or placebo o Stratified based on several genetic mutations associated with inferior outcome Outcomes: o Progression- free survival o Study stopped early due to efficacy Main Results 2

3 Implications Bottom line: othe combination of idelalisiband rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma Background: o In a phase 2 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-hodgkin s lymphomas. Question: o In patients with indolent non-hodgkin s lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies, does the addition of idelalisibincrease progression free survival? Design: o Single group, open-label, phase 2 study Allocation: o All patients in study received the drug and were aware of therapy Blinding: o Not blinded Follow-up Period: o Follow up ongoing Setting: o 41 sites in the US and Europe Patients: o Diagnosis of B-cell inhlwithout evidence of histological transformation who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered o N=125, median age 64 years, 64% male Intervention: o Idelalisib 150mg BID Outcomes: o Overall rate of response (both complete response and partial response) Patient follow-up: o Ongoing Main Results Main Results 3

4 Implications Bottom line: oin a single-group study, idelalisibshowed antitumor activity with an acceptable safety profile in patients with indolent non-hodgkin s lymphoma who had received extensive prior treatment. Idelalisib Administration and Dosing Dosing Considerations Idelalisibis an oral agent that can be taken with or without food. Continue treatment until disease progression or unacceptable toxicity. Recommended Dose Chronic Lymphocytic Leukemia The recommended dose of idelalisibis 150 mg administered orally twice daily in combination with rituximab (8 cycles of rituximab, first cycle at 375 mg/m 2, subsequent cycles at 500 mg/m 2 ). Follicular Lymphoma The recommended dose of idelalisibis 150 mg administered orally twice daily. 20 Monitoring and Laboratory Tests Hepatic Function (ALT,AST, T.B.): q2weeks x 3 months then q 1-3 months and as clinically indicated. Blood counts: CBC at least q 2 weeks x 3 months but at least weekly while neutrophils less than 1.0 x 10 9 /L Drug Interactions Cytochrome P450 (CYP) interactions Idelalisib is a strong CYP3A inhibitor Coadministrationof idelalisibwith CYP3A substrates may increase their systemic exposures Caution is recommended if idelalisibis coadministeredwith narrow therapeutic index CYP3A substrates Overview of AEs Reported in>20% of Patients in Any Idelalisib Group in Phase 2 and 3 Studies Adverse Event Phase 2 Study* Idelalisib only (N=125) n (%) Idelalisib + Rituximab (N=110) n (%) Placebo + Rituximab (N=107) n (%) Any grade Grade 3 Any grade Grade 3 Any grade Grade 3 Any Adverse Event 103 (82) 68 (54) 100 (91) 62 (56) 101 (94) 51 (48) Diarrhea 54 (43) 16 (13) 21 (19) 4 (4) 15 (14) 0 Nausea 37 (30) 2 (2) 26 (24) 0 23 (21) 0 Fatigue 37 (30) 2 (2) 26 (24) 3 (3) 29 (27) 2 (2) Cough 36 (29) 0 16 (15) 0 27 (25) 2 (2) Pyrexia 35 (28) 2 (2) 32 (29) 3 (3) 17 (16) 1 (1) Chills 8 (6) 0 24 (22) 2 (2) 17 (16) 0 Diarrhea/Colitis Severe diarrhea or colitis occurred in 106/760 (14%) patients Fatality: 1/1,192 ( 0.5%) patients o Fatality Narrative: Occurred in an ongoing phase 3 study Diarrhea concurrent with thrush, shingles, and stool positive for clostridium difficile Is severe diarrhea or colitis a class effect of PI3K inhibitors? o Currently unknown. o Grade 3 diarrhea reported with IPI-145 (a dual δ/γ PI3K inhibitor)* * In patients with indolent non-hodgkin lymphoma (Gopal A, et al. NEJM, 2014) +In patients with chronic lymphocytic leukemia (Furman F, et al. NEJM, 2014) Cited publications did not pool diarrhea and colitis adverse events. Data on File, Gilead Sciences, Inc, Foster City, CA 23 4

