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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

September 24, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf

On Sept. 24, 2018, the Food and Drug Administration granted regular approval to duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.

In addition, duvelisib received accelerated approval for adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies.

The CLL and SLL indication is based on a randomized, multicenter, open-label trial (NCT02004522) comparing duvelisib to ofatumumab in patients with relapsed or refractory CLL or SLL. The trial randomized patients (1:1) to either duvelisib 25 mg orally twice daily or ofatumumab. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.

Among 196 patients receiving at least 2 prior therapies (95 randomized to duvelisib, 101 to ofatumumab), the estimated median progression-free survival, as assessed by an independent review committee (IRC), was 16.4 months in the duvelisib arm and 9.1 months in the ofatumumab arm (hazard ratio of 0.40; standard error 0.2). The overall response rate (ORR) per IRC was 78% and 39% for the duvelisib and ofatumumab arms, respectively (39% difference, standard error 6.5%).

The FL indication is based on a single-arm multicenter trial of duvelisib (NCT02204982) enrolling 83 patients with FL who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. The ORR, determined by an IRC, was 42% (95% CI: 31, 54), with 41% of patients experiencing partial responses and one patient having a complete response. Of the 35 responding patients,15 (43%) maintained responses for at least 6 months and 6 (17%) maintained responses for at least 12 months. Continued approval for the FL indication may be contingent upon verification of clinical benefit demonstrated in a planned randomized trial.

The prescribing information contains boxed warnings for fatal and/or serious infections, diarrhea or colitis, cutaneous reactions, and pneumonitis and warnings for neutropenia and hepatotoxicity. Of 442 patients with hematologic malignancies treated with duvelisib at the approved dose, 65% had serious adverse reactions, with the most frequent being infection, diarrhea or colitis, and pneumonia. The most common adverse reactions (incidence ≥ 20%) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. Adverse reactions resulted in permanent discontinuation of duvelisib in 35% of patients., Dose reduction occurred in 24%.

The recommended duvelisib dose is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

View full prescribing Information for Copiktra.

FDA granted this application priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Duvelisib for the Treatment of Adult Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma After at Least Two Prior Therapies

Author: Caitlin Siebenaller, PharmD BCOP
Oncology Pharmacy Clinical Specialist
Cleveland Clinic
Cleveland, OH

What is the potential role for duvelisib in the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)?1-4

  • On September 24, 2018, the U.S. Food and Drug Administration (FDA) granted duvelisib, an oral dual inhibitor of phosphoinositide 3-kinase (PI3K) that inhibits both PI3K-δ and PI3K-γ, regular approval for adult patients with relapsed or refractory (RR) CLL or SLL after disease progression on at least two prior therapies.
  • This approval was based on the results of the DUO study, a phase 3 randomized open-label trial where duvelisib was compared to ofatumumab monotherapy for patients with RR CLL or SLL. Patients were randomized 1:1 to duvelisib 25 mg twice daily (n = 160) or ofatumumab (n = 159) standard dosing.
    • In an updated analysis the primary endpoint, median progression-free survival (PFS), was significantly longer in the duvelisib arm compared to ofatumumab (13.3 months vs. 9.9 months, hazard ratio [HR] = 0.52, 95% confidence interval [CI] 0.39–0.70, p < .0001) by independent review. This included patients with high-risk chromosome abnormalities (del17p) or mutations (TP53).
    • The overall response rate (ORR) was 74% with duvelisib versus 45% (HR = 0.52; p < .0001) with ofatumumab regardless of del17p status.
  • Another oral PI3K inhibitor, idelalisib, was previously studied in the relapsed CLL population and demonstrated increased PFS when used in combination with rituximab compared to rituximab monotherapy (not reached vs. 5.5 months, HR 0.15, 95% CI 0.08–0.28, p < .001). Idelalisib is currently approved by the FDA for relapsed CLL in combination with rituximab and also for relapsed SLL after at least two prior therapies.
    • Of note, idelalisib differs mechanistically from duvelisib in inhibiting only the PI3K-δ.
    • Incidence of common adverse events occurs at similar rates for idelalisib and duvelisib.
  • Other approved therapies in the RR CLL or SLL population include ibrutinib, an oral bruton tyrosine kinase inhibitor, which demonstrated increased ORR, PFS, and overall survival (OS) compared to ofatumumab in patients who received at least one prior therapy. Venetoclax, an oral inhibitor of protein B-cell lymphoma 2 (BCL-2), plus rituximab demonstrated increased ORR and PFS in RR CLL/SLL patients when compared to bendamustine plus rituximab.
  • The National Comprehensive Cancer Network (NCCN) currently lists ibrutinib or venetoclax plus rituximab as preferred regimens with category-1 recommendations for treating RR CLL/SLL regardless of del17p or TP53 status. Duvelisib and idelalisib plus rituximab are listed as preferred regimens with category-2A recommendations, with idelalisib plus rituximab specified for treating those patients for whom rituximab monotherapy would be considered given significant comorbidities.

What role can the pharmacist play in the management of patients on duvelisib?1,2,4,5

  • The approved dosing of duvelisib is 25 mg twice daily administered orally with or without food. It is supplied as 15-mg and 25-mg capsules.
  • Because duvelisib is metabolized primarily by CYP3A4, a dose reduction to 15 mg twice daily is recommended when it is given concomitantly with strong CYP3A4 inhibitors. There is no dose-adjustment recommendation for concomitant use of strong CYP3A4 inducers, and it is recommended that the combination be avoided.
  • There are no dosing adjustments in the labeling for renal impairment or hepatic impairment prior to treatment initiation. However, the labeling provides recommendations for withholding therapy when hepatotoxicity occurs during treatment:
    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation of 3 to 5 times the upper limit of normal (ULN): Continue therapy and monitor liver function weekly until resolution to less than 3 times ULN.
    • AST/ALT elevation greater than 5 to 20 times ULN: Withhold therapy, monitor weekly, and resume therapy upon resolution to less than 3 times ULN.
    • AST/ALT elevation greater than 20 times ULN: Discontinue therapy.
  • It is important to note that Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be provided during treatment and after completion of therapy until the absolute CD4+ count is greater than 200 cells/microliter. The labeling also suggests considering prophylaxis against cytomegalovirus (CMV) infection or reactivation.
  • Important monitoring parameters include complete blood count (CBC) every 2 weeks for the first 2 months (weekly in patients with grade 3 or 4 neutropenia), AST and ALT, signs and symptoms of infection including CMV and PJP, pulmonary symptoms, and interstitial infiltrates.
    • If CMV develops, duvelisib should be withheld until the CMV infection or viremia is resolved. A CMV polymerase chain reaction (PCR) or antigen test should be monitored monthly for reactivation when therapy is resumed.
  • Duvelisib contains boxed warnings for dermatologic toxicities, severe diarrhea or colitis, serious infections, and serious pneumonitis. Thirty-five percent of patients in the DUO study discontinued duvelisib because of adverse effects.
  • Common nonhematologic adverse effects (occurring in more than 20% of patients) include renal insufficiency (58%), sepsis (58%), colitis (57%), increased ALT (40%–42%), increased lipase (37%), hypophosphatemia (31%), infection (31%), increased amylase (28%–31%), rash (27%–31%), hyponatremia (27–31%), hypoalbuminemia (25%–31%), fever (26%–29%), fatigue (25%–29%), upper respiratory tract infection (21%–28%), pneumonia (21%–27%), hypocalcemia (23%–25%), nausea (24%), hypokalemia (10%–20%), and abnormal alkaline phosphatase, both increased (27%–29%) and decreased (34%).
  • Severe (grade 3–4) hematologic adverse effects include neutropenia (30%–49%, grade 3; 18%–32%, grade 4), lymphocytosis (21%–22%, grade 3), anemia (11%–20%, grade 3), thrombocytopenia (10%–16%, grade 3; 6%–7%, grade 4), lymphocytopenia (3%–9%. grade 3 or 4), and leukopenia (2%–8%, grade 3 or 4).

Clinical Pearls5,6

  • Duvelisib can be administered orally with or without food. It should be swallowed whole, and the capsules should not be opened. The 25-mg- and 15-mg-strength capsules are dispensed in two 28-count blister packs or a 56-count bottle. Blister packs should be stored in the original container. Capsules in bottles should remain in the original container until they are dispensed.
  • Patient assistance for duvelisib is available through the Verastem Cares program. There is a patient assistance program for those with specific income requirements and a co-pay assistance program with no income requirement. Information can be found at http://www.verastem.com/wp-content/uploads/2018/08/verastem-cares-form.pdf

References

  1. U.S. Food and Drug Administration. Duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm. Accessed October 28, 2018.
  2. Duvelisib (Copiktra) [package insert]. Needham, MA: Verastem Oncology; September 2018.
  3. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018; Epub ahead of print Oct 4.
  4. National Comprehensive Cancer Network. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed October 28, 2018.
  5. Duvelisib monograph. LexiComp, Lexi-Drugs [online database]. Wolters Kluwer Health Inc. Updated October 31, 2018. Accessed November 7, 2018.
  6. Verastem Oncology. Verastem Cares program for duvelisib. Available at http://www.verastem.com/wp-content/uploads/2018/08/verastem-cares-form.pdf. Accessed October 31, 2018.
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