5 Management Algorithm for Grade 1-2 Uncomplicated Diarrhea Management Obtain patient history and perform physical examination to rule out infection Instruct patient: o To stop all lactose-containing products, alcohol, and high-osmolar supplements o To drink 8 10 large glasses of clear liquids a day (e.g., Gatorade or broth) o To eat frequent small meals (e.g., bananas, rice, applesauce, toast, plain pasta) o To record the number of stools and report symptoms of life-threatening sequelae (e.g., fever or dizziness upon standing) Treatment Administer standard dose of loperamide; initial dose 4 mg followed by 2 mg every 4 hours, or after every unformed stool Management Algorithm for Unresolved Grade 2, and Grades 3-4 Diarrhea Initial Management Perform evaluation and workup to rule out infection Discontinue idelalisib Continue diet instruction IV fluid supplementation or oral hydration as warranted in case of signs of dehydration or grade 3 diarrhea/colitis Infectious Etiology Is Excluded Budesonide * or oral steroids (prednisone) : if patient can tolerate medications PO OR IV steroids: if patient is being treated with IV fluid therapy or cannot tolerate medications PO Patient Can Tolerate Medication PO Switch from IV steroid to budesonide or oral steroids Reassess hours later Diarrhea Resolving Continue instructions for dietary modification Gradually add solid foods to diet Discontinue loperamide after 12-hour diarrhea-free interval Diarrhea Unresolved Follow idelalisib-related diarrhea management recommendation Diarrhea Resolved to Grade 1 Continue instructions for dietary modification Gradually add solid foods to diet Consider taper off budesonide and/or oral steroid Reinstitute idelalisib at lower dose per clinical judgment and consider concomitant use of budesonide IV=intravenous; PO=per os *Recommended dosage: three 3 mg capsules by mouth once daily (9 mg total) 23 Based on panel members experience in clinical trials, prednisolone 1 mg/kg has been used with tapering off once diarrhea returns to Grade 1. Management of Idelalisib Treatment- Emergent Diarrhea (Grades 3-4) in Clinical Trials and Expert Panel Opinion Grade 3 diarrhea/colitis was observed in 106 of 760 (14%) patients 71/106 re-challenged 41/71 (58%) successfully rechallenged Time to resolution by management strategy: Idelalisib interruption alone Time to resolution: approximately 1 month All cases resolved with idelalisib interruption Enteric budesonide use: 23/106 were treated with enteric budesonide Mean time to resolution (in 18 evaluable subjects): 12.1 days (range, 1-35) Systemic corticosteroid use (e.g., prednisone): Prednisolone 1mg/kg/day ±enteric budesonide led to 1-2 weeks time to resolution Characteristics of Hepatic Adverse Events Elevations in ALT and AST (transaminase elevations) greater than 5x ULN observed in 109 of 760* patients (14%) Serious AEs: 109/760 (14%) Fatality: 1/1192 (<0.5%) Fatality Narrative: Received idelalisib + ofatumumab Cause of death was determined to be acute liver failure Concurrent Grade 4 sepsis at the time of death Rechallenged at lower dose with recurrence: 26% Rechallenged at lower dose without recurrence: 74% Onset: occurs early usually within the first 12 weeks 1 Identified with routine monitoring Most ALT/AST elevations are reversible with dose interruption Pneumonitis Observed Across the Idelalisib Clinical Trial Program Pneumonitis observed in 24 of 760 (3%) idelalisib-treated patients across clinical trials * o Serious AEs: 19/760 o Fatalities: 3/760 (<0.5%) Phase 2 CLL study of IDELA+R 1L in elderly patients (Study ): o 2 deaths o Autopsy findings for 1 revealed possible ARDS due to hypersensitivity to IDELA and/or R Phase 2 inhl Study (101-09): o 52-year-old patient with FL, previously exposed to bendamustine + rituximab x17 months prior to idelalisib exposure. o Lung wedge biopsy revealed possible hypersensitivity pneumonitis Adverse Event Phase 2 Study* Idelalisib only (N=125) Idelalisib + Rituximab (N=110) Placebo + Rituximab (N=107) Any grade Grade 3 Any grade Grade 3 Any grade Grade 3 Cough, n (%) 36 (29) 0 16 (15) 0 27 (25) 2 (2) Pneumonitis, n (%) 3 (2) 3 (2) 4 (4) 0 4 (4) 0 * In patients with indolent non-hodgkin lymphoma (Gopal A, et al. NEJM, 2014) +In patients with chronic lymphocytic leukemia (Furman R, et al. NEJM, 2014) Evaluation and Management Recommendations for Idelalisib-Treated Patients Presenting with Pneumonitis Evaluate any patient taking idelalisib who presents with pulmonary symptoms such as: o Cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic examination, or a decline in oxygen saturation by >5% should be evaluated for pneumonitis. o Appropriate and extensive evaluations should be performed for infectious etiologies of pneumonitis, including testing for Pneumocystis jirovecii pneumonia in patients with CLL. Management o If pneumonitis is suspected, idelalisib treatment should be interrupted until the cause is determined. o Idelalisib should be discontinued with any severity of symptomatic pneumonitis. o In clinical trials, some patients have been treated with corticosteroids in addition to continuing antibiotics if their pneumonitis had not improved. 5

6 Dose Modifications Event Grade 1-2 Grade 3 Grade 4 Gastrointestinal Diarrhea/Colitis Hematological For Grade 1, provide antidiarrheal (e.g., loperamide) and maintain idelalisib dose. For Grade 2, withhold idelalisib and monitor at least weekly until resolved to Grade 1 Neutropenia Maintain idelalisib dose Maintain idelalisib dose. Monitor ANC at least weekly. Hepatic ALT/AST Elevation Respiratory Pneumonitis Skin Rash Maintain idelalisib dose. Monitor at least weekly until ALT/AST are <1 x ULN. Withhold idelalisib. Consider addition of antiinflammatory agent (e.g., sulfasalazine, budesonide). Monitor at least weekly until resolved to Grade <1, then may resume idelalisib at 100 mg BID. Interrupt idelalisib. Monitor ANC at least weekly until ANC 0.5 G/L, then may resume idelalisib at 100 mg BID. Withhold idelalisib. Monitor at least weekly until ALT/AST are <1 x ULN, then may resume idelalisib at 100 mg BID. Interrupt idelalisib and evaluate for signs of infection: If non-infectious etiology or association with idelalisib treatment is suspected, discontinue txmt If infectious etiology established, monitor until resolved, then may resume idelalisib at 100 mg BID. For Grade 1, maintain idelalisib dose. For Grade 2, withhold idelalisib until Grade <1. Withhold idelalisib. Monitor at least weekly until resolved to Grade <1, then may resume idelalisib at 100 mg BID. Summary Place in therapy 1. CLL: o Alternative to chemotherapy in relapse elderly CLL patients who no longer can receive chemotherapy o?can it be combined with Ibrutinibanother non chemotherapy agent oral to further down regulate their pathway because BKT and PI3Kdelta do not intersect 2. inhl: More limited data o Indication: Patients with no other treatment options o Need to see results of Phase 3 clinical trials of idelalisib in combination with either rituximab or bendamustine/rituximab Note: More interventions by oncology pharmacists due to long term oral therapy Questions? 6